There are few natural health supplements whose reputation for effectiveness matches that of AOR Curcumin, the principle polyphenol found in the Indian spice turmeric. It has even been dubbed "curecumin" by certain scientists and all but revered as a panacea by many in the preventative health community. It has long been established as one of the most effective antioxidants and anti-inflammatories in the natural world, and modern science is further revealing an ever-proliferative list of capabilities. These include its use as a therapeutic agent in wound healing, diabetes, Alzheimer disease, Parkinson disease, cardiovascular disease, pulmonary disease, and even as an anti-angiogenic and chemopreventive agent. Its axiomatic anti-inflammatory function also enables it to be of potentially therapeutic value in the myriad of conditions for which inflammation is an underlying factor, including arthritis, inflammatory bowel disease and psoriasis.

Ayurveda, The Natural World and AOR Curecumin
During the period between 1981 and 2002, 61% of the 877 new molecular drugs developed were originally extracted from natural sources. It is therefore easy to appreciate ancient medicinal paradigms such as Ayurveda and traditional Chinese medicine which are so deeply rooted in such natural sources, and these paradigms have no staple more renowned, more widely utilized, and in the case of Ayurveda more revered, than curcumin.

AOR Curecumin (i.e. Curcuma Longa) is a perennial herb - commonly known as turmeric, especially in its powdered form - that belongs to the ginger family. The active constituents of curcumin are curcuminoids, of which there are three principal types, namely curcumin I (diferuloylmethane), curcumin II (demethoxycurcumin) and curcumin III (bisdemethoxycurcumin). There is also a fourth category encompassing ‘other' curcuminoids, but these comprise roughly 4-5% of the curcuminoid complex, with curcumin I (diferuloylmethane) usually forming more than three-quarters of this complex.

Traditional and Modern Roles of AOR Curecumin
Most people will likely be familiar with curcumin as a food spice used to provide curry with its distinctive flavour and colour. Practitioners of Ayurvedic medicine will refer to it as a treatment for ailments ranging from respiratory conditions such as asthma, bronchial hyperactivity, and allergies, to liver disorders, anorexia, rheumatism, diabetes, runny nose, cough, and sinusitis. In traditional Chinese medicine it is most often used to treat conditions associated with abdominal pain and as an anti-inflammatory. The latter has also been the focus of a great deal of modern research into the mechanism(s) of action for curcumin, particularly since such research has also isolated inflammation as the greatest common denominator behind a number of terminal conditions. The following table lists the range of inflammation mediators (cytokines) that are inhibited by curcumin supplementation:

Table 1: List of Inflammatory Cytokines and Transcription Factors Inhibited by AOR Curecumin

Interleukin-1	Interleukin-2
Interleukin-5	Interleukin-6
Interleukin-8	Interleukin-12
Interleukin-18	Monocyte chemoattractant protein
Migration inhibition protein	Tumor necrosis factor alpha
Macrophage inflammatory protein	Nuclear factor-kappa B

Modern scientific research has also identified some very potent anti-carcinogenic, anti-microbial, thrombosuppressive, cardiovascular, hypoglycemic and anti-arthritic capabilities within curcumin. AOR Curecumin's anti-carcinogenic and anti-tumour capabilities are heavily based on extensive laboratory animal (murine) studies, and a partial synopsis of those studies is provided in Table 2.

Table 2: Volume and Types of Murine Cancer Studies Successfully Demonstrating the Chemopreventive Capacity of AOR Curecumin

Type of Cancer	Number of Studies
Aberrant crypt foci (ACF)	1
Colon cancer	8
Colitis	3
Ulcerative colitis	1
Duodenal tumour	1
Esophageal cancer	1
Focal areas of dysplasia (FAD)	1
Familial adenomatous polyposis (FAP)	1
Forestomach neoplasia	2
Forestomach cancer	1
Stomach cancer	1
Liver cancer	2
Lung cancer	1
Lymphoma/leukemia	1
Breast cancer	9
Oral cancer	2
Prostate cancer	1
Skin cancer	9
Multi-organ cancer	1

The Real World: Clinical Trials
Curecumin's success is of course not exclusively based on trials with laboratory animals.  AOR Curecumin's status as an anti-inflammatory has produced a series of successful human trials involving conditions where inflammation is an underlying factor. In one study involving patients with post-operative inflammation, curcumin's effects were comparable to the drug phenylbutazone. In another study among patients of type II diabetes, curcumin was found to reduce inflammatory markers such as Interleukin-6 (IL-6) and Tumour Necrosis Factor (TNFα) in a manner comparable to the drug atorvastatin. However, Table 3 offers an exhaustive (but still not conclusive) list of clinical studies involving curecumin, a list by no means limited to inflammation.

Table 3: Curecumin Clinical Trial Summary

Clinical Study	Disease/Condition	Dosage/Duration	Number of Subjects	Conclusion
A.L. Cheng, C.H. Hsu, J.K. Lin, M.M. Hsu, Y.F. Ho and T.S. Shen et al., Phase I clinical trial of curecumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions, Anticancer Res 21 (2001), pp. 2895-2900.	Safety Study	500-12,000 mg/day × 90 days	25	Histologic improvement of precancerous lesions.
C.D. Lao, M.Tt. Ruffin, D. Normolle, D.D. Heath, S.I. Murray and J.M. Bailey et al., Dose escalation of a curcuminoid formulation, BMC Complement Altern Med 6 (2006), p. 10.	Safety Study	500-12,000 mg/day	24	Safe, well-tolerated even at 12 g/day.
S.D. Deodhar, R. Sethi and R.C. Srimal, Preliminary study on antirheumatic activity of curcumin (diferuloyl methane), Indian J Med Res 71 (1980), pp. 632-634.	Rheumatoid arthritis	1200 mg/day × 14 days	18	Improved symptoms
R.R. Satoskar, S.J. Shah and S.G. Shenoy, Evaluation of anti-inflammatory property of curcumin (diferuloyl methane) in patients with postoperative inflammation, Int J Clin Pharmacol Ther Toxicol 24 (1986), pp. 651-654.	Postoperative inflammation	400 mg; 3×/day × 5 days	46	Decrease in inflammation
R. Kuttan, P.C. Sudheeran and C.D. Josph, Turmeric and curcumin as topical agents in cancer therapy, Tumori 73 (1987), pp. 29-31.	External cancerous lesions	1% ointment × several months	62	Reduction in smell in 90% patients, reduction of itching in all cases, dry lesions in 70% patients reduction in lesion size and pain in 10% patients.
K.B. Soni and R. Kuttan, Effect of oral curcumin administration on serum peroxides and cholesterol levels in human volunteers, Indian J Physiol Pharmacol 36 (1992), pp. 273-275.	Cardiovascular	500 mg/day × 7 days	10	Decreased serum lipid peroxidase (33%),increased HDL cholesterol (29%), decreased total serum cholesterol (12%).
A. Ramirez Bosca, A. Soler, M.A. Carrion-Gutierrez, D. Pamies Mira, J. Pardo Zapata and J. Diaz-Alperi et al., An hydroalcoholic extract of Curcuma longa lowers the abnormally high values of human-plasma fibrinogen, Mech Ageing Dev 114 (2000), pp. 207-210.	Atherosclerosis	10 mg; 2×/day × 28 days	12	Lowered LDL and apoB, increased HDL and ApoA.
J.S. James, Curecumin: clinical trial finds no antiviral effect, AIDS Treat News (1996), pp. 1-2.	HIV	625 mg; 4×/day × 56 days	40	Well tolerated
A. Rasyid and A. Lelo, The effect of curcumin and placebo on human gall-bladder function: an ultrasound study, Aliment Pharmacol Ther 13 (1999), pp. 245-249.	Gall bladder function	20 mg, single dose (2 h)	12	Decreased gall bladder volume by 29%.
A. Rasyid, A.R. Rahman, K. Jaalam and A. Lelo, Effect of different curcumin dosages on human gall bladder, Asia Pac J Clin Nutr 11 (2002), pp. 314-318.Pac J Clin Nutr 11 (2002), pp. 314-318.	Gall bladder function	20-80 mg, singledose (2 h)	12	Decreased gall bladder volume by 72%.
B. Lal, A.K. Kapoor, O.P. Asthana, P.K. Agrawal, R. Prasad and P. Kumar et al., Efficacy of curcumin in the management of chronic anterior uveitis, Phytother Res 13 (1999), pp. 318-322.	Chronic anterior uveitis	375 mg; 3×/day × 84 days	32	Eighty-six percent decrease in chronic anterior uveitis.
B. Lal, A.K. Kapoor, P.K. Agrawal, O.P. Asthana and R.C. Srimal, Role of curcumin in idiopathic inflammatory orbital pseudotumours, Phytother Res 14 (2000), pp. 443-447.	Idiopathic Inflammatory Orbital Pseudotumors	375 mg; 3×/day × 180-660 days	8	Four patients recovered completely. One patient showed decrease in swelling, no recurrence.
M.C. Heng, M.K. Song, J. Harker and M.K. Heng, Drug-induced suppression of phosphorylase kinase activity correlates with resolution of psoriasis as assessed by clinical, histological and immunohistochemical parameters, Br J Dermatol 143 (2000), pp. 937-949.	Psoriasis	1% curcumin gel	40	Decreased PhK2, TRR3, parakeratosis, and density of epidermal CD8+ T cells
R.A. Sharma, H.R. McLelland, K.A. Hill, C.R. Ireson, S.A. Euden and M.M. Manson et al., Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancer, Clin Cancer Res 7 (2001), pp. 1894-1900.	Colorectal cancer	36-180 mg/day × 120 days	15	Lowered Glutathione-S-Transferase
R.A. Sharma, S.A. Euden, S.L. Platton, D.N. Cooke, A. Shafayat and H.R. Hewitt et al., Phase I clinical trial of oral curcumin: biomarkers of systemic activity and compliance, Clin Cancer Res 10 (2004), pp. 6847-6854.	Colorectal cancer	450-3600 mg/day × 120 days	15	Lowered inducible serum PGE2 levels.
R. Bundy, A.F. Walker, R.W. Middleton and J. Booth, Turmeric extract may improve irritable bowel syndrome symptomology in otherwise healthy adults: a pilot study, J Altern Complement Med 10 (2004), pp. 1015-1018.	Irritable bowel syndrome	72-144 mg/day × 56 days	207	Reduced symptoms
G. Garcea, D.P. Berry, D.J. Jones, R. Singh, A.R. Dennison and P.B. Farmer et al., Consumption of the putative chemopreventive agent curcumin by cancer patients: assessment of curcumin levels in the colorectum and their pharmacodynamic consequences, Cancer Epidemiol Biomarkers Prev 14 (2005), pp. 120-125.	Colorectal cancer	450-3600 mg/day × 7 days	12	Decreased M1G DNA adducts.
D. Shoskes, C. Lapierre, M. Cruz-Correa, N. Muruve, R. Rosario and B. Fromkin et al., Beneficial effects of the bioflavonoids curcumin and quercetin on early function in cadaveric renal transplantation: a randomized placebo controlled trial, Transplantation 80 (2005), pp. 1556-1559.	Cadaveric renal transplantation	480 mg; ×1-2/day × 30 days	43	Improved renal function, reduced neurotoxicity.
S. Durgaprasad, C.G. Pai, Vasanthkumar, J.F. Alvres and S. Namitha, A pilot study of the antioxidant effect of curcumin in tropical pancreatitis, Indian J Med Res 122 (2005), pp. 315-318.	Tropical pancreatitis	500 mg/day × 42 days	20	Reduction in the erythrocyte MDA levels, increased erythrocyte GSH levels.
P.R. Holt, S. Katz and R. Kirshoff, Curcumin therapy in inflammatory bowel disease: a pilot study, Dig Dis Sci 50 (2005), pp. 2191-2193.	Ulcerative proctitis	550 mg; × 2-3/day × 60 days	5	Improved symptoms
P.R. Holt, S. Katz and R. Kirshoff, Curcumin therapy in inflammatory bowel disease: a pilot study, Dig Dis Sci 50 (2005), pp. 2191-2193.	Crohn's disease	360 mg; ×3/day × 30 days; ×4 for 60 days	5	Improved symptoms
H. Hanai, T. Iida, K. Takeuchi, F. Watanabe, Y. Maruyama and A. Andoh et al., Curcumin maintenance therapy for ulcerative colitis: randomized, multicenter, double-blind, placebo-controlled trial, Clin Gastroenterol Hepatol 4 (2006), pp. 1502-1506.	Ulcerative colitis	2000 mg/day × 180 days	89	Low recurrence; improved symptoms.
M. Cruz-Correa, D.A. Shoskes, P. Sanchez, R. Zhao, L.M. Hylind and S.D. Wexner et al., Combination treatment with curcumin and quercetin of adenomas in familial adenomatous polyposis, Clin Gastroenterol Hepatol 4 (2006), pp. 1035-1038.	Familial adenomatous polyposis	480 mg; ×3/day × 180 days	5	Decrease in the number of polyps was 60.4%, decrease in the size of polyps was 50.9%.
T.P. Ng, P.C. Chiam, T. Lee, H.C. Chua, L. Lim and E.H. Kua, Curry consumption and cognitive function in the elderly, Am J Epidemiol 164 (2006), pp. 898-906.	Improves cognitive function	-	1010	Better standardized score.
F. Di Mario, L.G. Cavallaro, A. Nouvenne, N. Stefani, G.M. Cavestro and V. Iori et al., A curcumin-based 1-week triple therapy for eradication of Helicobacter pylori infection: something to learn from failure?, Helicobacter 12 (2007), pp. 238-243.	Helicobacter pylori infection2	300 mg/day × 7 days	25	Significant improvement of dyspeptic symptoms.

Pharmacokinetics and Bio-availability: A Point of Contention
While curecumin supplementation has always been very well-tolerated with no side effects seen even at doses of 12 grams, the issue of bioavailability has always been a contentious one. Most studies indicate that the bioavailability of curecumin is generally poor. Indeed, in the same study that determined the safety of a 12 gram dose, it was found that a single dose of at least 10 grams was required to produce even low serum levels of curecumin in test subjects. While it has been argued that systemic bioavailability of curecumin may not be essential in achieving some degree of bio-effectiveness, it cannot be logically disputed that greater bioavailability would only enhance that effectiveness.

It is for that reason that forward-thinking nutraceutical manufacturers have taken the necessary steps to enhance the bioavailability of curecumin, with an elite few employing nanotechnology in order to do so.

References:

Goel A, Kunnumakkara AB, Aggarwal BB. Curcumin as "Curecumin": from kitchen to clinic. Biochem Pharmacol. 2008 Feb 15;75(4):787-809.

Newman DJ, Cragg GM, Snader KM. Natural products as sources of new drugs over the period 1981-2002. J Nat Prod 2003;66:1022-37.

Usharani P, Mateen AA, Naidu MU, Raju YS, Chandra N. Effect of NCB-02, atorvastatin and placebo on endothelial function, oxidative stress and inflammatory markers in patients with type 2 diabetes mellitus: a randomized, parallel-group, placebo-controlled, 8-week study. Drugs R D. 2008;9(4):243-50.

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Bioavailability of curecumin: problems and promises.
Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB.
Mol Pharm. 2007 Nov-Dec;4(6):807-18. Epub 2007 Nov 14.

 

Curecumin, a polyphenolic compound derived from dietary spice turmeric, possesses diverse pharmacologic effects including anti-inflammatory, antioxidant, antiproliferative and antiangiogenic activities. Phase I clinical trials have shown that curcumin is safe even at high doses (12 g/day) in humans but exhibit poor bioavailability. Major reasons contributing to the low plasma and tissue levels of curcumin appear to be due to poor absorption, rapid metabolism, and rapid systemic elimination. To improve the bioavailability of curcumin, numerous approaches have been undertaken. These approaches involve, first, the use of adjuvant like piperine that interferes with glucuronidation; second, the use of liposomal curcumin; third, curcumin nanoparticles; fourth, the use of curcumin phospholipid complex; and fifth, the use of structural analogues of curecumin (e.g., EF-24). The latter has been reported to have a rapid absorption with a peak plasma half-life. Despite the lower bioavailability, therapeutic efficacy of curecumin against various human diseases, including cancer, cardiovascular diseases, diabetes, arthritis, neurological diseases and Crohn's disease, has been documented. Enhanced bioavailability of curecumin in the near future is likely to bring this promising natural product to the forefront of therapeutic agents for treatment of human disease.

Curecumin as "Curecumin": from kitchen to clinic.
Goel A, Kunnumakkara AB, Aggarwal BB.
Biochem Pharmacol. 2008 Feb 15;75(4):787-809.

Although turmeric (Curcuma longa; an Indian spice) has been described in Ayurveda, as a treatment for inflammatory diseases and is referred by different names in different cultures, the active principle called curcumin or diferuloylmethane, a yellow pigment present in turmeric (curry powder) has been shown to exhibit numerous activities. Extensive research over the last half century has revealed several important functions of curcumin. It binds to a variety of proteins and inhibits the activity of various kinases. By modulating the activation of various transcription factors, curcumin regulates the expression of inflammatory enzymes, cytokines, adhesion molecules, and cell survival proteins. Curecumin also downregulates cyclin D1, cyclin E and MDM2; and upregulates p21, p27, and p53. Various preclinical cell culture and animal studies suggest that curcumin has potential as an antiproliferative, anti-invasive, and antiangiogenic agent; as a mediator of chemoresistance and radioresistance; as a chemopreventive agent; and as a therapeutic agent in wound healing, diabetes, Alzheimer disease, Parkinson disease, cardiovascular disease, pulmonary disease, and arthritis. Pilot phase I clinical trials have shown curcumin to be safe even when consumed at a daily dose of 12g for 3 months. Other clinical trials suggest a potential therapeutic role for curcumin in diseases such as familial adenomatous polyposis, inflammatory bowel disease, ulcerative colitis, colon cancer, pancreatic cancer, hypercholesteremia, atherosclerosis, pancreatitis, psoriasis, chronic anterior uveitis and arthritis. Thus, curcumin, a spice once relegated to the kitchen shelf, has moved into the clinic and may prove to be "Curecumin".

 

Phase I Clinical Trial of Oral Curecumin
Clinical Cancer Research 2004;10:6847-6854.
Sharmal RA, Euden SA, Platton SL, Cooke DN, Shafayat A, Hewitt R, Marczylol TH, Morgan B, Hemingway D, Plummer SM, Pirmohamed M, Gescher AJ and Steward WP.

Curecumin, a polyphenolic antioxidant derived from a dietary spice, exhibits anticancer activity in rodents and in humans. Its efficacy appears to be related to induction of glutathione S-transferase enzymes, inhibition of prostaglandin E2 (PGE2) production, or suppression of oxidative DNA adduct (M1G) formation. We designed a dose-escalation study to explore the pharmacology of curcumin in humans. Fifteen patients with advanced colorectal cancer refractory to standard chemotherapies consumed capsules compatible with curcumin doses between 0.45 and 3.6 g daily for up to 4 months. Levels of curcumin and its metabolites in plasma, urine, and feces were analyzed by high-pressure liquid chromatography and mass spectrometry. Three biomarkers of the potential activity of curcumin were translated from preclinical models and measured in patient blood leukocytes: glutathione S-transferase activity, levels of M1G, and PGE2 production induced ex vivo. Dose-limiting toxicity was not observed. Curecumin and its glucuronide and sulfate metabolites were detected in plasma in the 10 nmol/L range and in urine. A daily dose of 3.6 g curcumin engendered 62% and 57% decreases in inducible PGE2 production in blood samples taken 1 hour after dose on days 1 and 29, respectively, of treatment compared with levels observed immediately predose (P < 0.05). A daily oral dose of 3.6 g of curcumin is advocated for Phase II evaluation in the prevention or treatment of cancers outside the gastrointestinal tract. PGE2 production in blood and target tissue may indicate biological activity. Levels of curcumin and its metabolites in the urine can be used to assess general compliance.

Mechanism of antiinflammatory actions of curecumine and boswellic acids.
J Ethnopharmacol 1993 Mar; 38(2-3): 113-9.
Ammon HP, Safayhi H, Mack T, Sabieraj J.

Curecumine from Curcuma longa and the gum resin of Boswellia serrata, which were demonstrated to act as anti-inflammatories in in vivo animal models, were studied in a set of in vitro experiments in order to elucidate the mechanism of their beneficial effects. Curcumine inhibited the 5-lipoxygenase activity in rat peritoneal neutrophils as well as the 12-lipoxygenase and the cyclooxygenase activities in human platelets. In a cell free peroxidation system curcumine exerted strong antioxidative activity. Thus, its effects on the dioxygenases are probably due to its reducing capacity. Boswellic acids were isolated from the gum resin of Boswellia serrata and identified as the active principles. Boswellic acids inhibited the leukotriene synthesis via 5-lipoxygenase, but did not affect the 12-lipoxygenase and the cyclooxygenase activities. Additionally, boswellic acids did not impair the peroxidation of arachidonic acid by iron and ascorbate. The data suggest that boswellic acids are specific, non-redox inhibitors of leukotriene synthesis either interacting directly with 5-lipoxygenase or blocking its translocation.


Inhibitory effect of dietary curecumin on skin carcinogenesis in mice.
Cancer Lett 1997 Jun 24; 116(2): 197-203.
Limtrakul P, Lipigorngoson S, Namwong O, Apisariyakul A, Dunn FW.

Laboratory animal model studies have suggested that curcumin may play an important role in inhibiting the process of carcinogenesis. Curecumin, the yellow pigment that is obtained from rhizomes of the plant Curecuma longa Linn (Family Zingiberaceae), is commonly used as a spice and food coloring agent. The present study was designed to investigate the chemopreventive action of dietary curcumin on 7,12-dimethylbenz[a]anthracene (DMBA)-initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA)-promoted skin tumor formation in male Swiss ablino mice. At 6 weeks of age, groups of animals were fed the standard (modified AIN-76 A) diet or a diet containing 1% curcumin. At 8 weeks of age, all animals, except those in the vehicle (acetone)-treated groups, received 100 microg of DMBA dissolved in 100 microl of acetone in a single application to the skin of the back. From 1 week after DMBA application, tumor promoter (2.5 microg of TPA dissolved in 100 microl of acetone) was applied to the same areas on mouse skin twice a week for 26 weeks. All groups continued on their respective dietary regimen until the termination of the experiment. The results indicate that dietary administration of curcumin significantly inhibited the number of tumors per mouse (P < 0.05) and the tumor volume (P < 0.01). The percentage of tumor-bearing mice tended to be lower in the mice on the curcumin diet than those on the standard diet. There was no difference in growth between mice of the standard and 1% curcumin groups. The results indicate the safety and the anti-carcinogenic effect of curcumin in mice.

Turmeric: A Brief Review of Medicinal Properties
Fitoterapia 1997; 68(6): 483-493.
Srimal RC

Turmeric has been attributed a number of medicinal properties in the traditional system of medicine and its internal as well local use has been advocated. The major claims have been for use as antiseptic, cure for poisoning, eliminating body waste products, for dyspesia, respiratory disorders and cure for a number of skin diseases including promotion of wound healing. Recent studies have confirmed some of the older claims and brought out several new useful properties. Curecumin, curcuminoids and essential oils are the major active constituents. The main activities have been found to be anti-inflammatory, hepatoprotective, antimicrobial, wound healing, anticancer, antitumor and antiviral. Discovery of antiviral properties in curecumin, particularly against HIV, is interesting and needs proper evaluation. The review highlights some of the newer researchers, which may explain the multifaceted activity of this natural product. Different extracts of turmeric and also curcumin have been tried clinically in several diseased conditions with gratifying results.