Artemisinin
Protocol:
Summary:
Artesunate and Artemether are more efficient than Artesiminin;
Tea and extracts (?) from the plants is almost ineffective due to the presence of 3CA (iron chelator).
Artesunate is water soluble (better for the liver?), while Artemisinin and Artemether are fat soluble.
All should be taken 2..4 hours away from food.
Absorption is reduced after 4..5 days of oral use. However, it has been applied by injection (the best way), rectally and topically (creams).
Artemisinin (Artemether ?) should be used at ~10mg/ml olive (fish, flax, coconut, .. (?)) oil
Note: should one rotate Artesunate (water soluble) and Artemeter (fat soluble) in order to increase absorption?
or rotate 4..5 days of each - oral/rectal application?
how about DMSO + Artesunate for topical use?
how about liposomal Artemeter and Artemisinin?
Pulsed application should also be better than continuous because in 1 article a resistance to artemisinin was reduced
by increasing the artemisinin levels. Therefore 2 days of 400mg/day should be better than 7 days of 100mg/day.
During the off period one can also use other supplements that might interract with artemisinin. For example
milk thistle, curcumin ...
For brain tumor low dose of Artemether (0.5mg/kg) used in 1 case.
Typical dose of Artemether is 1mg/kg with minimum of 0.5mg/kg and maximum of 2mg/kg.
Artemisinin dose typically used is between 100mg and 600mg, but some report as high as 1000mg. It is important to take it as 1 dose to avoid accumulation that can lead to increased toxicity. Accumulation also increases the half life, so detox slows down. Oil soluble forms are more toxic than artesunate (water soluble).
It seems that Artesunate can be used in the same doses as Artemisinin, but it is probably more effective.
Allergic reactions are rare. Typical symptoms are (link) - hives, rashes, itching, nasal congestion ... pain, anxiety, diarrhea ...
Liver toxicity is rare but has been reported at doses as low as 100mg.
Should start with low doses and run regular blood tests (albumin, ammonia, AFP, Bilirubin, INR, Liver enzymes, Transferrin).
Basic symptoms of liver toxicity:
- (link) - yellowish staining of skin and the white of the eyes; yellowish stool (feces); itchy skin, dark urine, joint pain
bloody or black stools, chronic fatigue, nausea, loss of appetite
Potential neuro-toxicity (link, see below).
Should be taken with:
- Sodium butyrate (~8mg/kg = ~500 .. 600 mg); +coconut oil + probiotic named Clostridium butyricum (link)
Considering that the daily limit of sodium (Na) is 2000 [mg].
Table salt (NaCl) has about 39 % Na (atomic weights: Na = 11, Cl = 17)
Sodium Butyrate (C4H7O2Na) (atomic weights: Na = 11, C = 6, H = 1, O = 8 => Na = 11/(11+4*6+7*1+2*8) = 19%)
Therefore the maximum daily quantity of sodium butyrate as a salt substitute would be about 2x the salt level = ~10g.
- Probiotics (increases the butyric acid in the intestines); both vegan and ketogenic diet increase the level of butyric acid
for the ketogenic diet levels of up to 20x increase have been reported.
- Resveratrol (not an iron chelator - link) but it can increase the liver toxicity risk (link).
- sodium salicylate (link)
- allicin (garlic extract), thiosulfinates ? (link); (arteeter + garlic oil for malaria (link))
- triptolid (?)
- for parasite cleaning it is combined with black walnut and cloves (link)
- Vitamins used in 1 case were 500mg Vit.C (increases iron absorption from food)
and 200IU Vit.E (protection from iron toxicity?link?).
The vitamins were taken in the morning and the artemether in the evening.
Iron supplementation may be used to keep iron levels at normal-high levels.
link - 250ug/dl, where for dogs the normal range is 46..240ug/dl (link).
(?) Feverfew (parthenolide), sulforaphane, Sulfasalazine (Asulfadine),
Hydroxychloroquine (Plaquenil), Chloroquine (Avelan), Mefloquin (Lariam)
Cannabis extracts, Gleditsia sinensis (Korean thorn), Ivermectin, ALA (link)
- chemotherapy drugs: Rituximab
- thymoquinone (black seed oil) (link)
- betulinic acid (birch bark) (link)
- nicotinamide (?) (link) (note: Nicotinamide is a PARP inhibitor)
- increase of ferroportin (?) (link, link2)
use iron supplements; avoid iron chelators! (link, link2) - not taken at the same time to avoid interaction in the stomach
- itraconazole (may also synergize with the ketogenic diet (mTOR)?) (link (CUSP9), link2)
- Aminolevulinic Acid (5-ALA) (link; not related to cancer: link, link, link)
According to (link):
- Vit C must be taken at different time! This is because it can increase the interaction of artemisinin with iron in the
food. Vit E (Trolox) was shown to decrease the effectiveness of Artemisinin (anti-angiogenesis (link - Vit E and
manitol)). Vit D3 and Dexamethasone showed no interactions. H2O2 showed strong additive effect.
Conclusions:
IV Vit C (+ lyposomal + sodium ascorbate) + artemisinin should be synergistic by both Vit. C alone
and also because of H2O2 created.
Vit E should be avoided.
- tagged to (holo)transferrin (?) to increase 1000 times the selectivity to cancer cells (link, link2, link3, link4, link5, link6)
link6: "were fabricated by simply combining ART, DHA or ATS with Tf",
Ph of 5.5 reduced the effectiveness.
diet + exercise + sodium bicarbonate(?) + (?) ... to maintain high Ph (should be monitored with blood/urine tests)
(low calorie) ketogenic diet does not lower Ph (link, link2)
- hyperbaric oxygen (HBOT) (link), metformin increases oxygen release into cells (link)
- anti fungal (?) (B3 (?), caprilic acid, olive leaf extract, oregano oil...)
- lactoferin (?) - must not be taken at the same time as artemisinin (?) (link)
- for liver toxicity
- artichokes, beets;
- milk thistle, curcumin - only on off days(?) + iron rich foods + vit C(?)
Should not be taken with:
- iron chelators (link), Vit. E
- NAC and anti-oxidants (link)
- glutathione (?)
- ferrostatin-1 (ferroptosis inhibitor)
- deferoxamine (iron chelator),
- Deferasirox (?), Exjade, Janedu, Deferiprone or L1 (Ferriprox) (?)
- Quercetin, Curcumin, EGCG, Phytic acid (IP6), Genistein, Pycnogenol, Baicalein,
Tetramethylpyrazine, ferulic acid, Grape seed extract, grape, wine, fruits, nuts, green/black tea, soy (?) (link) (table)
1/2 life of flavonoids = ~11h .. 28h
should not take these supplement / eat these foods on the days when artemisinin is taken (?)
should compensate with lactoferrin and iron rich foods / iron supplements (?) + vit. C (?)
- PEMF (?) (link)
- Antioxidant detoxification systems such as the glutathione redox cycle, thioredoxin redox cycle,
detoxifying enzymes such as catalase, superoxide dismutase etc., and the Nrf2 pathway all contribute
to counteract oxidative stress posed by artemisinins. These data fit well to the concept of ferroptosis,
where ferric ions induce oxidative stress and cell death. (link)
Not (less?) effective for:
- hepatocellular carcinoma occuring in a background of hemochromatosis, where tumors are depleted in iron
compared to non-tumor tissue. (link)
Mechanisms for action:
- kill tumor cells by induction of apoptosis, autophagy or necroptosis ... ferroptosis. ...
The mixture of different modes of cell death makes this class of compounds to attractive candidates
for cancer therapy. (link)
- anti angiogenesis (?)
Testimonials:
link : "My wife suffered from colon cancer stage 4, that metastisized into the liver, causing her to have two major cancer surgeries in 16 months. After a year of healthy eating, IR light treatments, and daily artemisinin, she is cancer free over a year later."
link : "1. The Sodium Butyrate has strong anti-cancer properties. The Sodium Butyrate is the sodium salt of butyric acid, which is a short-chain fatty acid. It's a natural byproduct of the fermentation of dietary fibers in your large intestine. It is anti-carcinogenic. The Sodium Butyrate increases the anti-carcinogenic effect of Artemizinin 10 times, according to laboratory tests. Should always be given at the same time with Artemizinin.
2. I gave the Sodium Butyrate together with the Artemizinin to my father in his fight with bladder cancer. After only 12 days of "Sodium Butyrate & Artemizinin" therapy, many dead tumors begun to be expelled with his urine. It was extremely effective.
3. The Artemizinin dose was 400 mg (4 pills) 4 times daily (daily total = 1600 mg), and the Sodium Butyrate dose was 2400 mg (4 pills) 4 times daily (daily total = 9600 mg). Also the Artemizinin has to be given together with some fat, because it is not soluble in water. He used 2 t.s. flax oil to dissolve the Artemizinin capsule content, then drank the mixture. The therapy time was 14 days non-stop, then 3 days off (break), then repeated for several months for total tumor destruction."
References: [Ref.1.32, 1.33, 1.34, 1.94]
Additional References:
Overview articles:
Artemisinins: Pharmacological actions beyond anti-malarial
www.futsci.com/uploads/project/file/b1d85dcff45436a0b9fb48995c6bdc6b12f49677.pdf
Artemisinin our Ultimate Cancer Weapon a Gift from China
jeffreydachmd.com/2016/02/artemisinin-our-ultimate-cancer-weapon-a-gift-from-china/
A discussion on a case of liver toxicity (100mg artemisinin):
http://scienceblogs.com/terrasig/2009/08/17/is-artemisinin-really-behind-t/
Potential neuro toxicity at high doses and prolonged exposures:
cdn.intechopen.com/pdfs-wm/35690.pdf,
www.sciencedirect.com/science/article/pii/S0006295200005566,
www.fda.gov/ohrms/dockets/ac/02/slides/3875S1_04__FDA-JohannLiang/sld022.htm,
www.ncbi.nlm.nih.gov/pubmed/16828992,
http://www.ncbi.nlm.nih.gov/pubmed/9063352,
(high doses, prolonged exposure - equivalent to about 300mg/day for 5..6 days intramuscular arteeter)
www.ncbi.nlm.nih.gov/pubmed/11037787,
These data indicate that once-daily oral administration of artesunate or artemether is relatively safe, ..., whereas constant exposure either from depot intramuscular injection of oil-based drug, or constant oral intake carries relatively greater neurotoxic potential.
(doses are equivalent to ~2000mg/day oral or 300mg/day injection to have neurotoxic effect or death in 50% of the animals)
aac.asm.org/content/46/3/821.full,
High dose of artemether on children:
http://www.ncbi.nlm.nih.gov/pubmed/10776745
"artemether 6 mg/kg (n=138) orally six times once every 3 weeks"
Note: this results in about 6x6/21 = ~1.7mg/kg, but other factors may have affected the absorption.
Recommendations from other sources is not to exceed 1mg/kg, although some mention 2mg/kg.
Article below for pituitary (brain) tumor used 40mg/day = 0.5mg/kg
The dose mentioned for the Artesunate (+ butyrate) was 100mg.
High dose of artemether in rats:
http://www.ncbi.nlm.nih.gov/pubmed/12135264
"80 mg/kg artemether administered once every 2 weeks is safe, and doses of 400 mg/kg do not result in evidence of neurotoxicology"
Note: this results in (80/14)/6 (for rats) = 0.95mg/kg - safe; 5mg/kg = no neurotoxicology
Artemisinin and Artesunate half-life: link
Artermisinin (250mg):
peak after 100min
peak level: 0.36 ug/ml
t1/2 (appearance half life): 0.62[h]
t1/2 (distribution half life): 2.61[h]
t1/2 (decline half life): 4.34[h]
total are under concentration curve (AUC): 1.19 [ug*h/ml]
Artesunate (250mg):
Ka (appearance rate constant): 2.11 [h-1] => t1/2 = ln(2)/Ka = 0.69/K => t1/2 = 0.32[h]
Ke (elimination rate constant): 1.18 [h-1] => t1/2 = 0.69/K => t1/2 = 0.58[h]
t1/2 (bio transformation half life): 0.33[h]
t1/2 (elimination half life): 0.65[h]
AUC : 0.74 [ug*h/ml]
Artesunate (link, link2):
t1/2 (half life) = 2.7 [h]
peak level after: 15 .. 40 min (oral), 35..86 min (rectal)
t1/2 (elimination half-life): 29[min] = ~0.5[h]
Artemether (link, link2):
t1/2 (half life) = 2 .. 3[h]; 1.6 (+/-0.7); 2.2 (+/-1.9)
Artemisinin-Resistant Mutants of Toxoplasma gondii Have Altered Calcium Homeostasis
www.ncbi.nlm.nih.gov/pmc/articles/PMC2151471/,
(for parasites)... artemisone > artesunate ≈ artemether > dihdyroartemisinin > artemisinin ... artemisone was more than 10-fold more active than artesunate ... and almost 30-fold potent than artemisinin.
Mechanistic Investigation of the Specific Anticancer Property of Artemisinin and Its Combination with Aminolevulinic Acid for Enhanced Anticolorectal Cancer Activity
Artesunate overcomes drug resistance in multiple myeloma by inducing mitochondrial stress and non-caspase apoptosis
Artemisinin derivatives induce iron-dependent cell death (ferroptosis) in tumor cells.
Combination of Artesunate and drugs for brain cancer: CUSP9 (link, link2)
Development of Resistance towards Artesunate in MDA-MB-231 Human Breast Cancer Cells
Note: resistance has been shown to reduce with increase of ferritin; artemisinin should not be used as a mono therapy.
Artemisinin and Nitric Oxide: Mechanisms and Implications in Disease and Health (p.32 .. p.34)
Dose dependent - 50uM had no effect while 100 and 150uM had very strong anti cancer effects.
Synergetic with chemotherapy (5-FU).
Progress on anti-tumor molecular mechanisms of dihydroartemisinin
Liver Cancer
- In vivo study of effects of artesunate nanoliposomes on human hepatocellular carcinoma xenografts in nude mice.
- Effect of oral coadministration of artesunate with ferrous sulfate on rat liver mitochondrial membrane permeability transition.
- Therapeutic effects of artesunate in hepatocellular carcinoma: repurposing an ancient antimalarial agent.
Artesunate inhibits growth and induces apoptosis in human osteosarcoma HOS cell line in vitro and in vivo
Artesunate Activates Mitochondrial Apoptosis in Breast Cancer Cells via Iron-catalyzed Lysosomal Reactive Oxygen Species Production
Artesunate Induces Apoptosis of Bladder Cancer Cells by miR-16 Regulation of COX-2 Expression
An Evaluation of the Anticancer Effects of Triptolide in Pancreatic Cancer
Comparative Cytotoxicity of Artemisinin and Cisplatin and Their Interactions with Chlorogenic Acids in MCF7 Breast Cancer Cells
Whole plant extracts versus single compounds for the treatment of malaria: synergy and positive interactions
http://doctorsaputo.com/a/artemisinin-a-cancer-smart-bomb
http://www.doctorsaputo.com/a/artemisinin-part-2-how-to-use-it
http://doctorsaputo.com/a/the-importance-of-iron-in-infections-and-cancer
https://www.google.ca/?tbm=pts&gws_rd=cr,ssl&ei=pzm4VayAJMXw-QG2uoXIDA#tbm=pts&q=artemisinin+cancer
https://www.google.ca/patents/CA2515761C?cl=en&dq=artemisinin&hl=en&sa=X&sqi=2&pjf=1&ved=0CBwQ6AEwAGoVChMIlOO376T_xgIVw3g-Ch348wbK
"cervical cancer cells, but not normal cervical cells, are efficiently killed by artemisinin."
https://www.google.ca/patents/US8394849?dq=artemisinin&hl=en&sa=X&sqi=2&pjf=1&ved=0CDgQ6AEwBGoVChMIlOO376T_xgIVw3g-Ch348wbK
https://www.google.ca/patents/US20100279976?dq=artemisinin+cancer&hl=en&sa=X&sqi=2&pjf=1&ved=0CEEQ6AEwBWoVChMIufOLyaX_xgIVSG4-Ch3SFwZ5
https://www.google.ca/patents/EP1594491B1?cl=en&dq=artemisinin+cancer&hl=en&sa=X&sqi=2&pjf=1&ved=0CFYQ6AEwCGoVChMIufOLyaX_xgIVSG4-Ch3SFwZ5
"Artemisinin is a relatively safe drug and produces few side-effects, even at high doses. Oral doses of 70 mg/kg/day for 6 days have been used in humans for malaria treatment. Furthermore, more potent analogs of this and similar compounds are also available. Higher efficacy of artemisinin action can be achieved by other means. For example, artemisinin is more reactive with heme than with free iron (Hong et al., 1974, Mol. Biochem. Parasit., 63:121-128). Iron can be introduced into target cells using transferrin (see, e.g., Stout et al., 1992, Biochim. Biophy. Res. Comm., 189:765-770) or the heme-carrying compound hemoplexin (see, e.g., Smith et al., 1988, Biochem. J., 256:941-950; Smith et al., 1990, Europ. J. Cell Biol., 53:234-245). The concentrations of agents for enhancing intracellular iron concentrations in the practice of the present invention will generally range up to the maximally tolerated dose for a particular subject and agent, which will vary depending on the agent, subject, disease condition and other factors. Dosages ranging from about 1 to about 100 mg of iron per kilogram of subject body weight per day will generally be useful for this purpose.
The dose of artemisinin or artemisinin derivative compounds administered to an individual in need of treatment will vary and will be determined for each individual with reference to, for example, the compound used, the route of administration, and the physical condition and body size of the individual. To illustrate, about 0.1 to about 100 mg per kilogram of body weight per day can be administered. In further embodiments, from about 1 to about 90 mg per kilogram of body weight per day is administered. Alternatively, from about 1 to about 75 mg per kilogram of body weight per day can be administered. The daily dosage may be administered as a single dosage or may be divided into multiple doses."
http://www.cam-cancer.org/CAM-Summaries/Herbal-products/Artemisia-annua/(merge)
https://pathwithpaws.com/blog/2011/03/26/artemisinin-when-cancer-cells-kill-themselves/
forum: http://www.topicalinfo.org/forum/topic.asp?TOPIC_ID=1657
attempt to use DMSO + Artemisinin.
comment for skin cancer: "when I don't sleep very much at night, the next day the area looks worse"
?effect from melatonin?
Case Report of a Pituitary Macroadenoma Treated With Artemether
http://thedcasite.com/Library/Artemisinin/Case_Report_of_a_Pituitary_Macroadenoma_Treated_With_Artemether.pdf
http://www.researchgate.net/profile/Narendra_Singh16
"A 75 year-old male patient presented with vision, hearing, and locomotion-related problems. Artemether was administered orally to the patient over a period of 12 months. Results: Although the tumor remained consistent in size, CT scan shows a reduction in its density, and clinically, the related symptoms and signs resolved significantly as therapy progressed. Discussion: Overall, the artemether treatment was beneficial in improving the patient's quality of life. Artemether and other artemisinin analogs offer promise for cancer therapy.
...
The patient was treated with 40 mg (approximately 0.5 mg/kg) of artemether orally daily for 29 days starting on April 16, 2004. This medication was given with milk 3 to 4 hours after dinner. Two hundred units of vitamin E (D alpha tocopherol) and 500 mg of vitamin C were given to the patient at breakfast. After 15 days of treatment, his left eyeball started moving slightly and there was a slight improvement in vision, and this treatment was continued for 2 more weeks. Artemether therapy was then reduced and given only every other day for a duration of 30 more days. Vitamin E and C were given every day. Artemether therapy was reduced further and given twice a week for approximately 10 more months. Vitamin E and C were given every day for the entire period.
...
Results
A CT scan performed on August 9, 2004 (approximately 4 months after the initial diagnosis and start of treatment), showed an increase in adenoma size to 3.0 × 2.4 cm. Although there was a slight increase in size of mass, the patient’s visual and other symptoms and signs had improved significantly. Another CT scan was performed on January 25, 2005 (approximately 9 months after the initial diagnosis and start of treatment). The tumor remained consistent in size measuring 3.33 × 2.25 cm. Additionally, the patient reported marked improvement in visual problems. The patient’s gait had returned to normal, and his hearing had improved significantly. Also, reduced doses of oral hypoglycemics were needed for control of diabetes. The patient was more alert and active than before. A CT scan on November 15, 2005, showed no significant change in tumor size (2.6 × 2.4 cm) compared to previous CT scans. However, this scan of November 2005 did show the density of the tumor (ranging from 51 to 59 HU) significantly decreased since the first scan (72-77 HU) in April 2004. Additionally, the November 2005 scan showed the tumor had become more heterogeneous. The patient also reported a nearly complete symptomatic recovery.
Discussion
We have previously reported that dihydroartemisinin selectively killed Molt-4 lymphoblastoid cells (a human leukemia cell line) after incubation with holotransferrin,9 whereas the same treatment had significantly less effect on normal human lymphocytes. A similar effect was observed in human breast cancer cells.10 Furthermore, we found that oral administration of an artemisinin analog and ferrous sulfate retarded the growth of implanted fibrosarcoma tumors in rats.16 Another study has also shown that artesunate can effectively retard the growth of various types of human cancer cells in vitro.17 We have also previously reported a case of a laryngeal cancer patient who responded well to artesunate (an analog of artemisinin) therapy.18 A recent report has shown that artesunate was effective in the long-term treatment of metastatic uveal melanoma in conjunction with conventional chemotherapy.19
This is the first report on the use of artemether as treatment for a pituitary tumor. Artemether (an analog of artemisinin) was chosen for the treatment because it easily crosses the blood-brain barrier, and similar to dihydroartemisinin,20 it kills cancer cells by apoptosis (data not shown), a preferable mode of cell death in cancer treatment. Also, it has a longer halflife compared with the more water-soluble artesunate, used previously.18
...
In this case, a combination of surgery and radiotherapy (the most common treatment option for such tumors) was offered to the patient, but he refused. Although these treatment options are often successful, the incidence of surgical complications24 and side effects from radiotherapy25 were of concern to this patient. Interestingly, though the patient reported relief of symptoms, artemether treatment did not significantly reduce the size of the tumor. Although the tumor measured approximately the same during the course of the treatment, there was a significant reduction in the density (72-77 HU in the first scan vs 51-59 HU in the last scan) and the tumor, which was initially homogenous, appeared heterogeneous in the later scan. We speculate that the remainder of the mass may consist mostly of dead cells after the treatment. We also hypothesize that it takes a longer time, particularly in older patients, for microglia and macrophage cells to scavenge dead cells from solid pituitary tumors. This change in composition, in addition to the reduction in the density of the tumor, may account for the resolution of the patient’s symptoms. Because the possibility of optic and sixth nerve compression exists, the decreased density may have eased the pressure on these structures. The patient is currently doing well and reports normal visual functioning without any complaint of hearing or gait and has stopped artemether but continues vitamins in the dosage mentioned above. It is likely that gait problems were vision related and longstanding hearing loss may have been due to existing diabetes."
Additive Cytotoxic Effects of Dihydroartemisinin and Sodium Salicylate on Cancer Cells
"at low concentrations, the combination of DHA and SS (sodium salt of aspirin) significantly reduced cancer cell proliferation, although no synergistic interaction between the two drugs was found. Even without a clear synergistic interaction, the combination of DHA and SS provides a safe and affordable form of cancer treatment."
Anticancer Effect of AntiMalarial Artemisinin Compounds.
"Experimental evidences suggest that artemisinin compounds may be a therapeutic alternative in highly aggressive cancers with rapid dissemination, without developing drug resistance. They also exhibit synergism with other anticancer drugs with no increased toxicity toward normal cells. It has been found that semisynthetic artemisinin derivatives have much higher antitumor activity than their monomeric counterparts via mechanisms like apoptosis, arrest of cell cycle at G0/G1, and oxidative stress. The exact mechanism of activation and molecular basis of these anticancer effects are not fully elucidated. Artemisinins seem to regulate key factors such as nuclear factor-kappa B, survivin, NOXA, hypoxia-inducible factor-1α, and BMI-1, involving multiple pathways that may affect drug response, drug interactions, drug resistance, and associated parameters upon normal cells. Newer synthetic artemisinins have been developed showing substantial antineoplastic activity, but there is still limited information regarding the mode of action of these synthetic compounds.
...
In a study, testing 55 cell lines showed that artesunate showed inhibitory effects against leukemia, colon, melanoma, breast, ovarian, prostate, central nervous system, and renal cancer cells.[39] The semisynthetic derivative DHA showed remarkable antineoplastic activity against pancreatic, leukemic, osteosarcoma, and lung cancer cells.[40] Moreover, artemisone was superior to artemisinin and showed better synergism with other anti-cancer agents.[41]
Artemisinin has also been found to act either directly by causing DNA damage or indirectly by interfering with several signaling pathways involved in carcinogenesis. The indirect DNA damage seems to be commoner than direct damage. In pancreatic cells, artesunate caused DNA fragmentation and membrane damage. Low doses of artesunate were associated with oncosis-like cell death, whereas higher concentrations caused apoptosis. But, extent and type of such damage can depend on the phenotype and the origin of cell line, varying in time- and dose-dependent manner. Notably, higher sensitivity to artesunate was observed in rapidly growing cell lines compared to slow growing cancer cells.[40]"
Effects of antioxidants and pro-oxidants on cytotoxicity of dihydroartemisinin to Molt-4 human leukemia cells.
"Vitamin C and vitamin D3 significantly interacted with DHA at the 48-h time point and with H2O2 at both 24-h and 48-h time points."
link to the full article
Hypoxia modulates the effect of dihydroartemisinin on endothelial cells.
"Low doses of DHA (achieved in the patients' plasma when treating malaria) were more inhibitory in hypoxia, whereas high doses (required for anti-angiogenic or anti-tumor activity) were more effective in normoxia. The peroxide bridge is essential for cellular toxicity (deoxyDHA was inactive). High doses of DHA caused HMEC-1 apoptosis and G2 cell cycle arrest. Effects were mediated by the generation of oxidative stress as demonstrated by DCF-DA fluorescence and membrane lipid peroxidation analysis. Overall, these results suggest that DHA inhibition of endothelial cell growth is related to the level of tissue oxygenation and drug concentration. This should be considered when studying both the effects of artemisinin derivatives as antimalarials and the potential therapeutic applications of these drugs as anti-tumor agents."
Note: should one combine artemisinin with hyperbaric oxygen therapy?
Effects of hyperbaric oxygen on S-180 sarcoma in mice.
"Apparently HBO can check the growth rate of sarcoma and accelerate the necrosis of S-180 sarcoma cells."
Artesunate inhibits the growth and induces apoptosis of human gastric cancer cells by downregulating COX-2.
Synergistic Cytotoxicity of Artemisinin and Sodium Butyrate on Human Cancer Cells
"The combination of 20 uM DHA and 1 mM sodium butyrate killed all Molt-4 cells at the 24-hour time-point and did not significantly affect lymphocytes. Conclusion: DHA in combination with butyric acid acts synergistically at low doses. The combination may provide a less toxic, inexpensive and effective cancer chemotherapy.
...
DMSO is an antioxidant and probably decreases the effectiveness of DHA
...
Several studies on different cancer cell types have shown butyrate exerting its cytotoxic effects via apoptosis (25, 26, 30-33), although the mechanism by which butyric acid induces apoptosis is not well understood
...
Two major mechanisms may possibly overlap to enhance the apoptotic effect of the two agents: i) butyric acid causes chromatin decondensation allowing free radicals formed by artemisinin to trigger apoptotic pathways, and ii) butyric acid redistributes intracellular iron in such a way that it is more readily available for interaction with artemisinin to generate free radicals. Several studies, exploring the role of iron in differentiation (39-41), have indicated that butyric acid is involved in intracellular iron redistribution. Our results, showing a synergistic effect of artemisinin and butyric acid in killing Molt-4 cells, may be due to these mechanisms.
...
the combination of low concentrations of sodium butyrate (1 mM) and DHA (20 ÌM) kills all leukemia cells in culture within 24 hours, suggesting that the combination of short chain fatty acids and artemisinin or its analogs may be an effective treatment for cancers.
...
The oral intake of artemisinin and its analogs (7, 43) and butyric acid (44) is safe. Oral administration of the artemisinin analogs, artesunate (100 mg in a healthy adult) resulted in micromolar plasma concentration of DHA (45). The basal plasma concentration of butyric acid is normally >1 uM (42). Oral or intravenous administration of sodium butyrate (50 mg/kg) has been shown to increase the plasma butyrate concentration to the millimolar range in rats (46). The artemisinin-butyrate combination may work well, particularly for colon cancer where butyrate concentrations can be raised by simple oral probiotic intake of butyric acidproducing Lactobacilli.
"
Note: for people the sodium butyrate dose should be adjusted by dividing by 6 (for rats), resulting in ~8mg/kg.
Topical application
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3340693/
http://www.google.com/patents/EP0428773A1?cl=en
Other references:
http://www.dogcancer.net.au/RP/Artemisinin-review.pdf
http://www.prostateawarenessfoundation.org/Artemisinin.pdf
Artesunate
Artesunate is stable for 6 months in dry form at 45oC/60%RH - link
Patents:
http://www.google.com/patents/EP0428773A1?cl=en
https://www.google.ch/patents/US5219880
https://www.google.ch/patents/WO2004071506A1?cl=en
look at the list of patents citing the above ones (found at the end of each patent) for more references.
from the first one:
"Included among these skin conditions are psoriasis; diseases and tumors induced by ultraviolet radiation or of viral origin, including primary premalignant and malignant skin tumors; blistering skin diseases; and hemorrhoids. Skin conditions induced by utraviolet radiation include polymorphous light eruption, collagen vascular disease, premalignant keratoses, Bowen's disease, lentigo maligna, basal cell cancer, squamous cell cancer, and malignant melanomas. Tumors and diseases of viral origin include warts, molluscum contagiosum, orf and ecthyma contagiosum.
The compounds which are discovered to have these properties, in accordance with this invention, include artemisinin; dihydroartemisinin; carbonate, sulfonate, ester, and ether derivatives of dihydroartemisinin, notably artemether, artesunate and artesunate salts, and dihydroartemisinin propyl carbonate; as well as the bisether artelinic acid. In the practice of the invention, formulations of these compounds are administered either parenterally, orally, or topically. For topical administration, the compounds are preferably formulated with vehicles which enhance the penetration of the formulations through the stratum corneum. These topical formulations are particularly effective in the treatment of viral tumors and diseases, blistering diseases and hemorrhoids."
application example:
"... for plaque psoriasis were treated with an ointment containing artemisinin at 1% by weight ... were applied twice daily and occluded with an elastic cloth bandage"
Methods of using artemisinin-like compounds to prevent or delay the appearance of cancer
rats: 10 mg/kg artemisinin with olive oil as 10 mg artemisinin / 1 ml of olive oil
Note: for humans, this would be ~1mg/kg artemisinin.
Results:
Experiment #1: 64% rats develop cancer vs 100% for control group after 38 weeks.
Experiment #2: 0% rats developed cancer vs 43% for the control group after 10 weeks.
Covalent conjugates between endoperoxides and transferrin and lactoferrin receptor-binding agents_
Summary:
Artesunate and Artemether are more efficient than Artesiminin;
Tea and extracts (?) from the plants is almost ineffective due to the presence of 3CA (iron chelator).
Artesunate is water soluble (better for the liver?), while Artemisinin and Artemether are fat soluble.
All should be taken 2..4 hours away from food.
Absorption is reduced after 4..5 days of oral use. However, it has been applied by injection (the best way), rectally and topically (creams).
Artemisinin (Artemether ?) should be used at ~10mg/ml olive (fish, flax, coconut, .. (?)) oil
Note: should one rotate Artesunate (water soluble) and Artemeter (fat soluble) in order to increase absorption?
or rotate 4..5 days of each - oral/rectal application?
how about DMSO + Artesunate for topical use?
how about liposomal Artemeter and Artemisinin?
Pulsed application should also be better than continuous because in 1 article a resistance to artemisinin was reduced
by increasing the artemisinin levels. Therefore 2 days of 400mg/day should be better than 7 days of 100mg/day.
During the off period one can also use other supplements that might interract with artemisinin. For example
milk thistle, curcumin ...
For brain tumor low dose of Artemether (0.5mg/kg) used in 1 case.
Typical dose of Artemether is 1mg/kg with minimum of 0.5mg/kg and maximum of 2mg/kg.
Artemisinin dose typically used is between 100mg and 600mg, but some report as high as 1000mg. It is important to take it as 1 dose to avoid accumulation that can lead to increased toxicity. Accumulation also increases the half life, so detox slows down. Oil soluble forms are more toxic than artesunate (water soluble).
It seems that Artesunate can be used in the same doses as Artemisinin, but it is probably more effective.
Allergic reactions are rare. Typical symptoms are (link) - hives, rashes, itching, nasal congestion ... pain, anxiety, diarrhea ...
Liver toxicity is rare but has been reported at doses as low as 100mg.
Should start with low doses and run regular blood tests (albumin, ammonia, AFP, Bilirubin, INR, Liver enzymes, Transferrin).
Basic symptoms of liver toxicity:
- (link) - yellowish staining of skin and the white of the eyes; yellowish stool (feces); itchy skin, dark urine, joint pain
bloody or black stools, chronic fatigue, nausea, loss of appetite
Potential neuro-toxicity (link, see below).
Should be taken with:
- Sodium butyrate (~8mg/kg = ~500 .. 600 mg); +coconut oil + probiotic named Clostridium butyricum (link)
Considering that the daily limit of sodium (Na) is 2000 [mg].
Table salt (NaCl) has about 39 % Na (atomic weights: Na = 11, Cl = 17)
Sodium Butyrate (C4H7O2Na) (atomic weights: Na = 11, C = 6, H = 1, O = 8 => Na = 11/(11+4*6+7*1+2*8) = 19%)
Therefore the maximum daily quantity of sodium butyrate as a salt substitute would be about 2x the salt level = ~10g.
- Probiotics (increases the butyric acid in the intestines); both vegan and ketogenic diet increase the level of butyric acid
for the ketogenic diet levels of up to 20x increase have been reported.
- Resveratrol (not an iron chelator - link) but it can increase the liver toxicity risk (link).
- sodium salicylate (link)
- allicin (garlic extract), thiosulfinates ? (link); (arteeter + garlic oil for malaria (link))
- triptolid (?)
- for parasite cleaning it is combined with black walnut and cloves (link)
- Vitamins used in 1 case were 500mg Vit.C (increases iron absorption from food)
and 200IU Vit.E (protection from iron toxicity?link?).
The vitamins were taken in the morning and the artemether in the evening.
Iron supplementation may be used to keep iron levels at normal-high levels.
link - 250ug/dl, where for dogs the normal range is 46..240ug/dl (link).
(?) Feverfew (parthenolide), sulforaphane, Sulfasalazine (Asulfadine),
Hydroxychloroquine (Plaquenil), Chloroquine (Avelan), Mefloquin (Lariam)
Cannabis extracts, Gleditsia sinensis (Korean thorn), Ivermectin, ALA (link)
- chemotherapy drugs: Rituximab
- thymoquinone (black seed oil) (link)
- betulinic acid (birch bark) (link)
- nicotinamide (?) (link) (note: Nicotinamide is a PARP inhibitor)
- increase of ferroportin (?) (link, link2)
use iron supplements; avoid iron chelators! (link, link2) - not taken at the same time to avoid interaction in the stomach
- itraconazole (may also synergize with the ketogenic diet (mTOR)?) (link (CUSP9), link2)
- Aminolevulinic Acid (5-ALA) (link; not related to cancer: link, link, link)
According to (link):
- Vit C must be taken at different time! This is because it can increase the interaction of artemisinin with iron in the
food. Vit E (Trolox) was shown to decrease the effectiveness of Artemisinin (anti-angiogenesis (link - Vit E and
manitol)). Vit D3 and Dexamethasone showed no interactions. H2O2 showed strong additive effect.
Conclusions:
IV Vit C (+ lyposomal + sodium ascorbate) + artemisinin should be synergistic by both Vit. C alone
and also because of H2O2 created.
Vit E should be avoided.
- tagged to (holo)transferrin (?) to increase 1000 times the selectivity to cancer cells (link, link2, link3, link4, link5, link6)
link6: "were fabricated by simply combining ART, DHA or ATS with Tf",
Ph of 5.5 reduced the effectiveness.
diet + exercise + sodium bicarbonate(?) + (?) ... to maintain high Ph (should be monitored with blood/urine tests)
(low calorie) ketogenic diet does not lower Ph (link, link2)
- hyperbaric oxygen (HBOT) (link), metformin increases oxygen release into cells (link)
- anti fungal (?) (B3 (?), caprilic acid, olive leaf extract, oregano oil...)
- lactoferin (?) - must not be taken at the same time as artemisinin (?) (link)
- for liver toxicity
- artichokes, beets;
- milk thistle, curcumin - only on off days(?) + iron rich foods + vit C(?)
Should not be taken with:
- iron chelators (link), Vit. E
- NAC and anti-oxidants (link)
- glutathione (?)
- ferrostatin-1 (ferroptosis inhibitor)
- deferoxamine (iron chelator),
- Deferasirox (?), Exjade, Janedu, Deferiprone or L1 (Ferriprox) (?)
- Quercetin, Curcumin, EGCG, Phytic acid (IP6), Genistein, Pycnogenol, Baicalein,
Tetramethylpyrazine, ferulic acid, Grape seed extract, grape, wine, fruits, nuts, green/black tea, soy (?) (link) (table)
1/2 life of flavonoids = ~11h .. 28h
should not take these supplement / eat these foods on the days when artemisinin is taken (?)
should compensate with lactoferrin and iron rich foods / iron supplements (?) + vit. C (?)
- PEMF (?) (link)
- Antioxidant detoxification systems such as the glutathione redox cycle, thioredoxin redox cycle,
detoxifying enzymes such as catalase, superoxide dismutase etc., and the Nrf2 pathway all contribute
to counteract oxidative stress posed by artemisinins. These data fit well to the concept of ferroptosis,
where ferric ions induce oxidative stress and cell death. (link)
Not (less?) effective for:
- hepatocellular carcinoma occuring in a background of hemochromatosis, where tumors are depleted in iron
compared to non-tumor tissue. (link)
Mechanisms for action:
- kill tumor cells by induction of apoptosis, autophagy or necroptosis ... ferroptosis. ...
The mixture of different modes of cell death makes this class of compounds to attractive candidates
for cancer therapy. (link)
- anti angiogenesis (?)
Testimonials:
link : "My wife suffered from colon cancer stage 4, that metastisized into the liver, causing her to have two major cancer surgeries in 16 months. After a year of healthy eating, IR light treatments, and daily artemisinin, she is cancer free over a year later."
link : "1. The Sodium Butyrate has strong anti-cancer properties. The Sodium Butyrate is the sodium salt of butyric acid, which is a short-chain fatty acid. It's a natural byproduct of the fermentation of dietary fibers in your large intestine. It is anti-carcinogenic. The Sodium Butyrate increases the anti-carcinogenic effect of Artemizinin 10 times, according to laboratory tests. Should always be given at the same time with Artemizinin.
2. I gave the Sodium Butyrate together with the Artemizinin to my father in his fight with bladder cancer. After only 12 days of "Sodium Butyrate & Artemizinin" therapy, many dead tumors begun to be expelled with his urine. It was extremely effective.
3. The Artemizinin dose was 400 mg (4 pills) 4 times daily (daily total = 1600 mg), and the Sodium Butyrate dose was 2400 mg (4 pills) 4 times daily (daily total = 9600 mg). Also the Artemizinin has to be given together with some fat, because it is not soluble in water. He used 2 t.s. flax oil to dissolve the Artemizinin capsule content, then drank the mixture. The therapy time was 14 days non-stop, then 3 days off (break), then repeated for several months for total tumor destruction."
References: [Ref.1.32, 1.33, 1.34, 1.94]
Additional References:
Overview articles:
Artemisinins: Pharmacological actions beyond anti-malarial
www.futsci.com/uploads/project/file/b1d85dcff45436a0b9fb48995c6bdc6b12f49677.pdf
Artemisinin our Ultimate Cancer Weapon a Gift from China
jeffreydachmd.com/2016/02/artemisinin-our-ultimate-cancer-weapon-a-gift-from-china/
A discussion on a case of liver toxicity (100mg artemisinin):
http://scienceblogs.com/terrasig/2009/08/17/is-artemisinin-really-behind-t/
Potential neuro toxicity at high doses and prolonged exposures:
cdn.intechopen.com/pdfs-wm/35690.pdf,
www.sciencedirect.com/science/article/pii/S0006295200005566,
www.fda.gov/ohrms/dockets/ac/02/slides/3875S1_04__FDA-JohannLiang/sld022.htm,
www.ncbi.nlm.nih.gov/pubmed/16828992,
http://www.ncbi.nlm.nih.gov/pubmed/9063352,
(high doses, prolonged exposure - equivalent to about 300mg/day for 5..6 days intramuscular arteeter)
www.ncbi.nlm.nih.gov/pubmed/11037787,
These data indicate that once-daily oral administration of artesunate or artemether is relatively safe, ..., whereas constant exposure either from depot intramuscular injection of oil-based drug, or constant oral intake carries relatively greater neurotoxic potential.
(doses are equivalent to ~2000mg/day oral or 300mg/day injection to have neurotoxic effect or death in 50% of the animals)
aac.asm.org/content/46/3/821.full,
High dose of artemether on children:
http://www.ncbi.nlm.nih.gov/pubmed/10776745
"artemether 6 mg/kg (n=138) orally six times once every 3 weeks"
Note: this results in about 6x6/21 = ~1.7mg/kg, but other factors may have affected the absorption.
Recommendations from other sources is not to exceed 1mg/kg, although some mention 2mg/kg.
Article below for pituitary (brain) tumor used 40mg/day = 0.5mg/kg
The dose mentioned for the Artesunate (+ butyrate) was 100mg.
High dose of artemether in rats:
http://www.ncbi.nlm.nih.gov/pubmed/12135264
"80 mg/kg artemether administered once every 2 weeks is safe, and doses of 400 mg/kg do not result in evidence of neurotoxicology"
Note: this results in (80/14)/6 (for rats) = 0.95mg/kg - safe; 5mg/kg = no neurotoxicology
Artemisinin and Artesunate half-life: link
Artermisinin (250mg):
peak after 100min
peak level: 0.36 ug/ml
t1/2 (appearance half life): 0.62[h]
t1/2 (distribution half life): 2.61[h]
t1/2 (decline half life): 4.34[h]
total are under concentration curve (AUC): 1.19 [ug*h/ml]
Artesunate (250mg):
Ka (appearance rate constant): 2.11 [h-1] => t1/2 = ln(2)/Ka = 0.69/K => t1/2 = 0.32[h]
Ke (elimination rate constant): 1.18 [h-1] => t1/2 = 0.69/K => t1/2 = 0.58[h]
t1/2 (bio transformation half life): 0.33[h]
t1/2 (elimination half life): 0.65[h]
AUC : 0.74 [ug*h/ml]
Artesunate (link, link2):
t1/2 (half life) = 2.7 [h]
peak level after: 15 .. 40 min (oral), 35..86 min (rectal)
t1/2 (elimination half-life): 29[min] = ~0.5[h]
Artemether (link, link2):
t1/2 (half life) = 2 .. 3[h]; 1.6 (+/-0.7); 2.2 (+/-1.9)
Artemisinin-Resistant Mutants of Toxoplasma gondii Have Altered Calcium Homeostasis
www.ncbi.nlm.nih.gov/pmc/articles/PMC2151471/,
(for parasites)... artemisone > artesunate ≈ artemether > dihdyroartemisinin > artemisinin ... artemisone was more than 10-fold more active than artesunate ... and almost 30-fold potent than artemisinin.
Mechanistic Investigation of the Specific Anticancer Property of Artemisinin and Its Combination with Aminolevulinic Acid for Enhanced Anticolorectal Cancer Activity
Artesunate overcomes drug resistance in multiple myeloma by inducing mitochondrial stress and non-caspase apoptosis
Artemisinin derivatives induce iron-dependent cell death (ferroptosis) in tumor cells.
Combination of Artesunate and drugs for brain cancer: CUSP9 (link, link2)
Development of Resistance towards Artesunate in MDA-MB-231 Human Breast Cancer Cells
Note: resistance has been shown to reduce with increase of ferritin; artemisinin should not be used as a mono therapy.
Artemisinin and Nitric Oxide: Mechanisms and Implications in Disease and Health (p.32 .. p.34)
Dose dependent - 50uM had no effect while 100 and 150uM had very strong anti cancer effects.
Synergetic with chemotherapy (5-FU).
Progress on anti-tumor molecular mechanisms of dihydroartemisinin
Liver Cancer
- In vivo study of effects of artesunate nanoliposomes on human hepatocellular carcinoma xenografts in nude mice.
- Effect of oral coadministration of artesunate with ferrous sulfate on rat liver mitochondrial membrane permeability transition.
- Therapeutic effects of artesunate in hepatocellular carcinoma: repurposing an ancient antimalarial agent.
Artesunate inhibits growth and induces apoptosis in human osteosarcoma HOS cell line in vitro and in vivo
Artesunate Activates Mitochondrial Apoptosis in Breast Cancer Cells via Iron-catalyzed Lysosomal Reactive Oxygen Species Production
Artesunate Induces Apoptosis of Bladder Cancer Cells by miR-16 Regulation of COX-2 Expression
An Evaluation of the Anticancer Effects of Triptolide in Pancreatic Cancer
Comparative Cytotoxicity of Artemisinin and Cisplatin and Their Interactions with Chlorogenic Acids in MCF7 Breast Cancer Cells
Whole plant extracts versus single compounds for the treatment of malaria: synergy and positive interactions
http://doctorsaputo.com/a/artemisinin-a-cancer-smart-bomb
http://www.doctorsaputo.com/a/artemisinin-part-2-how-to-use-it
http://doctorsaputo.com/a/the-importance-of-iron-in-infections-and-cancer
https://www.google.ca/?tbm=pts&gws_rd=cr,ssl&ei=pzm4VayAJMXw-QG2uoXIDA#tbm=pts&q=artemisinin+cancer
https://www.google.ca/patents/CA2515761C?cl=en&dq=artemisinin&hl=en&sa=X&sqi=2&pjf=1&ved=0CBwQ6AEwAGoVChMIlOO376T_xgIVw3g-Ch348wbK
"cervical cancer cells, but not normal cervical cells, are efficiently killed by artemisinin."
https://www.google.ca/patents/US8394849?dq=artemisinin&hl=en&sa=X&sqi=2&pjf=1&ved=0CDgQ6AEwBGoVChMIlOO376T_xgIVw3g-Ch348wbK
https://www.google.ca/patents/US20100279976?dq=artemisinin+cancer&hl=en&sa=X&sqi=2&pjf=1&ved=0CEEQ6AEwBWoVChMIufOLyaX_xgIVSG4-Ch3SFwZ5
https://www.google.ca/patents/EP1594491B1?cl=en&dq=artemisinin+cancer&hl=en&sa=X&sqi=2&pjf=1&ved=0CFYQ6AEwCGoVChMIufOLyaX_xgIVSG4-Ch3SFwZ5
"Artemisinin is a relatively safe drug and produces few side-effects, even at high doses. Oral doses of 70 mg/kg/day for 6 days have been used in humans for malaria treatment. Furthermore, more potent analogs of this and similar compounds are also available. Higher efficacy of artemisinin action can be achieved by other means. For example, artemisinin is more reactive with heme than with free iron (Hong et al., 1974, Mol. Biochem. Parasit., 63:121-128). Iron can be introduced into target cells using transferrin (see, e.g., Stout et al., 1992, Biochim. Biophy. Res. Comm., 189:765-770) or the heme-carrying compound hemoplexin (see, e.g., Smith et al., 1988, Biochem. J., 256:941-950; Smith et al., 1990, Europ. J. Cell Biol., 53:234-245). The concentrations of agents for enhancing intracellular iron concentrations in the practice of the present invention will generally range up to the maximally tolerated dose for a particular subject and agent, which will vary depending on the agent, subject, disease condition and other factors. Dosages ranging from about 1 to about 100 mg of iron per kilogram of subject body weight per day will generally be useful for this purpose.
The dose of artemisinin or artemisinin derivative compounds administered to an individual in need of treatment will vary and will be determined for each individual with reference to, for example, the compound used, the route of administration, and the physical condition and body size of the individual. To illustrate, about 0.1 to about 100 mg per kilogram of body weight per day can be administered. In further embodiments, from about 1 to about 90 mg per kilogram of body weight per day is administered. Alternatively, from about 1 to about 75 mg per kilogram of body weight per day can be administered. The daily dosage may be administered as a single dosage or may be divided into multiple doses."
http://www.cam-cancer.org/CAM-Summaries/Herbal-products/Artemisia-annua/(merge)
https://pathwithpaws.com/blog/2011/03/26/artemisinin-when-cancer-cells-kill-themselves/
forum: http://www.topicalinfo.org/forum/topic.asp?TOPIC_ID=1657
attempt to use DMSO + Artemisinin.
comment for skin cancer: "when I don't sleep very much at night, the next day the area looks worse"
?effect from melatonin?
Case Report of a Pituitary Macroadenoma Treated With Artemether
http://thedcasite.com/Library/Artemisinin/Case_Report_of_a_Pituitary_Macroadenoma_Treated_With_Artemether.pdf
http://www.researchgate.net/profile/Narendra_Singh16
"A 75 year-old male patient presented with vision, hearing, and locomotion-related problems. Artemether was administered orally to the patient over a period of 12 months. Results: Although the tumor remained consistent in size, CT scan shows a reduction in its density, and clinically, the related symptoms and signs resolved significantly as therapy progressed. Discussion: Overall, the artemether treatment was beneficial in improving the patient's quality of life. Artemether and other artemisinin analogs offer promise for cancer therapy.
...
The patient was treated with 40 mg (approximately 0.5 mg/kg) of artemether orally daily for 29 days starting on April 16, 2004. This medication was given with milk 3 to 4 hours after dinner. Two hundred units of vitamin E (D alpha tocopherol) and 500 mg of vitamin C were given to the patient at breakfast. After 15 days of treatment, his left eyeball started moving slightly and there was a slight improvement in vision, and this treatment was continued for 2 more weeks. Artemether therapy was then reduced and given only every other day for a duration of 30 more days. Vitamin E and C were given every day. Artemether therapy was reduced further and given twice a week for approximately 10 more months. Vitamin E and C were given every day for the entire period.
...
Results
A CT scan performed on August 9, 2004 (approximately 4 months after the initial diagnosis and start of treatment), showed an increase in adenoma size to 3.0 × 2.4 cm. Although there was a slight increase in size of mass, the patient’s visual and other symptoms and signs had improved significantly. Another CT scan was performed on January 25, 2005 (approximately 9 months after the initial diagnosis and start of treatment). The tumor remained consistent in size measuring 3.33 × 2.25 cm. Additionally, the patient reported marked improvement in visual problems. The patient’s gait had returned to normal, and his hearing had improved significantly. Also, reduced doses of oral hypoglycemics were needed for control of diabetes. The patient was more alert and active than before. A CT scan on November 15, 2005, showed no significant change in tumor size (2.6 × 2.4 cm) compared to previous CT scans. However, this scan of November 2005 did show the density of the tumor (ranging from 51 to 59 HU) significantly decreased since the first scan (72-77 HU) in April 2004. Additionally, the November 2005 scan showed the tumor had become more heterogeneous. The patient also reported a nearly complete symptomatic recovery.
Discussion
We have previously reported that dihydroartemisinin selectively killed Molt-4 lymphoblastoid cells (a human leukemia cell line) after incubation with holotransferrin,9 whereas the same treatment had significantly less effect on normal human lymphocytes. A similar effect was observed in human breast cancer cells.10 Furthermore, we found that oral administration of an artemisinin analog and ferrous sulfate retarded the growth of implanted fibrosarcoma tumors in rats.16 Another study has also shown that artesunate can effectively retard the growth of various types of human cancer cells in vitro.17 We have also previously reported a case of a laryngeal cancer patient who responded well to artesunate (an analog of artemisinin) therapy.18 A recent report has shown that artesunate was effective in the long-term treatment of metastatic uveal melanoma in conjunction with conventional chemotherapy.19
This is the first report on the use of artemether as treatment for a pituitary tumor. Artemether (an analog of artemisinin) was chosen for the treatment because it easily crosses the blood-brain barrier, and similar to dihydroartemisinin,20 it kills cancer cells by apoptosis (data not shown), a preferable mode of cell death in cancer treatment. Also, it has a longer halflife compared with the more water-soluble artesunate, used previously.18
...
In this case, a combination of surgery and radiotherapy (the most common treatment option for such tumors) was offered to the patient, but he refused. Although these treatment options are often successful, the incidence of surgical complications24 and side effects from radiotherapy25 were of concern to this patient. Interestingly, though the patient reported relief of symptoms, artemether treatment did not significantly reduce the size of the tumor. Although the tumor measured approximately the same during the course of the treatment, there was a significant reduction in the density (72-77 HU in the first scan vs 51-59 HU in the last scan) and the tumor, which was initially homogenous, appeared heterogeneous in the later scan. We speculate that the remainder of the mass may consist mostly of dead cells after the treatment. We also hypothesize that it takes a longer time, particularly in older patients, for microglia and macrophage cells to scavenge dead cells from solid pituitary tumors. This change in composition, in addition to the reduction in the density of the tumor, may account for the resolution of the patient’s symptoms. Because the possibility of optic and sixth nerve compression exists, the decreased density may have eased the pressure on these structures. The patient is currently doing well and reports normal visual functioning without any complaint of hearing or gait and has stopped artemether but continues vitamins in the dosage mentioned above. It is likely that gait problems were vision related and longstanding hearing loss may have been due to existing diabetes."
Additive Cytotoxic Effects of Dihydroartemisinin and Sodium Salicylate on Cancer Cells
"at low concentrations, the combination of DHA and SS (sodium salt of aspirin) significantly reduced cancer cell proliferation, although no synergistic interaction between the two drugs was found. Even without a clear synergistic interaction, the combination of DHA and SS provides a safe and affordable form of cancer treatment."
Anticancer Effect of AntiMalarial Artemisinin Compounds.
"Experimental evidences suggest that artemisinin compounds may be a therapeutic alternative in highly aggressive cancers with rapid dissemination, without developing drug resistance. They also exhibit synergism with other anticancer drugs with no increased toxicity toward normal cells. It has been found that semisynthetic artemisinin derivatives have much higher antitumor activity than their monomeric counterparts via mechanisms like apoptosis, arrest of cell cycle at G0/G1, and oxidative stress. The exact mechanism of activation and molecular basis of these anticancer effects are not fully elucidated. Artemisinins seem to regulate key factors such as nuclear factor-kappa B, survivin, NOXA, hypoxia-inducible factor-1α, and BMI-1, involving multiple pathways that may affect drug response, drug interactions, drug resistance, and associated parameters upon normal cells. Newer synthetic artemisinins have been developed showing substantial antineoplastic activity, but there is still limited information regarding the mode of action of these synthetic compounds.
...
In a study, testing 55 cell lines showed that artesunate showed inhibitory effects against leukemia, colon, melanoma, breast, ovarian, prostate, central nervous system, and renal cancer cells.[39] The semisynthetic derivative DHA showed remarkable antineoplastic activity against pancreatic, leukemic, osteosarcoma, and lung cancer cells.[40] Moreover, artemisone was superior to artemisinin and showed better synergism with other anti-cancer agents.[41]
Artemisinin has also been found to act either directly by causing DNA damage or indirectly by interfering with several signaling pathways involved in carcinogenesis. The indirect DNA damage seems to be commoner than direct damage. In pancreatic cells, artesunate caused DNA fragmentation and membrane damage. Low doses of artesunate were associated with oncosis-like cell death, whereas higher concentrations caused apoptosis. But, extent and type of such damage can depend on the phenotype and the origin of cell line, varying in time- and dose-dependent manner. Notably, higher sensitivity to artesunate was observed in rapidly growing cell lines compared to slow growing cancer cells.[40]"
Effects of antioxidants and pro-oxidants on cytotoxicity of dihydroartemisinin to Molt-4 human leukemia cells.
"Vitamin C and vitamin D3 significantly interacted with DHA at the 48-h time point and with H2O2 at both 24-h and 48-h time points."
link to the full article
Hypoxia modulates the effect of dihydroartemisinin on endothelial cells.
"Low doses of DHA (achieved in the patients' plasma when treating malaria) were more inhibitory in hypoxia, whereas high doses (required for anti-angiogenic or anti-tumor activity) were more effective in normoxia. The peroxide bridge is essential for cellular toxicity (deoxyDHA was inactive). High doses of DHA caused HMEC-1 apoptosis and G2 cell cycle arrest. Effects were mediated by the generation of oxidative stress as demonstrated by DCF-DA fluorescence and membrane lipid peroxidation analysis. Overall, these results suggest that DHA inhibition of endothelial cell growth is related to the level of tissue oxygenation and drug concentration. This should be considered when studying both the effects of artemisinin derivatives as antimalarials and the potential therapeutic applications of these drugs as anti-tumor agents."
Note: should one combine artemisinin with hyperbaric oxygen therapy?
Effects of hyperbaric oxygen on S-180 sarcoma in mice.
"Apparently HBO can check the growth rate of sarcoma and accelerate the necrosis of S-180 sarcoma cells."
Artesunate inhibits the growth and induces apoptosis of human gastric cancer cells by downregulating COX-2.
Synergistic Cytotoxicity of Artemisinin and Sodium Butyrate on Human Cancer Cells
"The combination of 20 uM DHA and 1 mM sodium butyrate killed all Molt-4 cells at the 24-hour time-point and did not significantly affect lymphocytes. Conclusion: DHA in combination with butyric acid acts synergistically at low doses. The combination may provide a less toxic, inexpensive and effective cancer chemotherapy.
...
DMSO is an antioxidant and probably decreases the effectiveness of DHA
...
Several studies on different cancer cell types have shown butyrate exerting its cytotoxic effects via apoptosis (25, 26, 30-33), although the mechanism by which butyric acid induces apoptosis is not well understood
...
Two major mechanisms may possibly overlap to enhance the apoptotic effect of the two agents: i) butyric acid causes chromatin decondensation allowing free radicals formed by artemisinin to trigger apoptotic pathways, and ii) butyric acid redistributes intracellular iron in such a way that it is more readily available for interaction with artemisinin to generate free radicals. Several studies, exploring the role of iron in differentiation (39-41), have indicated that butyric acid is involved in intracellular iron redistribution. Our results, showing a synergistic effect of artemisinin and butyric acid in killing Molt-4 cells, may be due to these mechanisms.
...
the combination of low concentrations of sodium butyrate (1 mM) and DHA (20 ÌM) kills all leukemia cells in culture within 24 hours, suggesting that the combination of short chain fatty acids and artemisinin or its analogs may be an effective treatment for cancers.
...
The oral intake of artemisinin and its analogs (7, 43) and butyric acid (44) is safe. Oral administration of the artemisinin analogs, artesunate (100 mg in a healthy adult) resulted in micromolar plasma concentration of DHA (45). The basal plasma concentration of butyric acid is normally >1 uM (42). Oral or intravenous administration of sodium butyrate (50 mg/kg) has been shown to increase the plasma butyrate concentration to the millimolar range in rats (46). The artemisinin-butyrate combination may work well, particularly for colon cancer where butyrate concentrations can be raised by simple oral probiotic intake of butyric acidproducing Lactobacilli.
"
Note: for people the sodium butyrate dose should be adjusted by dividing by 6 (for rats), resulting in ~8mg/kg.
Topical application
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3340693/
http://www.google.com/patents/EP0428773A1?cl=en
Other references:
http://www.dogcancer.net.au/RP/Artemisinin-review.pdf
http://www.prostateawarenessfoundation.org/Artemisinin.pdf
Artesunate
Artesunate is stable for 6 months in dry form at 45oC/60%RH - link
Patents:
http://www.google.com/patents/EP0428773A1?cl=en
https://www.google.ch/patents/US5219880
https://www.google.ch/patents/WO2004071506A1?cl=en
look at the list of patents citing the above ones (found at the end of each patent) for more references.
from the first one:
"Included among these skin conditions are psoriasis; diseases and tumors induced by ultraviolet radiation or of viral origin, including primary premalignant and malignant skin tumors; blistering skin diseases; and hemorrhoids. Skin conditions induced by utraviolet radiation include polymorphous light eruption, collagen vascular disease, premalignant keratoses, Bowen's disease, lentigo maligna, basal cell cancer, squamous cell cancer, and malignant melanomas. Tumors and diseases of viral origin include warts, molluscum contagiosum, orf and ecthyma contagiosum.
The compounds which are discovered to have these properties, in accordance with this invention, include artemisinin; dihydroartemisinin; carbonate, sulfonate, ester, and ether derivatives of dihydroartemisinin, notably artemether, artesunate and artesunate salts, and dihydroartemisinin propyl carbonate; as well as the bisether artelinic acid. In the practice of the invention, formulations of these compounds are administered either parenterally, orally, or topically. For topical administration, the compounds are preferably formulated with vehicles which enhance the penetration of the formulations through the stratum corneum. These topical formulations are particularly effective in the treatment of viral tumors and diseases, blistering diseases and hemorrhoids."
application example:
"... for plaque psoriasis were treated with an ointment containing artemisinin at 1% by weight ... were applied twice daily and occluded with an elastic cloth bandage"
Methods of using artemisinin-like compounds to prevent or delay the appearance of cancer
rats: 10 mg/kg artemisinin with olive oil as 10 mg artemisinin / 1 ml of olive oil
Note: for humans, this would be ~1mg/kg artemisinin.
Results:
Experiment #1: 64% rats develop cancer vs 100% for control group after 38 weeks.
Experiment #2: 0% rats developed cancer vs 43% for the control group after 10 weeks.
Covalent conjugates between endoperoxides and transferrin and lactoferrin receptor-binding agents_