Wormwood (herbal)

Wormwood (herbal)

"Research professor Henry Lai and assistant research professor Narendra Singh have exploited the chemical properties of a wormwood derivative to target breast cancer cells with surprisingly effective results. A study in the latest issue of the journal Life Sciences describes how the derivative killed virtually all human breast cancer cells exposed to it within 16 hours."

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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 BC 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 1972, and investigators at the Walter Reed Army Institute of Research located and crystallized the active component in 1984. (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 viva. Further, it is possible to increase or enhance iron flux in cancer cells using the conditions that increase intracellular iron concentrations. However, intact in viva 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 semisynthetic 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 (G150 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 esta blished antitumor drugs. Leukemia lines resistant to either doxorubicin, vincristine, methotrexate, or hydroxy-urea 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 mitochondira 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 concen-trations." IV vitamin C may be one of the bestdocumented 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 viva. A human leukemia cell culture, Molt-4lymphblastoid 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 viva 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."

Case reports

1. Patient D.A. a 47 year-old mechanic who presented with a 4.5 cm. NonHodgkin'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 CoQ 10, 600mg daily).

3. Patient D.E., a 47 year-old Alaska resident with stage 4 breast cancer and metastases to Ti 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 quartersized 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 els e!

6. Patient J.M., a 60 year-old woman with ovarian cancer presented to the office with liver metastases, trans-aminases 400-500, WBC of 2600 and CA 125 of nearly 50. She had failed a complete cycle of full dose chemotherapy a few years ago. Her appetite was still intact, but reduced. She received detoxification, Kelly sympathetic diet, pancreatic enzymes, low dose chemotherapy (via insulin potentiation therapy), artemisinin 400mg BID (Allergy Research Group), oral Carnivora (www.carnivora.com) and high dose intravenous vitamin C. By the eighth week, all enzymes were 20-30 except the GGT which had fallen to 110, WBC was 6000 and CA 125 was well within the normal range. There was no physical or laboratory toxicity observed in the regimen other than feeling some nausea from the abundance of nutritional supplements and enzymes, through which she persevered. As of this submission, all treatments are being tapered.

Comment: This is a rather dramatic reversal of an end stage cancer. I believe it shows the value of a comprehensive management strategy. Cancer ought to be macromanaged with multiple approaches instead of conventional approaches of single strategy management. While it is too early to determine this case's final outcome, clearly management was far less expensive, far less toxic, and far more effective than what might have been expected from any conventional approach. The quality of her life has been far superior, no matter the final outcome.

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 fill 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, H202, or higher oxygen tension itself) may add significant synergism. Adding artemisinin to low dose chemo-therapeutic 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.

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. Trod. Chin. Med 2, 17, 1982.

(3.) Keith Arnold, Than Tinh Hien, Nguyen Than 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, 1996.

(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 Rod 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.

Correspondence: Robert Jay Rowen, MD

95 Montgomery Dr., Suite 220

Santa Rosa, California 95472 USA

Email: drrowen@sonic.net

Website: www.doctorrowen.com

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The species of wormwood known as Artemisia annua has been used in Traditional Chinese Medicine for the treatment of fevers and malaria for many centuries. The active antimalarial compound known as artemisinin was isolated by Chinese researchers in the early 1970s. Since then research has focussed on artemisinin and its semi-synthetic derivatives such as artemether and artesunate. These drugs have become established as safe and effective antimalarial drugs which have particular value in the treatment of chloroquine-resistant parasites. However, a group of German scientists (1) have focussed their research effort on the use of the whole herb, particularly when taken as an infusion with boiling water. The motivation behind this research is to understand the value of the traditional use of Artemisia annua for the treatment of malaria, because this application could readily be adopted in poor countries such as in Africa where the semi-synthetic drugs are relatively expensive.

Artemisia annua can be cultivated with relative ease and there are new hybrids than can yield up to 1% artemisinin. One of the questions which needed to be answered was whether an infusion of the herb can deliver significant quantities of artemisinin into the bloodstream. Fourteen healthy male volunteers received 1 liter of tea prepared from 9g of Artemisia annua leaves. Blood samples were taken and artemisinin was measured by HPLC. Significant quantities of the phytochemical were found in the plasma. Artemisinin was absorbed faster from the herbal tea than from oral solid dosage forms, but its bioavailability was similar. The 1 liter of tea (from 9g of Artemisia annua) contained 94.5mg of artemisinin, which is approximately one-fifth of the usually recommended daily dose. The authors concluded that artemisinin plasma concentrations after intake as an herbal tea are sufficient for clinical effects, but insufficient to recommend such preparations as equivalent substitutes for modern artemisinin-based drugs in malaria therapy.

The same research team also investigated the clinical efficacy of an Artemisia annua tea in the treatment of subacute malaria in Africa. (2) In an uncontrolled study, 48 patients received the tea for 4 days (5g dried leaves infused in 1 liter of hot water). After the treatment, 92% of patients had no detectable parasites in their bloodstream and there were significant improvements in subjective symptoms in 70% of the treated patients.

Commentary

One of the questions I am sometimes asked is whether the traditional galenical fluid extract of Artemisia annua can be used to provide clinically significant doses of artemisinin. The above pharmacokinetic study would support that this is the case. Interestingly, the pilot trial of the Artemisia annua tea preparation in malaria suggests that there could well be a synergistic advantage in using the tea or the galenical prepared from the whole herb, rather than the isolated compound artemisinin or its derivatives. The tea used in the pilot trial only delivered at best 10% of the normal therapeutic dose of artemisinin, but resulted in a substantial clinical effect.

These findings have particular relevance to the recently suggested use of Artemisia annua, or more specifically artemisinin, as an anticancer agent. This development is based on the finding that cancer cells have a much higher concentration of iron than normal cells. (It is thought that artemisinin interacts with iron to generate reactive oxygen species (free radicals) which kill the malaria parasite.) Tests on cancer cell lines have established that artemisinin is also selectively toxic to cancer cells, presumably because their higher iron levels result in cytotoxic effects following free radical generation after contact with artemisinin. (3-5)

References

1. Rath K, Taxis K, Walz G et al. Pharmacokinetic study of artemisinin after oral intake of a traditional preparation of Artemisia annua L. (annual wormwood). Am J Trop Med Hyg 2004; 70(2): 128-132

2. Miller M, Heide L. Malaria in Afrika: Wie hilfreich sind Arzneipflanzen? Z Phytother 2001; 22:77-81

3. Chen HH, Zhou HJ, Fang X. Inhibition of human cancer cell line growth and human umbilical vein endothelial cell angiogenesis by artemisinin derivatives in vitro. Pharmacol Res 2003; 48(3):231-236

4. Efferth T, Dunstan H, Sauerbrey A et al. The anti-malarial artesunate is also active against cancer. Int J Oncol 2001; 18(4):767-773

5. Woerdenbag HJ, Moskal TA, Pras N et al. Cytotoxicity of artemisinin-related endoperoxides to Ehrlich ascites tumor cells. J Nat Prod 1993; 56(6): 849-856

Urban & Fischer Verlag

Abstract
In this double-blind study carried out at five sites in Germany, 40 patients suffering from Crohn's disease receiving a stable daily dose of steroids at an equivalent of 40 mg or less of prednisone for at least 3 weeks were administered a herbal blend containing wormwood herb (3 x 500mg/day) or a placebo for 10 weeks. Besides steroids, 5-aminosalicylates, if dose remained constant for at least 4 weeks prior to entering the trial and/or azathioprine, stable dose for at least 8 weeks, or methotrexate, stable dose for at least 6 weeks, were permitted as concomitant medications. The recruited 40 patients--20 in each treatment group, were evaluated with the help of a Crohn's Disease Activity Index (CDAI) questionnaire, an Inflammatory Bowel Disease Questionnaire (IBDQ), the 21-item Hamilton Depression Scale (HAMD) and an 8-item Visual Analogue Scale (VA-Scale) in 2-week intervals during the first 10 study weeks, and then at week 12, 16 and 20, which were the trial-medication free observation periods. The initial stable dose of steroids was maintained until week 2, after that a defined tapering schedule was started so that at the start of week 10 all the patients were free of steroids. At the end of week 10 the trial medication was also discontinued. The concomitant medications were maintained at the same dose levels till the end of the observation period that was the end of week 20.
There was a steady improvement in CD symptoms in 18 patients (90%) who received wormwood in spite of tapering of steroids as shown by CDA-Index, IBDQ, HAMD, and VAS. After 8 weeks of treatment with wormwood there was almost complete remission of symptoms in 13 (65%) patients in this group as compared to none in the placebo group. This remission persisted till the end of the observation period that was week 20, and the addition of steroids was not necessary. In two (10%) patients did the re-starting of corticoids become necessary? On the other hand, the CD conditions of the patients who received the placebo deteriorated after the tapering of steroids, and re-starting steroids became necessary in 16 (80%) patients in this group after week 10. These results strongly suggest that wormwood has a steroid sparing effect. The improvements in HAMD scores indicate that wormwood also has an effect on the mood and quality of life of CD patients, which is not achieved by other standard medications.
[c] 2007 Published by Elsevier GmbH.
Keywords: Wormwood; Artemisia absinthium; Steroid sparing effect; Anti-depressant effect; Crohn's disease; Regional colitis; Seda Crohn
Introduction
Herba Artemisia absinthium, also known as wormwood, is described in pharmacopoeia books in many countries around the world. It is known by a variety of names, depending upon the country. Wormwood enjoyed a wide spread use and held a high reputation in medicine among the ancients (Weis, 1988; Encyclopaedia of Common Natural Ingredients Used in Food, Drugs, and Cosmetics, 1996). For medicinal purposes, leaves and stems not thicker than 4 mm are used. The dry leaves and stems contain, among others, 0.25-1.32% essential oil, absinthin, anabsin, anabsinthin, artabsin and matricin. The essential oil contains thujone and thujyl alcohol and other terpene-derivatives, which are neurotoxic. The herb is usually standardised based on absinthin. High-quality wormwood should contain at least 0.2% absinthin (List and Horhammer, 1973). Thujones are considered to be the major toxic agents present in the wormwood oil; [alpha]-thujone being more toxic than [beta]-thujone (Chaisson et al., 2000).
The Crohn's disease (CD) is usually treated with 5-aminosalicylates, mostly in combination with steroids. Azathioprine, and sometimes, methotrexate is added to more severe cases. Side effects occur frequently, particularly during the co-treatment with steroids. Low-dose corticosteroids and alternate day corticosteroids are not effective steroid-sparing alternatives. Azathioprine, 6-mercaptopurine, methotrexate and the new antitumour necrosis factor monoclonal antibody infliximab are steroid sparing therapies, but these agents have their own side effects, which are also serious (Hanauer et al., 2002; Sandborn et al., 2000; Feagan et al., 1995). Therefore, a good therapy of CD must take into account the side effects caused by standard medication and must be able to reduce the use of steroids to a minimum.
The etiology and pathogenesis of CD is poorly understood. CD may be a primary autoimmune disease due to pathogenic effect of cytokines, but intestinal vasculitis has also been implicated. Recent studies have shown that a high prevalence of herpes virii such as CMV, HHV6 and EBV in CD patients (Wakefield et al., 1992; Berk et al., 1985). Yanai and his colleagues (1999) detected EBV in tissues of CD (63.8%) and ulcerative colitis (60%) and none in the non-inflammatory areas of colon specimen. These experiments suggested that all these viruses might be playing a significant role in the pathogenesis of CD.
In vitro studies done by Karim et al., from the Department of Biology, University of Minnesota at Duluth showed that water extracts of Artemisia absinthium were capable of protecting African green monkey kidney cells (Vero-Cells) and human epithelial type two (HEp-2) cells against herpes viruses at non-cytotoxic concentrations levels. In descending order of susceptibility, the virii against which wormwood extract exhibited anti-viral activity in vitro were HSV I, VZV, EBV, human herpes virus 6 (HHV6), CMV and HSV 2 virus. Combination of wormwood water extract with cardamom, rose petals fruit water extracts resulted in synergetic or additive effects in in vitro studies (Karim et al., unpublished data). Kojima et al. have described a substance isolated from Artemisia absinthium and other plants belonging to artemisia family which induces the production of interferon and is at the same time not toxic to animal cells (German Patent Office 30 00 521; Patent Japan P 1540-79, 1979).
We hypothesised that wormwood, because of its anti-herpes properties may be a useful additive in the standard treatment of CD. The aim of the study was to add wormwood to the medication of CD patients receiving stable doses of corticosteroids, and see if wormwood was capable of reducing the patients' dependence on corticosteroids.
The outcomes in CD clinical trials are traditionally reported in terms of remission and response rates according to the Crohn's Disease Activity Index (CDAI) (Best et al., 1976). However, CDAI does not measure the overall burden of the illness experienced by the patients. CD produces a high psychological burden for the patients and many exhibit symptoms of moderate-to-severe depression. The study of Gregor and his colleagues (1997) underscores the belief that the health-related qualities of life (HRQL) in CD patients is significantly worse than in the general population. Therefore, there is a strong need to find a therapy that also improves the HRQL and possesses some antidepressant effect. Quality of life can be evaluated using either the Short-Form-36 (SF-36) HRQL rating scale or inflammatory Bowel Disease Questionnaire (IBDQ). HRQL questionnaire not only measures the benefits of the therapy on disease symptoms, but also its impact on the social and emotional lives of the patients. The secondary objective of this study was therefore to find evidence that the addition of wormwood to the standard treatment of CD will not only improve the HRQL but also improve the symptoms of depression (Karim and Omer, 1996). To study this effect, we incorporated 21-item Hamilton's Scale of Depression in our observations.
Materials and methods
Application forms
We used herba Artemisia absinthium pulvis (wormwood) capsules being marketed by Noorherbals.com LLC, P.O. Box 758, Hockessin, Delaware, USA under the name of SedaCrohn[R]. Each 400 mg of SedaCrohn[R] capsule contained besides 250 mg of wormwood powder, 100 mg of rose, 40 mg of cardamom and 10 mg of mastic resin. The placebo were identically looking capsules of the same size and weight (400 mg), containing only the fill substances rose-petals (100 mg), cardamom seeds (40 mg), resin of mastic (10 mg) and starch (100 mg). In vitro trials done by Karim et al. at the Minnesota University, Department of Biology, Duluth, USA, showed that neither roses, nor mastic resin or cardamom or any of their combinations, provided the combinations did not contain wormwood, expressed any anti-viral activity (Karim et al., unpublished data).
Standardisation
The wormwood used in Seda Crohn[R] was cultivated in Germany under standardised biological conditions, and was supplied by Galke Arzneipflanzen, Gittelde, Germany (Control No.: D-NI-LG-12-9304-BC, Code-No.: DE-012-OKO, EU regulation No.: 2092/91). Leaves and stems not thicker than 4 mm were used for processing. The herb was air-dried, powdered, mixed with powdered carriers (rose-petals, cardamom seeds and resin of mastic), and finally filled in capsules of the size 00. HPLC fingerprint were obtained using absinthin as marker. According to the data supplied by Noorherbals, Seda Crohn[R] preparation contains 0.2-0.38% absinthin and 0.25-1.52% essential oils, depending upon the batch.
Toxicity data
In 1979, the FAO/WHO Codex Committee on Food additives restricted the use of [alpha]- and [beta]-thujones to the maximum levels in final products ready for consumption: 0.5 ppm in food. In the capsules used in our study, the thujone contents were less than 5 ppm. They were estimated according to the Official Methods of Analysis of the Association of Official Analytical Chemists, 13th Ed., 1980, Section 9.129 (Data provided by Noorherbals.com). The amount of absinthin present in the trial batch was 0.37% as required by Deutsches Arzneibuch (DAB VII) for a good medicinal wormwood (Data provided by Noorherbals.com).
Acute (24h), sub-acute (4 weeks) and chronic (6 months) toxicity data of the above composition in powder form was provided by LiTaka Pharmaceutical Laboratories, Pune, India. In acute toxicity studies done 5 doses ranging from 0.575 to 5.812 g/kg were administered. No mortality in mice was observed. For sub-acute (4 weeks) toxicity 10 albino rats were fed with 45 mg/100 g and 90 mg/100g rats daily for 4 weeks. There was a significant gain in weight at the end of 4 weeks feeding. In 6 months toxicity studies same doses as for sub-acute toxicity were given for 6 months. Body weight, organ weights and hematological findings did not show signs of toxicity. Teratogenic studies on rats after 6 months feeding of the above-mentioned dose did not show any changes in uterus, ovaries and corpora lutea and there were no dead fetes or reabsorbed embryos (unpublished data of Li Taka Pharmaceuticals). This laboratory has been assigned the Labeler Code No. 58317 by the Department of Health and Human Services, Food and Drug Administration, Rockville, MD, USA).
Study protocol
The protocol of this study was designed to assess the steroid-sparing effect, remission inducing properties and quality of life improving effect of wormwood. It was a multi-centre, randomized, double-blind trial in which patients received either the wormwood powdered herb preparation described above or identically looking placebo for 10 weeks. The study was carried out at five sites in Germany. The protocol of the study was approved by the institutional review boards and the ethical committees of the participating sites. Written informed consent was obtained from all patients.
The goal was to recruit 40 patients with CD. The CD was to be verified by coloscopy and histology and h as to be of at least 3 months duration with a score of 170 or above on CDAI questionnaire (Best et al., 1976). Patients between the age of 18-80, receiving CD treatments with 5-aminosalicylates, if dose remained constant for at least 4 weeks prior to entering the trial and corticosteroids (prednisolone, prednisone or bude-sonide) at the equivalent of 40 mg/day of prednisone or less, stable dose for 3 weeks, were selected for the trial. Patients receiving azathioprine, stable dose for 8 weeks, or methotrexate stable dose for 6 weeks in addition to corticosteroids and 5-aminosalicylates qualified, however, patients treated with infliximab were excluded from the trial.
Patients were screened for eligibility 2 weeks prior to entering the trial (week-2) based on their medical history, physical examination, routine blood tests, electrocardiogram (ECG), urine analyses, CDI-Index scores and CD medication. For women, pregnancy tests were done at baseline evaluation where appropriate. Patients with serious pathological findings in ECGs, liver, kidney and heart functions, or coexisting organic diseases such as a history of cancer, asthma or other autoimmune disease requiring steroid treatments, were excluded from the trial. Any condition that, in the investigators opinion placed the patient at undue risk by participating in the 5-months study period were also excluded from taking part in the study. The recruited patients were assessed again at week 0 with the help of CDAI questionnaire, an Inflammatory Bowel Disease Questionnaire (IBDQ), a Visual Analogue Scale (VA-Scale) and 21-item Hamilton Depression Scale (HAMD). VA-Scale was an 8-item polar scale, at the positive end was the subjective condition of "Feeling Excellent" and the other negative end was the item "Feeling Worse" than before. The middle point of the scale was "Subjectively Unchanged". The patients were asked to mark with a cross their present subjective feelings at each assessment period. None of the concomitant medications, except that of steroids, already being taken by the eligible patients were increased, decreased or discontinued during the entire study period. At week 0, the eligible patients were assigned to either of the two treatment group: Group I taking wormwood and Group II taking similarly looking placebo capsules under double-blind conditions. Three capsules, containing either wormwood powder or placebo, were to be taken twice a day. This trial medication was given for 10 weeks. Patients were assessed at weeks 2, 4, 6, 8, and 10, and then at weeks 12, 16 and 20 (which was the trial-medication-free observation period) with the help of the scales used at week 0 assessment.
The dose of corticosteroids taken by the patients at baseline (week 0) evaluation was maintained constant until week 2; after that a defined tapering schedule was started. Patients who entered the trial receiving prednisone or its equivalent above 20mg/day had their treatment tapered at a rate of 5 mg/week. The tapering rate for patients receiving 20 mg prednisone equivalent or less was 2.5-3 mg/week. The tapering rate was selected so that at the start of week 10 all corticosteriods were tapered and the patients were free of this medication. Aminosalicylates and other immune-modulators were maintained at the same dose level, but the trial medication was discontinued.
Patients were excluded from the study if their CD or general health condition worsened. Worsening was defined as an increase in CDAI score of at least 70 points from the qualifying baseline score. Any condition that necessitated the introduction of a new treatment or additional treatment with corticosteroid also resulted in the removal of patients from the study. Also, hospitalisation for any reason resulted removal from the study. Patients whose CD worsened by less than 70 points on CDAI due to tapering of steroids, were not dropped from the study, but were eligible to restart the steroids after week 10, thereby the same level of steroids was reached as it was before the begin of tapering. All data obtained during treatment with trial medication was included in the safety analyses.
Response to treatment was defined as a decrease in the CDAI score of at least 70 points from the qualifying score, or a decrease in 30% of CDAI score from the baseline score. For the HAMD total score, the primary outcome measure was the absolute decrease of the Hamilton total depression score between baseline and the following treatment weeks. We defined response as a decrease in total score of >50% from baseline and remission as a score < 10 points. Statistical methods used for comparison of the groups were Student's t-test and [chi square]-test. A p-value of 0.01 was set to define significance. [chi square]-test compared the patients of the two treatment groups who responded to the study medication during the observation weeks: 2, 4, 6, 8, 10 and then at 12, 14, 16, and 20. Median CDAI, IBDQ and HAMD scores were compared at pre-defined study visits.
Results
Forty patients who fulfilled the inclusion criteria of CD were enrolled in 5 study centres in Germany. Twenty patients were assigned to each treatment group under double-blind conditions. The patient population comprised 42% men and 58% women with a median age of 37 (range 18-82) years. Their baseline disposition, medication and other characteristics are summarised in Table 1.
All patients started with 3 x 2 capsules of wormwood or placebo besides their CD basic treatment at week 0. The CD basic treatment was maintained throughout the clinical trial period of 20 weeks, except that of steroids. Study medication was given, as the protocol required, for 10 weeks. None of the patients discontinued the treatment before the final evaluation at week 20.
Fig. 1 shows the average doses of corticosteroids during the study period. The steroid dose was maintained stable until week 2, after that, tapering off started and was completed at week 10. In the placebo group, 16 patients (80%) showed CD exacerbation due to reduction in steroid dose, whereas there were only two (10%) such patients in the group, which was receiving wormwood. The exacerbation of CD symptoms necessitated the re-start of steroids in 11 patients in the placebo and two from the wormwood group.
Fig. 2 shows the score development on CDA-Index of the two treatment-groups. At week-10, 13 patients (65%) of group I were almost free of CD symptoms and there was no need to restart the steroid treatment in the following follow-up weeks. These patients continued to benefit from the previous wormwood treatment in spite of discontinuation of steroids and wormwood without loss of remission. The worsening of CD severity as indicated by CDA-Index scores was observed only in two patients of this group during the tapering period of steroids. Five patients from this group tolerated the reduction of steroids, but their CDA-Index scores remained almost unchanged during the first 10 weeks, but they gradually improved in the following 10 weeks.
In the placebo group the worsening of CD severity was observed in 16 patients during tapering of steroids as indicated by increase in CDA-Index scores. In 11 patients (55%) of this group it became necessary to restart the steroid treatment at week 11 onward. Nine patients of this group tolerated the reduction in steroids as indicated by a un-change in their CDA-Index scores. In the following follow-up observation period (week 10-20), 11 patients of this group were still depending on steroids. Already after 6 weeks the number of patients who showed clinical improvement (reduction of CDAI to 70 or more) were significantly higher (p = 0.01) in group I as compared to group II. This significant difference continued beyond week-10. The results of the IBD Questionnaire scores were similar to the CDA-Index scores (Fig. 3).
VA-Scale score showed pattern similar to that seen in CDA-Index scores (Fig. 4). There was almost no change in the subjective feelings of illness in self-assessment (VA-Scale) of the patients in the placebo group, whereas in the wormwood group the self-assessment evaluation of the patients indicated significant improvement.
Hamilton total scores decreased by an average of 9.8 (SD 5.8) points for wormwood group and by 3.4 (SD 6.6) points for placebo group. At the end of the acute treatment phase (week 10), 70% of the patients in the wormwood group and none in the placebo group showed remission of depressive symptoms (Fig. 5).
Discussion
A very significant and unexpected finding was that at week 10, 13 patients (65%) of the group that received wormwood were almost free of CD symptoms as compared to none in the placebo group. Moreover, in these patients there was no need to restart corticosteroids in the follow-up weeks, and there was no remission of disease and the patients continued to benefit from 10-week wormwood treatment. This observation suggests that wormwood might be having a kind of "curing" effect on a sub-group of CD patients. This effect can be attributed to the virus elimination by wormwood. As mentioned before, wormwood has anti-DNA virus properties, and there are studies indicating that a DNA-Virus might be playing a role in the CD disease. The registered effect can also be attributed to immune system modulation by wormwood. More in vitro and in vivo trials are to be done in order to understand the observed efficacy of this herb.
The fact that five patients showed little response to the wormwood treatment, indicate that there is a subgroup of CD patients, which is resistant to wormwood treatment. The five patients from this group tolerated the reduction of steroids, but their CDA-Index scores remained almost unchanged during the first 10 weeks. As these patients gradually improved in the following 10 weeks, indicates that this improvement can be attributed to the concomitant basic CD treatment.
CD patients usually suffer from mood disturbance. Hamilton's Depression Scale is a good validated instrument to assess changes in mood. The average baseline scores on this scale showed that CD patients were moderately depressed. Their mood improved gradually and there was a statistically significant difference at week 10 and 12 evaluation. For an antidepressant drug, these finding will amount to an evidence for an anti-depressant activity. This conclusion cannot be drawn from these finding as the selection of the patients was not based on the depression criteria but on the criteria of CD severity. It is still striking to note that wormwood not only possesses beneficial effects for the patients with CD but also has a significant effect on the quality of life and mood. Very few trials on CD patients have taken into consideration this aspect. From the results presented, a conclusion can be drawn that wormwood has not only steroid-sparing effect on CD patients, but this effect continues for several weeks after the end of the 10-week treatment period. The trial opens new doors to investigate this ancient traditional herb.
Acknowledgement
The authors wish to thank all those co-investigators who participated in this trial at different centres in Germany. They would also like to thank with pleasure Professor R. H. Wagner, University of Munich, Department of Pharmacy, Munich, Germany, for his helpful comments. Competing interests: The materials for this study was provided by Noorherbals.com LLC, P.O. Box 758, Hockessin, Delaware, USA. The design of the trial was conceived by B. Omer and the study was organized and monitored by S. Krebs and T. O. Noor, and analysed by H. Omer. The authors have not received any consulting fee from Noorherbals.com
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B. Omer (a), S. Krebs (b,*), H. Omer (c), T.O. Noor (d)
(a) Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
(b) Department of Internal Medicine I, Faculty of Medicine, University of Saarland, Homburg/Saar, Germany
(c) Department of Physics, University of Heidelberg, Germany
(d) Medical Faculty, University of Freiburg, Germany
*Corresponding author. Tel.: +49 7623 62430; fax: +49 7623 8469.
E-mail addresses: s_s_krebs@web.de, harun.omer@urz.uni-heidelberg.de (S. Krebs).

Table 1. Patients disposition, baseline characteristics, concomitant
medications

Group I Group II
(wormwood) (placebo)

Males 12 11
Females 8 9
Age (median) 46 (21-75) 41 (22-67)
Duration of disease (years) 6.1 (3.9-14.2) 4.5 (2.7-11.2)

Involved intestine
Ileum 3 2
Colon 20 20
Ileum + colon 20 20
Gastro-duodenum 3 5
Resection 17 14
CDAI (median) 298 (240-321) 277 (238-317)
IBDQ (median) 121 (110-152) 125 (123-147)

Concomitant medication
Glucocorticoids
Below 20 mg 8 6
Above 20 mg 12 14
5-Aminosalicylates 16 18
Azathioprines 8 6
Methotrexate 4 2