Complaint to TGA – Australian NaturalCare Products Curcumin · 2019. 10. 18. · Complaint to TGA...

Complaint to TGA – Australian NaturalCare Products Curcumin

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Acknowledgment: This brochure illustrated in this complaint was sent to a National Seniors Australia member whose concern about the claims resulted in this complaint.1

The product: Australian NaturalCare Products Pty Ltd Curcumin (ARTG: 202390)

Dosage Form: Film coated tablet contains Curcumin 90mg (Meriva® Curcumin phospholipid complex 500mg).

Route of Administration: One tablet twice daily with food, or as advised by your healthcare professional.

Sponsor: Australian NaturalCare Products Pty Ltd.

Advertiser: National Seniors Australia, Level 18 15 Adelaide St, Brisbane QLD 4000, and others.

Previous complaints: There have been ten complaints about products containing curcumin upheld by the TGACRP.2 This included one by Australian NaturalCare Products Pty Ltd (2016-05-009), also advertised by the National Seniors Australia, and three about other products containing the identical formulation of Meriva® curcumin (2016-06-006), (2016-10-017) and (2016/10/037)

N.B.1. Not all these determinations can be downloaded in their entirety because of unresolved problems with the TGACRP web site, e.g. Invalid File crp-2016-10-037-wagner-bio-curcumin.pdf.

N.B.2. Because of a previous upheld complaint about the same product from the same sponsor I request this complaint be categorised as “medium” according to the TGA’s Risk Based Activity Model.3

The promotion

• National Seniors Australia brochure (received on 26 September 2019) • https://www.ausnaturalcare.com.au/vitamins/curcumin • https://issuu.com/ausnaturalcare/docs/anc-catalogue-2018 • https://www.priceline.com.au/australian-naturalcare-curcumin-60-tablets • https://www.amazon.com.au/Australian-NaturalCare-Curcumin-Anti-Inflammatory-

Reliever/dp/B07CLLWLK4 • https://www.jointhealthmagazine.com/australian-naturalcare-curcumin-review.html • Etc.

The claims (1-6 from National Seniors Brochure appended):

1. “Although curcumin is widely available in supplement form, not all brands contain curcumin in a form which can be effectively absorbed by your body. Or to put it another way, the curcumin in them has poor bioavailability”.

2. “CURCUMIN contains a unique form of curcumin called Meriva®…. The Phytosome® helps to shield the curcuminoids from degradation and acts like a "super shuttle". Improving absorption ... increases the bioavailable amount... And if you suffer from (mild) osteoarthritis, that good news for you, as it means unlike the curcumin used in some supplements the Meriva® in CURCUMIN is more efficient at helping to reduce the pain and inflammation that slows you down and stops you doing the things you love..."

3. “1 film coated tablet is equivalent to 18 teaspoons of turmeric”.

4. “Potent relief from pain, swelling and inflammation of mild arthritis”.

5. “Put the technologically enhanced power of this ancient herb to work on your painful joints”.

6. “Many of our customers have personally written to me to tell me what a difference CURCUMIN has made to their lives“. Testimonials follow….

1 https://nationalseniors.com.au/ 2 http://www.tgacrp.com.au/complaint-register/?_search=curcumin 3 https://www.tga.gov.au/publication/complaints-handling-advertising-therapeutic-goods-australian-public

https://www.ausnaturalcare.com.au/vitamins/curcumin

https://issuu.com/ausnaturalcare/docs/anc-catalogue-2018

https://www.priceline.com.au/australian-naturalcare-curcumin-60-tablets

https://www.amazon.com.au/Australian-NaturalCare-Curcumin-Anti-Inflammatory-Reliever/dp/B07CLLWLK4


https://www.jointhealthmagazine.com/australian-naturalcare-curcumin-review.html

https://nationalseniors.com.au/

http://www.tgacrp.com.au/complaint-register/?_search=curcumin

https://www.tga.gov.au/publication/complaints-handling-advertising-therapeutic-goods-australian-public


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7. “Can assist with swollen joints”.4

8. “Curcumin promises to increase your joint mobility by reducing the swelling and pain in your joints”.5

Relevant extracts from upheld TGACRP determinations 2016-05-09 & 2016-10-017:

The study entitled “Product-evaluation registry of Meriva, a curcumin-phosphatidylcholine complex, for the complementary management of osteoarthritis” (Belcaro 2010 #1 attached) appeared to be modest preliminary evidence that the Meriva curcumin-phosphatidyl choline complex used in the advertised product could have benefits in relation to osteoarthritis at dosages of 200mg curcumin per day, using a range of outcome measurements such as walking performance on a treadmill and, for inflammation, levels of C-reactive protein. The weight that could be given to this study was limited by the fact that two of its authors were employees of the manufacturer of the Meriva ingredient, and that the study itself was sponsored by the manufacturer. Moreover, this study did not appear to involve blinding or randomisation. It appeared to record a greater decrease in the use of other painkillers for the treatment group but did not appear to show the baseline levels of such use. The measures of results in the study were made after two and three months of intervention. It was expressly a “pilot study”.

The study entitled “Efficacy and safety of Meriva®, a curcumin-phosphatidylcholine complex during extended administration in osteoarthritis patients” (“Belcaro 2010 #2 attached) involved more subjects than Belcaro 2010 #1, also with osteoarthritis, and a range of outcome measures including walking performance on a treadmill and measures of inflammatory markers in blood. It measured results after eight months of intervention. This study was of limited weight for the same reasons as Belcaro 2010 #1.

The study entitled “Comparative absorption of a standardized curcuminoid mixture and its lecithin formulation” (Cuomo 2011 attached) included one author associated with the manufacturer of the Meriva ingredient. It involved a very small number of subjects but nevertheless appeared to be modest preliminary evidence that the Meriva ingredient, taken orally, would increase plasma levels of curcuminoids more than a “corresponding unformulated mixture of curcuminoids”. However, there was no evidence before the Panel that the “corresponding unformulated mixture of curcuminoids” used in the study was representative of other products containing curcumin in the Australian market.

The Panel noted that it did not necessarily follow from increased bioavailability that there would be a “much more potent benefit” or that the relative bioavailability would “increase the efficacy” of the advertised product. The Panel also noted that the material before the Panel did not appear to substantiate the claim that the mechanism by which bioavailability was increased (assuming it was increased) was “allowing the entry of the curcumin molecule into the cell, via its phospholipid membrane”.

Alleged breaches of the Therapeutic Goods Advertising Code (No.2) 20186 and the Therapeutic Goods Act 19897:

Claims 1 & 2 imply that other brands are less effectual or ineffectual; a breach of the Code s.9(b) & 9(c).

Claim 2 (as the CRP previously noted) is also a breach of the Code s.9(a), 9(b) & 15(2)(a) & 15(2)(b).

Claim 3 is a breach of the Code s.9(a) & 9(b).

Claim 4 "Potent relief" is not in keeping with the modest effect found in the clinical trials (which have the limitations described above); a breach of the Code s.9(a) & 9(b).

Claim 5 & 7 "painful joints" & "swollen joints" are unqualified; a breach s.9(d); "Product presentation must only refer to mild joint symptoms" (ARTG Public Summary attached); also a breach of the Act .s22B.

Claim 6 Testimonials. These need verification to ensure they do not breach s.17(2).

4 https://www.amazon.com.au/Australian-NaturalCare-Curcumin-Anti-Inflammatory-Reliever/dp/B07CLLWLK4 5 https://www.jointhealthmagazine.com/australian-naturalcare-curcumin-review.html 6 https://www.legislation.gov.au/Details/F2018L01524 7 https://www.legislation.gov.au/Details/C2019C00066



https://www.legislation.gov.au/Details/F2018L01524

https://www.legislation.gov.au/Details/C2019C00066


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Penalties to be applied:

Given the prior offence and the ongoing breach of the Act and Code I suggest that the maximum civil penalties available under s.22B of the Act be applied: (a) for an individual—5,000 penalty units and (b) for a body corporate—50,000 penalty units (a Commonwealth penalty point is currently valued at $210).

Sincerely --- Dr Ken Harvey

MB BS, FRCPA, AM Associate Professor Public Health and Preventive Medicine Monash University Level 1, 553 St Kilda Rd Melbourne VIC 3004 M: +61 419181910 E: [email protected] W: monash.edu President, Friends of Science in Medicine W: scienceinmedicine.org.au Director, Medreach Pty Ltd W: medreach.com.au 1 October 2019

Screen shots: (30/09/2019)


mailto:[email protected]

http://monash.edu/



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https://www.amazon.com.au/Australian-NaturalCare-Curcumin-Anti-Inflammatory-

Reliever/dp/B07CLLWLK4





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Public Summary Summary for ARTG Entry: 202390 Curcumin

ARTG entry for Medicine Listed

Sponsor Australian Naturalcare Products Pty Ltd

Postal Address PO Box 946,NORTH RYDE BC, NSW, 1670 Australia

ARTG Start Date 26/10/2012

Product category Medicine

Status Active

Approval area Listed Medicines

Conditions

Colouring agents used in listed medicine for ingestion, other than those listed for export only under section 25 of the Act, shall be only those included in the list of 'Colourings permitted in medicines for oral use'.

The sponsor shall keep records relating to this listed medicine as are necessary to: (a) Expedite recall if necessary of any batch of the listed medicine, (b) Identify the manufacturer(s) of each batch of the listed medicine. Where any part of or step in manufacture in Australia of the listed medicine is sub-contracted to a third party who is not the sponsor, copies of relevant Good Manufacturing Practice agreements relation to such manufacture shall be kept.

The sponsor shall retain records of the distribution of the listed medicine for a period of five years and shall provide the records or copies of the records to the Complementary Medicines Branch, Therapeutic Goods Administration, upon request.

The sponsor of the listed medicine must not, by any means, intentionally or recklessly advertise the medicine for an indication other than those accepted in relation to the inclusion of the medicine in the Register.

All reports of adverse reactions or similar experiences associated with the use or administration of the listed medicine shall be notified to the Head, Officeof Product Review, Therapeutic Goods Administration, as soon as practicable after the sponsor of the goods becomes aware of those reports. Sponsors of listed medicines must retain records of such reports for a period of not less than 18 months from the day the Head, Office of Product Review is notifiedof the report or reports.

The sponsor shall not supply the listed medicine after the expiry date of the goods.

Where a listed medicine is distributed overseas as well as in Australia, product recall or any other regulatory action taken in relation to the medicine outside Australia which has or may have relevance to the quality, safety or efficacy of the goods distributed in Australia, must be notified to the National Manager Therapeutic Goods Administration, immediately the action or information is known to the sponsor.

Products

1. Curcumin

Product Type Single Medicine Product Effective date 3/05/2019

Permitted Indications

Antioxidant/Reduce free radicals formed in the body

Helps reduce/decrease free radical damage to body cells

Anti-inflammatory/relieve inflammation

Decrease/reduce/relieve symptoms of mild arthritis/mild osteoarthritisLinked indication - Decrease/reduce/relieve mild joint stiffnessLinked indication - Maintain/support joint mobility/flexibilityLinked indication - Decrease/reduce/relieve mild joint pain/sorenessLinked indication - Decrease/reduce/relieve mild joint aches and painsLinked indication - Decrease/reduce/relieve mild joint inflammation/swelling

Indication Requirements

Product presentation must not imply or refer to bone disease or disorders e.g. rheumatoid arthritis, juvenile arthritis, debilitating osteoarthritis, osteoporosis.

Label statement: If symptoms persist, talk to your health professional.

Product presentation must only refer to mild joint symptoms.

Standard Indications

No Standard Indications included on Record

Specific Indications

Warnings

If symptoms persist consult your healthcare practitioner (or words to that effect).

Additional Product information

Public Summ

ary

Page 1 of 2 Produced at 01.10.2019 at 08:25:15 AESTThis is not an ARTG Certificate document.The onus is on the reader to verify the current accuracy of the information on the document subsequent to the date shown. Visit www.tga.gov.au for contact information

Pack Size/Poison information

Pack Size Poison Schedule

Components

1. Formulation 1

Dosage Form Tablet, film coated

Route of Administration Oral Visual Identification

Active Ingredients

curcumin 90 mg

© Commonwealth of Australia.This work is copyright.You are not permitted to re-transmit, distribute or commercialise the material without obtaining prior

written approval from the Commonwealth.Further details can be found at http://www.tga.gov.au/about/website-copyright.htm.

Public Summ

ary

Page 2 of 2 Produced at 01.10.2019 at 08:25:15 AESTThis is not an ARTG Certificate document.The onus is on the reader to verify the current accuracy of the information on the document subsequent to the date shown. Visit www.tga.gov.au for contact information

http://www.tga.gov.au/about/website-copyright.htm

V O L U M E 5 2 · S U P P L . 1 T O N o . 2 · J U N E 2 0 1 0

PRODUCT-EVALUATION REGISTRY OF MERIVA®,A CURCUMIN-PHOSPHATIDYLCHOLINE COMPLEX,

FOR THE COMPLEMENTARY MANAGEMENTOF OSTEOARTHRITIS

G. BELCARO, M. R. CESARONE, M. DUGALL, L. PELLEGRINI, A. LEDDA, M. G. GROSSI, S. TOGNI, G. APPENDINO

PANMINERVA MED 2010;52(Suppl. 1 to No. 1):55-62

Product-evaluation registry of Meriva®,a curcumin-phosphatidylcholine complex,

for the complementary management of osteoarthritis

Aim. A proprietary complex of curcumin with soy phos-phatidylcholine (Meriva®, Indena SpA) was evaluated in a reg-istry study to define its efficacy in 50 patients with osteoarthri-tis (OA) at dosages corresponding to 200 mg curcumin perdiem. Methods. OA signs/symptoms were evaluated by the WOMACscores. Mobility was studied by walking performance (tread-mill), and inflammatory status was assessed by measurementsof C-reactive protein (CRP). Results. After three months of treatment, the global WOMACscore decreased by 58% (P<0.05), walking distance in the tread-mill test was prolonged from 76 m to 332 m (P<0.05), and CRPlevels decreased from 168 ± 18 to 11.3 ±. 4.1 mg/L in the sub-population with high CRP. In comparison, the control groupexperienced only a modest improvement in these parameters(2% in the WOMAC score, from 82 m to 129 m in the treadmilltest, and from 175 ± 12.3 to 112 ± 22.2 mg/L in the CRP plas-ma concentration), while the treatment costs (use of anti-inflam-matory drugs, treatment and hospitalization) were reducedsignificantly in the treatment group.Conclusion. These results show that Meriva® is clinically effectivein the management and treatment of osteoarthritis and suggeststhat the increased stability and better absorption of curcumininduced by complexation with phospholipids has clinical rele-vance and sets the stage for larger and more prolonged studies.

KEY WORDS: Osteoarthritis – Curcumin - Meriva® - WOMAC –Joints – Pain - Anti-inflammatory drugs.

Over 2,500 preclinical investigations have validat-ed the diarylheptanoid curcumin, the yellow pig-

ment of turmeric (Curcuma longa L.), as a potential

agent to treat chronic diseases such as inflammation,cancer, and Alzheimer’s disease.1 These pathologiesare currently at the forefront of biomedical researchbecause of their large incidence, suboptimal treatment,and growing financial burden to society. However, theclinical translation of these research findings has sofar been hampered by the chemical instability of cur-cumin at intestinal pH values, by its low water solubilityand poor oral bioavailability, and by its quick conju-gation and excretion. Curcumin undergoes fast (t1/2<10 min) retro-Claisen hydrolytic cleavage at pH 7,2 itsoverall oral absorption is dismally low, barely over-coming 50 ng/mL after administration of the clinical-ly unrealistic dosage of 12 g/day,3 and only phase IImetabolites (sulfates and glucuronides) have been con-sistently detected in biological fluids (plasma, urine)after oral administration in humans.3 Conjugation canstabilize curcumin in plasma, but its hydrolytical insta-bility and insolubility, poor absorption, and quick elim-ination generate unfavorable conditions for therapeu-tic use. As a result, several human studies on curcum-in have failed,4 and the important clinical potential ofthis compound is still substantially untapped.5-11

To improve the poor oral pharmacokinetics of cur-cumin, two distinct strategies have been pursued. Thefirst one is the co-administration of compounds that

1Irvine3 LabsDepartment of Biomedical Sciences

Chieti-Pescara University, Pescara, Italy2Indena S.p.A., Milano, Italy

3Dipartimento di Scienze ChimicheAlimentari, Farmaceutiche e Farmacologiche

Università del Piemonte Orientale, Novara, Italy

Conflict of interest.—The Authors S. Togni and G. Appendino are mana-gers of Indena S.p.A., producer and distributor of the product Meriva.

Corresponding author: G. Appendino, Università del Piemonte Orientale,Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche eFarmacologiche, Via Bovio 6, 28100 Novara, Italy.E-mail: [email protected]

G. BELCARO 1, M. R. CESARONE 1, M. DUGALL 1, L. PELLEGRINI 1, A. LEDDA 1,M. G. GROSSI 1, S. TOGNI 2, G. APPENDINO 3

Vol. 52 - Suppl. 1 to No. 2 PANMINERVA MEDICA 55

BELCARO PRODUCT-EVALUATION REGISTRY OF MERIVA®

56 PANMINERVA MEDICA June 2010

interfere with its metabolic process, such as the alka-loid piperine, a potent inhibitor of hepatic and intesti-nal transformations of xenobiotics.6 However, sincecurcumin can already interfere with drug metabolismby inhibiting several classes of cytochromes,4 severereactions might occur when the curcumin-piperineassociation is administered with other drugs.4

Furthermore, although an increased absorption hasbeen shown for the curcumin-piperine combination,7 itsclinical efficacy and safety are still largely unknown.The second strategy to improve the oral absorption ofcurcumin is based on its tendency to form non-covalentadducts with phospholipids, host-guest complexes withcyclodextrins, and liposome inclusion products.3-9

However, these formulation strategies intended toimprove bioavailability also need clinical validation.

Curcumin has a high affinity for biological mem-branes and has the ability to rapidly penetrate themand form dimeric complexes that span the extra- tointracellular-length.3-8 As a poorly water soluble phe-nolic, curcumin can form non-covalent links withphospholipids, and in particular phosphatidylcholine(PC).9-12 The formation of these complexes couldimprove the curcumin pharmacokinetics by shieldingcurcumin from retro-Claisen hydrolysis and stabiliz-ing it at intestinal pH values. Furthermore, capitaliz-ing on the fast exchange of PC between biologicalmembranes and the interstitial fluid, PC could alsochaperone curcumin into cell membranes,9-12 where,thanks to membrane fluidity, the PC-curcumin complexmay next move from the luminal to the visceral side ofenteric cells. In this way, a substantial increase ofabsorption could be foreseen.3, 9-12

Curcumin as PC complex (Meriva®) has shownpromising results in terms of hydrolytical stability 10

and oral absorption.11 Within its many possible clini-cal indications, curcumin could be particularly bene-ficial1 in the management of osteoarthritis (OA), sinceit can affect most molecular processes involved in thiscondition.12 The long-term side effects and costs ofCOX2-inhibitors have indicated the need for a com-plementary treatment in osteoarthritis,13-15 promptinga registry study on Meriva® to evaluate and define itseffects on osteoarthritic pain and its associated phys-ical impairment.

Materials and methods

Two groups of subjects with symptomatic OA weredefined: Group A was managed using the “best avail-

able treatment” as defined by patient’s GP and by spe-cialists; and Group B was managed using the “bestavailable treatment” as above in association withMeriva® administered as a food supplement.

A total of 50 patients with osteoarthritis (confirmedby x-ray) were included in this study. Patients wererecruited from the San Valentino Vascular ScreeningProject. For clinical homogeneity, the main localiza-tion of OA in these subjects and the source of most oftheir signs and symptoms were in either or both knees.Patients were informed about the aim of the study andmanagement procedure and gave oral informed con-sent.

Meriva® (distributed by Indena SpA, Italy) is alreadyincluded as an ingredient in over-the-counter foodsupplements marketed in the USA and Europe. In thisstudy, a finished form in capsules prepared by ThorneResearch Inc. (Dover, Idaho, USA) was used at adosage of 1g Meriva® complex per day (correspond-ing to 200 mg curcumin per day). Curcumin 16-22 hasbeen used in several clinical and preventive applicationswithout side effects.

Inclusion criteria

Primary osteoarthritis in one or both knees was diag-nosed by x-ray investigation. Subjects had mild tomoderate pain not adequately or completely controlledwith anti-inflammatory drugs. They had to be able toperform the treadmill walking test and to understandall questions from the WOMAC questionnaire.

Exclusion criteria

Exclusion criteria were cardiovascular disease requir-ing drug treatment, diabetes, BMI>25, severe metabolicdisorders, surgery or arthroscopy within the 3 monthsbefore inclusion, and any oncological condition orsevere bone or joint deformation or condition makingthe patient unable to walk.

Evaluation of signs/symptoms of osteoarthritis

The questionnaire developed by the Western Ontarioand McMaster Universities was applied to describeand rate the symptoms of OA. The questionnaire givesscores for the diverse symptoms of OA (WOMACscores).13-15 The status of OA signs/symptoms wasevaluated by the investigator together with the patientat inclusion and after at least 3 months of treatment.


PRODUCT-EVALUATION REGISTRY OF MERIVA® BELCARO

Table I shows the types of responses and the attributionof the WOMAC score.

Evaluation of physical performance

Patients were able to walk on a treadmill (as testedin two tutorial tests). At inclusion and after 3 monthsperformance was evaluated by treadmill at a speed of3 km/h and an inclination of 10%. The total distancethat could be covered without pain was recorded.

Evaluation of associated treatments needed to man-age osteoarthritis

A diary was kept to record the use of any other drugprescribed by the patient’s GP, the use of which wasfree (with a warning not to use excessive amounts).

Evaluation of costs and side effectsThe costs of treatment and other costs occurring

during the trial period (including work disruption andhospital admission) were recorded in a file specifi-cally designated for costs.

Evaluation of edema

Lower limb edema 23-25 was evaluated using an ede-ma score (0-4) as previously defined:

0) no edema; 1) distal, below-knee minimal edema visible only

after prolonged standing (all day); not present everyday; completely resolving after rest; no other symp-toms;

2) below-knee edema visible only after long stand-ing (>3 hours); disappearing after rest and leg eleva-tions; minimal symptoms. Present every day;

3) edema present every day; only partially regress-ing with night rest; important symptoms; requirespharmacological treatment;

4) edema present day and night not reversible with-

out pharmacological treatment. Impairs daily activities.Often extending proximal to knees and visible also inother body parts (i.e.hands).

Edema was present at inclusion in most patients(88%) as a consequence of reduced activity associat-ed to pain and walking impairment.

Evaluation of plasma C-reactive protein

C reactive protein (CRP) 26 was evaluated by lasernephelometry. Diagnostic use CRP is used mainly asa marker of inflammation. Apart from liver failure,there are few known factors that interfere with CRPproduction.16 Measuring C-reactive protein values isuseful in determining disease progression or the effec-tiveness of treatments.

Reference ranges for blood tests

CRP was quantified with laser nephelometry. Thetest gives results in 30 minutes and is sensitive enoughto detect 0.04 mg/L. CRP concentration in healthysubjects is usually lower than 10 mg/L, slightly increas-ing with age. Higher levels are found in late stages ofpregnancy, mild inflammation and viral infections(10–40 mg/L), active inflammation, bacterial infec-tion (40-200 mg/L), and severe bacterial infectionsand burns (>200 mg/L). Viral infections tend to give alower CRP level than bacterial infection. In our pop-ulation normal reference ranges for blood tests wereless than 5-6mg/L.

Standards

All test were performed according to our standardsdefined in several publications. 27, 28

Statistical analysis

The results were evaluated using analysis of variance(ANOVA with the Bonferroni correction) and the non-parametric Mann-Whitney U test.

TABLE I.—WOMAC scoring and interpretation. Each response is asso-ciated with a conventional score expressed in points, as follows.

Response Points

None 1Slight 2Moderate 3Severe 4Extreme 5

TABLE II.—Main patient characteristics.

Response Points

Age 44.4 SD 7.2 45.3 SD 8.6range 40-53 range 44-53

Male / female ratio 12:11 13:12

BMI 23.6; 1.4 23.7;1.1



At least 50 subjects should have been observed in thestudy (with at least 20 completing the study/observa-tion period in each group). This number was chosen toovercome spontaneous or intra-individual variationsand to overcome inter-individual variability. A con-dition such as OA may have periods of high-levelsigns/symptoms followed by other periods of low-lev-el signs/symptoms. These variations may be due toseveral factors including individual inflammatory sit-uations as well as environmental and climate changes,working or standing patterns, etc.

Results

Table II shows details of the patients. The treatmentand control groups were comparable for age, sex dis-

tribution, and presence and intensity of their signs/symptoms. Routine hematochemical tests (hematocrit,hepatic and renal function tests, including blood andurinary Ca) were within normal limits at inclusion andat the end of the study.

Table III shows details of the variations in score foreach WOMAC item. There was a significant decreaseat 2 months (P<0.05) with a further, significant decreaseat 3 months (P<0.05). Pain, stiffness, and physicalfunction were all positively affected by treatment(P<0.05). In treatment patients the WOMAC score(median 83.4 at inclusion vs. 80.6 in controls)decreased to 41.1 (vs. 75.2 in controls) at 2 monthsand was down to 34.8 at 3 months (vs. 78.8 in controls)(P<0.05).

Table IV shows performance concerning social func-

TABLE III.—Details of the variations in score for each WOMAC item (score at inclusion, with SD, in comparison with the score at 2 AND 3months of treatment). The comparative decrease in controls was significantly lower with minimal, non-significant variations between twoand three months.

Pain Inclusion 2 months P1 P2 3 months

1) walking T 3.1;1 C 3.2;0.8 T 2;0.8 C 3.3;1.2 S ns T 2.1;0.4 C 3.2;0.92) stair climbing 3.4;1.1 3.1;1.1 1.5;1.1 2.1;0.8 S S 1.5;0.6 2.2;13) nocturnal 3.3;1.1 3.2;1 1.4;0.6 2.1;1.1 S S 1.1;0.4* 2.2;0.84) rest 3.6;1 3.1;1.1 1.6;1.2 2.6;1.2 S S 1.5;1 2.5;0.45) weight bearing 3.3;1.2 3.4;1 2.6;1.1 3.4;1.1 S ns 2.3;0.4* 3.2;0.4

16.9 16 9,1 13.4 S ns 8.5*# 13.3 ns4Stiffness:1) morning stiffness 3.8;1.1 3.6;1.2 2.2;1.2 3.4;1 S ns 2.1;1 3.5;1.12) stiffness late in day 3.6;1.1 3.2;1.3 1.4;0.8 3.1;2 S ns 1.2;0.5* 3.2;1

7.4 6.8 3.6 6.5 3.3*# 6.7 nsPhysical function:1) descending stairs 3.2;1 3.3;1.1 1.8;1 2.9;1.1 S S 1.1;0.3* 2.8;12) ascending stairs 3.6;1.1 3.4;1.2 1.1;1.1 2.9;1.1 S S 1.05;0.6 3;1.13) rising from sitting 3.7;1.2 3.5;1.2 1.3;0.9 3.2;1.1 S S 1.23;0.5 3.3;14) standing 3.6;1.1 3.5;1.1 1.5;1 3;1.4 S S 1.4;0.4 3.2;15) bending to floor 3.8;1.2 3.7;1.3 2;1.2 3;1.1 S S 2.1;0.3 3.2;16) walking on flat 3.7;1.1 3.3;1.2 1.6;0.9 3.4;1.2 S ns 1.5;0.4 3.3;0.87) getting in/out (car) 3.9;1 3.6;1.1 1.1;0.4 2.8;1 S S 1;0.4 2.9;18) going shopping 3.7;1.2 3.8;1.2 1.4;0.3 3.1;1.1 S S 1.2;0.4 3.6;1.19) putting on socks 3.8;1 3.9;1.1 2;1.2 3.1;1.2 S S 1.5;0.4* 3.2;1

10) rising from bed 3.9;1.3 3.7;1.2 2.8;1.2 3.3;1.1 S S 2.5;1 3.4;1.311) taking off socks 3.7;1.1 3.8;1.2 1.5;0.7 3.5;1.4 S S 1.1;0.5* 3.7;1.112) lying in bed 2.7;0.5 2.7;1 1.1;1.1 2.6;1.1 S ns 1;0.3 2.8;0.413) sitting (a) 2.8;1.1 2.7;1.3 1.3;0.8 2.8;1.1 S ns 1.1;0.3 2.9;0.914) sitting (b) 2.4;1 2.5;1.3 1.2;1.1 2;0.7 S S 1.1;0.5 2.5;0.415) getting on/off toilet 3.3;1.1 3.3;1.2 2;0.5 3.3;1.1 S ns 1.3;0.3* 3.6;116) heavy house duties 3.5;1.1 3.4;0.5 2.1;1.2 3.5;1.2 S ns 1.7;1* 3.8;0.417) light house duties 3.8;1 3.7;0.7 1.8;0.4 3.6;1.4 S ns 1.1;0.5* 3.8;0.8

Total 59.1 57.8 28.4 55.3 22.98*# 58.84 ns

WOMAC Score 83.4 80.6 41.1 75.2 34.8*# 78.8 ns

Interpretation of the table: the first numbers (T) indicate the score relative to patients using active treatment (AVERAGE AND SD); C-column numbers indicate con-trols. P1: significance: inclusion value VS after (2 months) value. P2: significance: treatment vs controls at 2 months. Results at 3 months: *difference between 2 and 3months; # difference between groups.



tion and the status of emotional function. These aspectswere also improved in treatment patients as the scoredecreased at 2 months from a median value of 34.9(vs 34.1 in controls) down to 13.4 (P<0.05) in com-parison with 37.9 in controls. At 3 months there was afurther decrease down to a median value of 10.5(P<0.05) in Meriva® patients vs. 35.9 (not significant)in controls.

Table V shows the results of the exercise (treadmill)

tests (median and range). The treadmill (at a speed of3 km/hour, with a 10% inclination) indicates animprovement of 201% of the initial distance (P<0.05)at 2 months (vs. a 26% increase in controls) and a fur-ther increase (+44% at three months) for a total of336% compared to value at inclusion vs. a total increaseof 30.8% in controls (the difference between the twoincreases is significant; p<0.05). Meriva® treatmentproduced an increase 5.568 times greater than “the besttreatment” when considering physical performance.

Edema was on average 2.81(sd 0.33) in Meriva®

patients in comparison with 2.76(0.4) in controls. At3 months it was reduced in both groups: 1.2 (0.3) inMeriva® patients compared with 2.13 (p<0.05 betweengroups) in controls.

Table VI shows the variations in CRP in a subgroup

TABLE IV.—Performance of social functions and the status of emotional function.

Social function Inclusion 2 months P1 P2 3 months

Negative alterations in:1) in leisure activities T 3.3;1 C 3.4;2) T 2.2;1 C 3.2;2 S S T 2.1;0.3 C 3.5;12) community events 3.5;1.1 3.2;1.1 2.2;1 3.3;1.1 S ns 2;0.1 3.2;1.13) church attendance 3.5;1.1 3.6;1 1.8;1.1 3.5;1.1 S ns 1.1;0.5* 3.6;14) with spouse 3.5;1 3.6;1.3 1;1.2 2.1;1.2 S S 1.1;0.6 2.3;1.15) with family 3.6;1.1 3.5;1.2 1.4;1.1 3.3;1.1 S S 1.3;0.4 3.2;16) with friends 3.4;0.8 3.3;0.7 1.4;0.8 3.3;1.2 S ns 1.1;0.3 3.6;1.27) with others 3.7;1 2.1;1.4 1.3;0.5 3.2;0.9 S S 1.2;0.3 3.3;1Total 24,5 22.8 11.3 21.9 * ** 9.9 22.7

Emotional function:1) anxiety 3.7;1.1 3.6;1 1.1;0.4 3.4;1 S ns 1;0.3 3.5;1.12) irritability 3.8;1.1 3.7;1.2 1.3;0.4 3.6;1.1 S ns 1.1;0.7 3.4;1.23) frustration 3.5;1.1 3.6;1.2 1.1;0.2 3.7;1.3 S ns 1;0.3 3.6;0.44) depression 3.3;1 3.3;1.2 1.4;0.8 3.1;0.8 S ns 1.1;0.4* 3.3;15) relaxation 2.8;0.3 2.7;0.4 1.1;0.3 2.9;1 S ns 1;0.3 3.4;36) insomnia 2.9;1.1 2.8;1 1.1;0.4 2.8;1.1 S ns 1.1;0.2 3.1;0.77) boredom 3.6;1 3.3;1.2 1.1;0.3 3.3;1.3 S ns 1;0.2 3.4;0.4 8) loneliness 3.6;1.2 3.6;1 1.2;0.4 3.4;0.5 S ns 1.1;0.2 4.1;19) stress 3.9;1 3.8;1.1 2;1.1 3.9;0.6 S ns 1.2;0.4* 4.3;1.1

10) well-being# 3.8;1 3.7;1.1 1;0.3 3.9;1.2 S ns 0.9;0.4 3.8;0.8Total 34.9 34.1 13.4 37.9 * ** 10.5*# 35.9

#Indicates alterations in well being. Score = SUM (points for relevant items). Average score = (total score) / (number of items). Interpretation: minimum total score:0; maximum total score: 96; minimum pain subscore: 0; maximum pain subscore: 20; minimum stiffness subscore: 0; maximum stiffness subscore: 8; minimum physi-cal function subscore: 0; maximum physical function subscore: 68.

TABLE V.—Results of the exercise tests (median and range). The tread-mill test was performed with the treadmill at the speed of 3 km/hour,with an inclination of 10%.

Treatment Controls Time Groupsdiffer. differ.

Inclusion76 m (15-188) 82m (19-210) NS *

2 months229 m (106->400) 104m (38-336) P<0.05 *(+201%)# (+26.8%) #

3 months331 (112- >400) 129 (44-383) P<0.05 *+44% vs +24% vs2-month data 2-month data

Difference before-after#.

TABLE VI.—CRP variations.

Treatment Controls

Inclusion 168 (SD18)mg/Lt 175 (12.3)

8 weeks 10.2 (SD 3.51)* 132 (18.2)

12 weeks 1.31 (SD 4.11) 112 (SD22.2)

* p <0.05 (Mann Whitney).



of subjects treated with Meriva®. Twelve patients in thetreatment group (age 43.3;5.1; 8 females) and 11 (age44.2;4.8; 6 females) in controls had increased CRP atinclusion. The average decrease in CRP values of thesesubgroups of patients at inclusion and at 8-12 weeksis shown in the table. The decrease in CRP was sig-nificant in both groups at 8 weeks with a limited, notsignificant further decrease at 12 weeks; the decreasein CRP was significantly greater in the Meriva® group(P<0.05).

Table VII shows other observations concerning sev-eral aspects of the treatment of OA. The decrease inNSAIDs and painkillers during the study was, globally,63% in the treatment group vs. 12% in controls(P<0.05).

The decrease in gastrointestinal complications was38% in Meriva® patients vs. 15% in controls (P<0.05).The decrease in the use of other drugs/treatment was38% in treatment subjects vs. 11% in controls (P<0.05).The global decrease in management costs was 49%in Meriva® patients compared to a decrease of 3% (notsignificant) in controls (difference between groups:P<0.05%).

The median decrease in distal edema was 65% vs.5% in controls (P<0.05). The presence of edema inthese patients is mainly associated with a combina-tion of inflammation, forced reduced activity (causedby pain on motion), and relative impaired limb mobil-ity altering the venous pump function and the venousreturn, particularly of the lower limbs.

Hospital admissions, consultation and radiological,imaging or instrumental tests decreased (median) 38%(P<0.05) in comparison with a 6% (not significant)decrease in controls (difference between groups:P<0.05).

The specific decrease in non-drug treatment (i.e.physiotherapy) costs due to different types of com-

plications, new consultations or blood tests was 44%(P<0.025) in Meriva® patients vs. 8% (not significant)in controls (the difference between the two groupswas significant: P<0.05).

Discussion

Curcumin is one of the most extensively investi-gated products of natural origin. Its broad spectrumof bioactivity and low oral toxicity have expanded itsuse to several clinical conditions.1, 12 Many potentialbeneficial properties of the natural product have notproduced effective clinical results because curcuminshows a poor water solubility and stability, a low andunpredictable oral absorption, and a quick metabo-lism. All these problems have hampered the clinicaldevelopment of curcumin as a drug as well as an effi-cacious health food ingredient.

The clinical trials of curcumin reported so far arecharacterized by a small number (<50) of participants,large doses (>1 g) of the natural product 4 and, often,controversial results.

To overcome the problematic use and dosage of thenatural product, a phospholipid complex (Meriva®)was developed by combining curcumin and phos-phatidylcholine in a 1:2 ratio.9 Complexation withphospholipids led to an improved aqueous stabilityand oral absorption of curcumin.10, 11

The management of OA is one of the best clinicalpossibilities for the use of curcumin in the light of eth-no-pharmacological data and its mechanisms of action.Thus, turmeric is used in Asian medicine to treatinflammation and joint pain; curcumin protects chon-drocytes from the catabolic action of inflammatorycytokines (IL-1beta, AP-1, NF-kB) and enzymes

TABLE VII.—Other observations during the study (median).

Meriva® Controls

1) Decrease in use of nsaids/painkillers 63% 13%2) Decrease in gastrointestinal complications 69% 15%3) Decrease in use of other drugs/treatments 38% 11%4) Decrease in management costs 49% 3%5) Distal edema decrease 65% 5%6) Hospital admissions, consultation and tests decrease 38% 6%7) Specific decrease in non-drug treatment (i.e. physiotherapy),

costs due to different complications, new consultations, test et cet. 44% 8%



(MMP-3, collagenases) and may block proteoglycanedegradation.12

Curcumin has shown high potency in animal mod-els of rheumatoid arthritis 18 and in a clinical trial thatcompared its activity with that of the non-steroidanti-inflammatory drug phenylbutazone.19 This studywas the first indication of its clinical efficacy inOA.20

Meriva® shows a marked improvement in hydrolyt-ic stability and oral absorption in comparison withnon-complexed curcumin.9-11

In this product-evaluation registry, a dosage (200mg) much lower than those employed in previous orcurrent clinical studies (usually greater than 1g/day)was employed.20

This dosage was only slightly higher than the dietaryintake of curcumin (up to 2 mg/Kg die) in the Indiandiet,20 where turmeric is mainly consumed in an oilymatrix favoring the absorption of curcumin.3

Meriva® (with curcumin embedded in a phospholipidcomplex) is a comparable molecular translation of thishealthy dietary habit.

This product evaluation registry in patients with OAused the WOMAC 29 score (now considered a stan-dard of evaluation for these clinical problems) for theevaluation of physical performance, which is the mostbothersome problem for most patients and leads to aninability to take care of themselves (as, for example, theinability to shop alone). Some secondary outcomes(i.e. consumption of NSAID, management costs, andoverall quality of life) are less predictable and mayreflect the social context and the possibility offeredby healthcare providers.

In this pilot registry a very significant decreaseof WOMAC scores was observed, which was asso-ciated with an improvement in walking. These resultssuggest that Meriva® can be used as a complemen-tary treatment in the management of OA, particu-larly to relieve pain and increase the mobility ofpatients. Meriva® improves their quality of life andphysical function, but it may also produce a signif-icant decrease in treatment costs. The reduced use ofNSAID, physical treatments and hospitalization wasobserved in the treatment group. Curcumin is gen-erally a gastroprotective agent19 that might protectfrom the adverse gastric side effects of many anti-inflammatory drugs.

At this stage, it is difficult to define whether theimproved physical performance observed with Meriva®

is due to a better control of inflammation, pain andrigidity, or to a direct action on muscular function. Inthe subpopulation with higher CRP, there was adecrease from abnormally increased values (168 ± 18mg/L) to almost normality (11.3 ±. 4.1 mg/L), sug-gesting a possible important decrease of inflamma-tion by Meriva®.

Conclusions

These results suggest that Meriva® is effective inOA as a complementary management tool, and thestudy provides a clinical validation of the effective-ness of phospholipid complexation to improve thehydrolytic instability and poor oral absorption of cur-cumin.

References

1. Aggarwal BB, Sung B. Pharmacological basis for the role of curcu-min in chronic diseases: an age-old spice with modern targets. TrendsPharmacol Sci 2009;30:85-94.

2. Wang Y-J, Pan M-H, Cheng, A-L, Lin, L-I, Ho Y-S, Hsieh C-Y, Lin J-K. Stability of curcumin in buffer solutions and characterization of itsdegradation products. J Phar Biomed Anal 1997;15:1867-76.

3. Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB.Bioavailability of curcumin: Problems and promises. Mol Pharm2007;4:807-18.

4. Mancuso C, Barone E. Curcumin in clinical practice: myth or reality?Trends Pharmaco Sci 2009;30:333-4.

5. Goel A, Kunnumakkara, AJ, Aggarwal BB. Curcumin as “curecu-min”: From kitchen to clinic. Biochem Pharmacol 2008;75:787-809.

6. Srinivasan K. Black pepper and its pungent principle-piperine: areview of diverse physiological effects. Crit Rev Food Sci Nut2007;47:735-48.

7. Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS.Influence of piperine on the pharmacokinetics of curcumin in ani-mals and human volunteers. Planta Med 1998;64:353-6.

8. Barry J, Fritz M, Brender JR, Smith PES, Lee D-K, Ramamoorthy, A.Determining the effects of lipophilic drugs on membrane structure bysolid-state NMR spectroscopy: the case of the antioxidant curcumin.J Am Chem Soc 2009;131:4490-8.

9. a) Kidd PM. Bioavailability and activity of phytosome complexesfrom botanical polyphenols: The silymarin, curcumin, green tea andgrape seed extracts. Alt Med Rev 2009;14: 226-46. b) Semalty A,Semalty M, Rawat MA, Franceschi F. Supramolecular phospholi-pids-polyphenolics interactions: The Phytosome® strategy to impro-ve the bioavailability of phytochemicals. Fitoterapia 2009. In press.

10. Giori A, Franceschi F. Unpublished: Indena: investigator’s brochure:data on file. 2005.

11. Marczylo TH, Vershoyle RD, Cooke DN, Morazzoni P, Steward WP,Gesher AJ. Comparison of systemic availability of curcumin withthat of curcumin formulated with phosphatidylcholine. CancerChemother Pharmacol 2007;60:171-7.

12. Henrotin,Y, Clutterbuck AL, Allaway D, Lodwig EM, Harris PM,Mathy-Harterty M, et al. Biological actions of curcumin on articularchondrocytes. Osteoarthritis Cartilage 2010;18:141-9.



13. Read SJ, Dray A. Osteoarthritic pain: a review of current, theoreticaland emerging therapeutics. Expert Opin Investig Drugs 2008;17: 619-40.

14. Söderman P. On the validity of the results from the Swedish NationalTotal Hip Arthroplasty register. Acta Orthop Scand Suppl 2000;71:1-33.

15. Baron G, Tubach, F, Ravaud P, Logeart I, Dougados M. Validation ofa short form of the Western Ontario and McMaster UniversitiesOsteoarthritic Index function subscale in hip and knee osteoarthritis.Arthritis Rheum 2007;57:633-8.

16. Krishnaswamy K. Traditional Indian spices and their health signifi-cance. Asia Pac J Clin Nutr 2008;17:265-8.

17. Funk JL, Oyarzo JN, Frye JB, Chen G, Lantz RC, Joland SD, et al.Turmeric extracts containing curcuminoids prevent experimentalrheumatoid arthritis. J Nat Prod 2006; 69:351-5.

18. Deodhar SD, Sethi R, Srimal RC. Preliminary studies of antirheu-matic activity of curcumin (diferuloyl methane). Ind J Med Res1980;70:632-4.

19. Jurenka JS. Anti-inflammatory properties of curcumin, a major con-stituent of Curcuma longa: a review of preclinical and clinical resear-ch. Altern Med Rev 2009;14:141-53.

20. Thimayamma VS, Rao P, Radhaiah G. Use of spices and condimentsin the diet of urban and rural families. Ind J Nut Diet 1983;20:153-62.

21. Mahattanadul S, Nakamura T, Panichayupakaranant P, PhdoongsombutN, Tungsinmunkong K, Bouking P. Comparative antiulcer effect of

bisdemethoxycurcumin and curcumin in a gastric ulcer model system.Phytomedicine 2009;16:342-51.

22. DeSanctis MT, Cesarone MR, Incandela L, Belcaro G,Acerbi G. Methodsof evaluation and quantification of microangiopathy in high perfusionmicroangiopathy (chronic venous insufficiency and diabetic microan-giopathy). J Cardiovasc Pharmacol Ther 2002;Suppl 1:S3-6.

23. Cesarone MR, Belcaro G, Nicolaides AN, Arkans E, Laurora G, DeSanctis MT et al. The edema tester in the evaluation of swollen limbsin venous and lymphatic disease. Panminerva Med 1999;41:10-4.

24. Cesarone MR, Laurora G, De Sanctis MT, Steigerwalt R, Belcaro G.Edema tester. Assessment of edema of the legs. Minerva Med 1998;89:309-13.

25. Stuard S, Cesarone MR, Belcaro G, Ledda A, Cornelli U, Di RenzoA et al. Screening nelle farmacie: documento e linee guida 2008. Lostudio clinico NPT. Minerva Cardioangiol 2008;56(5 Suppl):11-20.

26. Thompson D, Pepys MB, Wood SP. The physiological structure ofhuman C-reactive protein and its complex with phosphocholine.Structure 1999;7:69-77.

27. Belcaro G, Nicolaides AN. Noninvasive Investigations In VascularDiseases. Imperial College Press, London; 2001.

28. Belcaro G, Nicolaides AN, Stansby G. The venous Clinic. ImperialCollege Press, London; 2002.

29. Nilsdotter AK, Isaksson F. Patient relevant outcome 7 years after totalhip replacement for OA - a prospective study. BMC MusculoskeletDisord 2010;11:47.

Original Research

Giovanni Appendino-Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Universita del Piemonte Orientale, Novara, Italy. Correspondence address: Universita del Piemonte Orientale, Dipartimento di Scienze Chimiche Alimentari, Farmaceutiche e Farmacologiche, Via Bovio, 6 - 28100 Novara, Italy Email: appendino@pharrn. unipmn.it

Gianni Belcaro- lrvine3 Circulation-Vascular Laboratory, Department of Biomedi· cal Sciences, Chieti-Pescara University, Italy

Maria Rosaria Cesaronelrvine3 Circulation-Vascular Laboratory, Department of Biomedical Sciences, Chieti· Pescara University, Italy

Mark Dugall- lrvine3 Circulation-Vascular Labora· tory, Department of Biomedical Sciences, Chieti·Pescara University, Italy

Luciano Pellegrini - lrvine3 Circulation-Vascular Labora· tory, Department of Biomedi· cal Sciences, Chieti-Pescara University, Italy

Andrea Ledda- lrvine3 Circulation-Vascular Labora· tory, Department of Biomedi· cal Sciences, Chieti·Pescara University, Italy

Maria Giovanna Grossilrvine3 Circulation-Vascular Laboratory, Department of Biomedical Sciences, Chieti· Pescara University, Italy

Stefano Togni- lndena S.p.A., Viale Ortles 12, Milano, Italy

Efficacy and Safety of Meriva®, a Curcumin-phosphatidylcholine Complex, during Extended Administration in Osteoarthritis Patients Gianni Belcaro; Maria Rosaria Cesarone; Mark Dugal!; Luciano Pellegrini; Andrea Ledda;

Maria Giovanna Grossi; Stefano Togni; Giovanni Appendino

Abstract In a previous three-month study of Meriva"', a proprietary curcumin-phosphatidylcholine phytosome complex, decreased joint pain and improvement in joint function were observed in SO osteoarthritis (OA) patients. Since OA is a chronic condition requiring prolonged treatment, the long-term efficacy and safety of Meriva were investigated in a longer (eight months) study involving 100 OA patients. The clinical end points (Western Ontario and McMaster Universities [WOMAC) score, Karnofsky Performance Scale Index, and treadmill walking performance) were complemented by the evaluation of a series of inflammatory markers (interleukin [IL]-1 p, IL-6, soluble CD40 ligand [sCD40LJ, soluble vascular cell adhesion molecule (sVCAM)-1, and erythrocyte sedimentation rate [ESR]). This represents the most ambitious attempt, to date, to evaluate the clinical efficacy and safety of curcumin as an anti-inflammatory agent. Significant improvements of both the clinical and biochemical end points were observed for Meriva compared to the control group. This, coupled with an excellent tolerability, suggests that Meriva is worth considering for the long-term complementary management of osteoarthritis. (A/tern Med Rev 2010;15(4):337-344)

Introduction Curcumin is the yellow pigment of turmeric

(Curcuma longa L.), the most popular spice in Indian cuisine and a major ingredient of curry powders.1 Turmeric has a long history of medicinal use, especially to treat inflammation.2 and many of its traditional uses have been mechanistically validated in cellular systems as well as in animal models of disease. Indeed, with almost 3,000 preclinical investigations, curcumin is one of the best investigated botanical constituents in the biomedical literature.2 These studies have

demonstrated that curcumin acts as a master switch of inflammation by acting at the level of pro-inflammatory enzymes (cyclooxygenases [COX] and lipoxygenases) and inflammatory transcription factors (nuclear factor-kappaB [NF-KB) and signal transducer and activator of transcription 3 [STAT3]) and their genomic expression.3 Most of the beneficial effects of curcumin are suggested by epidemiological studies, supported by studies in animal models, and extrapolated from in vitro studies, but not validated clinically.2 This paradoxical situation is due to the poor stability of curcumin, which is highly unstable at intestinal pH (half-life at pH 7 <10 min),4 and low oral absorption. Plasma concentrations barely reach 50 ng/mL of phase II metabolites (glucuronides and sulfates) after oral administration of dosages as high as 12 g/day.4 Once in the plasma, however, curcumin enjoys a surprising stability and even permeability to tissues hard to reach like the brain.4

Similar to most dietary phenolics, curcumin is sparingly water and lipid soluble. It has polar groups (two phenolic hydroxyls and one enolic hydroxyl) that can interact via hydrogen bonds and polar interactions with a complementary group, like the polar heads of phospholipids.5

•6 Phenolics

show a high affinity for biological membranes and, once complexed with phospholipids, are embedded into a lipid matrix that, while shielding them from hydrolytic degradation, can lead to an increased cellular uptake by capitalizing on the rapid exchange of phospholipids between biological membranes and the extracellular fluids. These principles are the basic tenets of the phytosome strategy to improve the bioavailability of phenolics and have now been successfully

337 Alternative Medicine Review Volume 15, Number 4

applied to curcumin,5•6 a patented complex with phosphatidylcholine (Meriva"). Capitalizing on very promising results in terms of improved hydrolytical stability (unpublished), human pharmacokinetics,5•7 and a previous OA clinical study,8 this study investigated the long-term efficacy and safety of this curcumin phytosome in the management of osteoarthritis, a condition in need of novel therapeutic options.9

Osteoarthritis is the leading cause of physical disability and impairment in life quality for millions of elderly people, both in industrialized and in developing countries, and its d ramatic influence on healthcare costs is likely worsened because of the aging population and current epidemic of obesity. 10 An effective cure for osteoarthritis remains elusive. Typically, osteoarthritis is managed with palliative measures that focus on symptom reduction - lifestyle modification (weight loss and exercise) and analgesics providing the primary treatments.11.12 Despite the serious adverse effects associated with long-term use of non-steroidal anti-inflammatory drugs (NSAIDs), these compounds remain the most widely used treatment option for OA. Given this scenario, it is not surprising that OA is the leading medical condition for which people use alternative therapies.13

A recent three-month registry study (n=SO) demonstrated Meriva improved symptoms and joint function in OA patients, as assessed by the Western Ontario and McMaster Universities (WOMAC) score and the treadmill walking performance, respectively.8 The current study was performed to evaluate the long-term efficacy and safety of Meriva in OA. This larger (n=lOO). eight-month study extended the end points of the previous study to include a series of biochemical markers of inflammation (interleukin [IL)-1~, IL-6, soluble CD40 ligand [sCD40L], soluble vascular cell adhesion molecule [sVCAM]-1, erythrocyte sedimentation rate [ESR]) of general relevance for inflammatory conditions. 1-1.i

5 This study is the most extensive, to date, to evaluate the clinical efficacy of curcumin as an anti-inflammatory agent.3

Material and Methods Subjects

The study enrolled 100 patients with osteoarthritis, confirmed by x-ray analysis. Patients were recruited using the database of the San Valentino vascular screening project,

an epidemiological study mainly following the evolution of asymptomatic cardiovascular atherosclerosis. Subjects were considered eligible for the study when they fulfilled the criteria for primary knee osteoarthritis (grade 1or2) according to the American Rheumatism Association. These patients participated in an open, product evaluation registry for the complementary management of osteoarthritis. Patients were informed about the aim of the study and treatment procedure according to the Declaration of Helsinki and provided informed consent. Patients were informed that they could leave the study at any time and were allowed to medicate with NSAIDs during the eight-month trial. Two groups of subjects with symptomatic osteoarthritis were defined: Group A was managed using the "best available treatment"

Table 1. Karnofsky Performance Scale Index

Original Research

Key words: curcumin, osteoarthritis, Meriva, anhrit1s, inflammation, joint, phytosome, turmenc. NSAIDs, anti·inflammatory, curcuma

Able to carry on normal 100 Normal no complaints; no evidence of disease activity and to work; no special care needed 90 Able to carry on normal activity; minor signs or

symptoms of disease

80 Normal activity with effort; some signs or symptoms of disease

Unable to work; able to live 70 Cares for self; unable to carry on normal activity at home and care for most or do active work personal needs; varying amount of assistance 60 Requires occasional assistance, but is able to care needed for most personal needs

50 Requires considerable assistance and frequent medical care

Unable to care for self; 40 Disabled; requires special care and assistance requires equivalent of institutional or hospital 30 Severely disabled; hospital admission is indicated care; disease may be although death not imminent progressing rapidly

20 Very sick; hospital admission necessary; active supportive treatment necessary

10 Moribund; fatal processes progressing rapidly

0 Deceased

Volume 15, Number 4 Alternative Medicine Review 338

Original Research

as defined by the patient's general practitioner and specialists; and Group B used best available treatment plus Meriva. For clinical homogeneity, the primary location of osteoarthritis was one or both knees.

Inclusion Criteria Primary osteoarthritis in one or both knees was

diagnosed by x-ray investigation. Subjects had mild-to-moderate pain not adequately or completely controlled with anti-inflammatory drugs. They were required to perform the treadmill walking test and to understand all questions from the WOMAC questionnaire.16

Exclusion Criteria Exclusion criteria were cardiovascular disease

requiring drug treatment, diabetes, body mass index > 25, severe metabolic disorders, surgery or arthroscopy within three months prior to inclusion, any oncological condition, or severe bone or joint deformation or condition making the patient unable to walk. Pregnancy, breast feeding, and planned conception were also exclusion criteria.

Measurements Evaluation of Functional Impairment

The Karnofsky Performance Scale Index was used to classify patients as to their functional impairment. The Karnofsky Performance Scale Index can be used to compare effectiveness of different therapies and to assess the prognosis in individual patients. The lower the Karnofsky score, the worse the functional impairment (Table 1). 17

Evaluation of Signs/Symptoms of Osteoarthritis The WOMAC questionnaire was applied to

describe and rate the symptoms of OA.16 The status of OA signs/ symptoms was evaluated by the investigator together with the patient at inclusion and after eight months of treatment.

Evaluation of Physical Performance Patients were trained to perform the treadmill

test in two tutorials. Performance was evaluated by the treadmill test at a speed of 3 km/hour and an inclination of 10 percent. The total distance that could be covered without pain was noted at the beginning and end of the trial.

Evaluation of Associated Treatments Needed to Manage Osteoarthritis

A diary was kept to record the use of any drug prescribed by the patient's physician, the use of


which was free (with only a warning not to use an excess of treatment).

Evaluation of Costs and Side Effects The treatment and other costs (including work

disruption and hospital admission) occurring during the trial period were recorded in a specific file.

Laboratory Testing At baseline, a heparinized venous blood speci

men was collected and deep frozen; after completion of the eight-month investigation, blood was drawn again. The oxidative stress status of patients was investigated by quantifying direct reactive oxygen metabolites (D-ROM) using the Free Radical Analytical System (FRAS; Diacron, Grosseto, Italy). In brief, the assay estimates hydroperoxides in a small blood sample (20 µL) after incubation in buffer solution together with a chromogenic agent. Photometric analysis provides oxidative stress status in Carr units, with 1 Carr unit corresponding to 80 µg H

20 / dL. Values above

300 Carr units suggest oxidative stress. lL-lP. IL-6, sCD40L, and sVCAM-1 (inflammatory markers) were determined by enzyme-linked immunosorbent assay (Millipore; Billerica, MA).

Materials Meriva (developed by Indena, S.p.A.) tablets

were prepared by Sig1nar Italia S.p.A. (Alme, Italy). The treatment consisted of two 500-rng tablets daily, one after breakfast and one after dinner (1,000 mg/day, corresponding to 200 mg curcu1nin/ day). The con1position of the test material was a natural curcuminoid mixture (203), phosphatidylcholine (40o/o), and microcrystalline cellulose (403). The composition of the curcuminoid mixture was 75-percent curcumin, 15-percent demethoxycurcumin, and 10-percent bisdemethoxycurcumin.

Statistical Analysis The variations of results (i.e., walking distance)

were considered parametric. Non-parametric observations (e.g., WOMAC score) were evaluated using the analysis of variance (ANOVA with the Bonferroni correction). Considering possible intra-individual and inter-individual data variations, completion of the entire follow-up period by at least 40 subjects in each group was required. This number was defined - on the basis of our previous study - in order to overcome spontaneous variability and temporal variations. OA and its related signs/symptoms, even in conditions of

Original Research

relative stability, may have a spontaneous degree of variability associated with periods of improvement. Clinical variations in signs/symptoms, walking distance, and the Karnofsky scale may be due to different clinical and non-clinical (e.g., environmental or climatic) factors, including individual, psychological, and drug-related elements.

Results In a previous three-month pilot study, 50

patients suffering from mild-to-moderate knee osteoarthritis received either the "best available treatment" or the "best available treatment and Meriva." Pain sensation, joint stiffness, and physical function improved signifi-

Table 2. Variations of Karnofsky Performance Scale Index {median and range)

Inclusion After 8 months

Treatment 73.3 (57-79.4) 92.2 (88-100)*

Control 74.2 (58-83) 81 (71-86.3)

'p<O.OS

Table 3. Patient Characteristics at Inclusion cantly with Meriva, as judged by WOMAC scores. Furthermore, a significant improvement of mobility, measured under controlled conditions on a treadmill, was also observed.8 Blood samples at baseline and after completion of the three-month trial demonstrated a statistically significant reduction of C-reactive protein (CRP) levels in the subgroup with elevated CRP treated with Meriva.8

•14

Patient Data Treatment Group Control Group

In the current study, the treatment group (n=50) and the control group (n=SO) did not differ in respect to Karnofsky Performance Scale Index (Table 2), 17 age, male-to-female ratio, overall WOMAC score, or performance on the treadmill test (Table 3). Five patients in the treat-ment group and six patients in the control group left the study for non-medical reasons, including moving or work prob-lems. The results of the Karnofsky Performance Scale Index are presented in Table 2. Meriva significantly improved the Karnofsky Scale (from 73.3 at inclusion to 92.2 at the completion of the study), with no significant improvements in the control group.

WOMAC scores are presented in Table 4. Scores for pain dropped significantly (p<0.05) following Meriva administration from 16.6 to 7.3, with no significant effects in the control group. The scores for stiffness in the treatment group were reduced significantly from 7.4 to 3.2 (p<0.05), while scores for the control group remained substantially unchanged after eight months. The scores for physical function in the Meriva group were significantly

Age (years) 43.6 SD 5.5 44.2 SD 6

Male/female ratio 23/27 28/22

Mean global WOMAC score 81.2 79.6

Treadmill test mean distance 77.3 meters (15-188) 82.3 meters (19-210) achieved*

' 8 kmlh with an inclination of 10%

Table 4. Change of Mean WOMAC Scores after Eight Months of Treatment

Treatment Group Control Group

WOMAC items Enrollment Smooths Enrollment Smonths

Pain 16.6 7.3 16 15.2

Stiffness 7.4 3.2 6.6 6.7

Physical functions 56.6 22.8 55.2 46.9

Total 80.6 33.3 77.8 68.8


Original Research

Table 5. Alterations in WOMAC Social and Emotional Function


WOMAC items Enrollment 8months Enrollment 8months

Social functions 24.4 10.3 23.8 21.9

Emotional functions 33.9 10.2 33.1 33.9

Table 6. Results of Treadmill Test {median and range)


Enrollment 8 months Enrollment

Distance 77.3 meters 344.4 meters 82.3 meters (15-188) (113-478)* (19-210)

The treadmill test was performed with the treadmill at the speed of 3 km/hour, with an md1nation of 10%. 'p<O.OS

Table 7. Changes in Inflammatory Markers

8months

156 meters (46-383)*


Enrollment 8 months Enrollment 8months

sC040L (ng/ml) 2.47 1.39* 2.34 2.46

ll -1 B (pg/ml) 0.88 0.31* 0.92 0.89

ll -6 (pg/ml) 1.38 1.01* 1.36 1.39

s~1(nglml) 644 456* 652 641

ESR (mm/hr) 35.23 26.3* 37.59 36.63

'p<O.OS versus values at enrollment


reduced, from 56.6 to 22.8 during the course of the study (p<0.05), while the improvement in the con trol group was not significant. The global WOMAC score decreased significantly following Meriva treatment, from 80.6 to 33.3; while in the control group the decrease from 77.8 to 68.8 was statistically insignificant. Negative effects on social function caused by osteoarthritis decreased significantly in the treatment group (p<0.05), but not in the control group (Table 5). The well-being of patien ts was significantly enhanced (p<0.05) in the t reatment group, as reflected in scores for emotional function (Table 5), while in the control group there was only a marginal improvement. In conclusion, all WOMAC scores improved significantly (p<0.05) after eight months treatment, compared to baseline as well as to the control group.

Table 6 illustrates t he results of the exercise (treadmill) tes ts (median and range). The treadmill (at a speed of 3 km/ hour, with a 10% inclination) indicates an improvement of 345 percent from the baseline initial distance (p<0.05) after eight months, compared to an 89-percent increase in the controls. This represents a statistically significant difference between the improvement in the treatment group compared to the control group (p<0.05) . In other words, Meriva treatment produced a 3.87-times greater improvement in physical performance than the control group (best treatment available).

Table 7 illustrates the results of sCD40L, IL-lp, IL-6, sVCAM-1, and ESR. Following treatment for eight months, Meriva induced a statistically significant reduction of all markers of inflammation. Conversely, the con trol group had only marginal and nonsignificant effects on all parameters. There were no other hematological changes noted.

Table 8 illustrates other observations noted in the study. Most relevant is the decreased (63o/o) use of NSAIDs and other painkillers (acetaminophen 2 g/day or celecoxib 200 mg/day as needed by the patients in either group and according to physicians' recommendations) in the treatment group compared to 12 percent

Original Research

Table 8. Other Observations (median decrease after eight months)

Decrease in use of NSAIDs/painki llers

Decrease in gastrointestinal complications

Decrease in use of other drugs/treatments

Decrease in management costs

Decrease in distal edema

Decrease in hospital admissions, consultation, and tests

Specific decrease in non-drug treatment (e.g., physiotherapy), costs due to other complications, new consultations, tests, etc.

•p<0.05 versus values at enrollment

in controls (p<0.05) . This was accompanied by a decrease in gastrointestinal complaints by 38 percent in Meriva patients compared to 15 percent in controls (p<0.05) (presu1nably, due to decreased use of NSAIDs and the reported GI-protective effect of curcumin). The decrease in use of other medicat ions or treatments was 38 percent in treatment subjects versus 11 percent in controls (p<0.05). The global decrease in management costs was 49 percent in Meriva patients compared to three percent (not significant) in controls (difference between groups: p<0.05).

The median decrease in distal edema was 65 percent versus five percent in controls (p<0.05). The presence of edema in these patients is mainly associated with a combination of inflammation, forced reduced activity (caused by pain on motion), and relative impaired limb mobility altering the venous pump function and venous return, particularly of the lower limbs. Hospital admissions, consultation, imaging, and instrumental tests decreased (median) 38 percent (p<0.05) in the treatment group compared with a six percent (not signjficant) decrease in controls (difference between groups: p<0.05). The specific decrease in


63.4o/o 8%

66.7% 12.4%

42.4% 7.4%

63.5% 3.7%

69% 1.7%

44.6% 2.6%

46.6% 5.5%

non-drug treatment (i.e., physiotherapy) costs due to different types of complications, new consultations, or blood tests was 44 percent (p<0.025) in Meriva patients compared with eight percent (not significant) in controls (the difference between the two groups was significant: p<0.05).

Discussion Curcumin is one of the most extensively investi

gated natural products, 1·3 and its broad spectrum of preclinical activity and low oral toxicity suggest benefit for the treatment of a host of inflammatory conditions. However, few successful clinical studies of curcumin have been reported3 because of its poor oral bioavailability. Unrealistically high dosages (>10 g/day) are often required to achieve plasma concentrations corresponding to those suggested by the preclinical studies.4 To overcome these issues, a phytosome was developed, complexing curcumin with phosphatidylcholine.18 In the wake of studies showing promising data for hydrolytic stabilization at physiological pH (unpublished), approximately 20-fold improvement of oral absorption compared to non-complexed curcumin in animal19 and human7 pharmacokinetic


Original Research

studies, and nutrigenomic veterinarian evidence of anti-inflammatory activity,20 clinical studies on Meriva were commenced,8 focusing on OA because of the strong rat ionale for the use of curcumin in this condition.21

The hallmark of OA is an imbalance between inflammatory and anti-inflammatory signaling in chondrocytes and synovial cells, with an abnormal activation of cytokine cascades and an overproduction of inflammatory mediators.11·12·21 The upregulation of inflammatory cytokines like !L-1~ and tumor necrosis factor-alpha leads to a decrease in collagen synthesis and, by activation of matrix metalloproteinases (MMPs), to a corresponding increase in collagen degradation, with further up-regulation of mediators and effectors like IL-8, IL-6, prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), and reactive oxygen species (ROS). 11 12

·21 Remarkably, curcumin can regulate in

a beneficial fashion the activity of all the major inflammatory players involved in OA.11

OA, as a chronic disease, requires continuous treatment. However, while there is no shortage of effect ive pharmacological treatments for OA, they cannot be used continuously because of severe side effects (e.g., gastrointestinal problems with NSA!Ds and hypercorticosteroidism with corticosteroids).11 12 It was therefore critical to evaluate the efficacy and safety profile of Meriva over a longer treatment time than the initial three-month evaluation;8 this was the rationale for the present study. No attempt to evaluate the clinical efficacy of curcumin as an anti-inflammatory agent in studies of this duration, enrolln1ent, and diversity of end-points has previously been reported.3 Also, the low dosage employed (1 g Meriva, corresponding to 200 mg/day curcumin) has few clinical precedents, 1 3 but was validated in a previous study8 and supported by a human pharmacokinetic study that confirmed the > 20-fold increase of bioavailability for Meriva compared to uncomplexed curcumin observed in a previous ani1nal study.7

In this trial, positive results were obtained for all end-poirrts evaluated. Thus, after eight months of continuous use of 1 g/day Meriva, the WOMAC score for OA symptoms decreased by more than 50 percent, while the treadmill test showed an overall three-fold increase in walking distance compared to the control group. The objective and subjective clinical outcomes were substantiated by interesting findings in the biochemical evaluation of inflammatory status and oxidative stress in patients in the treatment group. The significant decrease of all


inflammatory markers measured suggests that the clinical improvements observed have a clear mechanistic basis that validates previous in vitro observations of curcumin on joint cells.

The improvement of physical function and quality of Life evidenced in the WOMAC questionnaires deserve comment. Patients were able to engage more in social activities, reportedly feeling markedly "in a better mood." Pain and osteoarthritis symptoms are known to limit social interactions, and any improvement in these conditions is Likely to have a socio-emotional effect. It is, however, interesting to note that preclinical investigations have also suggested a direct antidepressive effect of curcumin.22

A somewhat related observation could be made in regard to the marked reduction of NSAIDassociated gastrointestinal problems in the treatment group. This might be related to a reduced use of these drugs, to the known gastrointestinal protective effects of curcumin, 1 or to a combination of both. Finally, the cost effectiveness associated with the use of Meriva is also worth noting.

Conclusions Meriva is an effective and safe agent for the

complementary management of osteoarthritis, leading to better disease control, a decreased use of NSA!Ds, and an overall improvement in quality of life. Although no direct comparison study of Meriva versus NSAIDs has been conducted,2326 the decreased use of these drugs observed in the t reatment group provides a rationale for evaluating whether the biochemical improvement in t he inflammatory status associated with Meriva could eventually translate to a phase out of NSAID use, at least for mild-to-moderate OA. Studies with an even larger population and longer treatment period are needed to confirm these findings and evaluate the efficacy and safety of Meriva in a head-to-head comparison with NSAIDs. Never theless, our study exemplifies the potent ial of combining traditional knowledge and modern science to provide dietary ingredients that can stand the litmus test of modern medical evaluation in terms of safety and efficacy.

Acknowledgement We are grateful to Sigmar Italia S.p.A. (Alme,

Italy) for providing the Meriva tablets used in this investigation.

Original Research

Conflict of Interest 9. Zhang W, Moskowitz RW, Nuki G, et al. 18. Giori A, Franceschi F. European Patent

S. Togni is a manager and G. OARST recommendations for the Application EP1837030

Appendino is a consultant at lndena management of hip and knee osteoar- 19. Marczylo TH, Vershoyle RD, Cooke DN,

S.p.A., the company producing Meriva. thritis, Part II: OARSI evidence-based, et al. Comparison of systemic availabil-

expert consensus guidelines. ity of curcumin with that of curcumin

References Osteoarthritis Cartilage formulated with phosphatidylcholine.

1. Goel A, Kunnumakkara AJ, Aggarwal 2008;16:137-162. Cancer Chemother Phannacol BB. Curcumin as "curecu1nin": from 10. Felson DT, Zhang Y, Anthony JM. 2007;60:171-177.

kitchen to clinic. Biochem Pharmacol Weight loss reduces the risk of 20. Farinacci M, Gaspardo B, Colitti M,

2008;75:787-809. symptomatic knee osteoarthritis in Stefanon B. Dietary administration of

2. Aggarwal BB, Sung B. Pharmacological women. The Framingham Study. Ann curcumin modifies transcriptional

basis for the role of curcumin in chronic Inter Med 1992;116:535-539. profile of genes involved in infla1nma-

diseases: an age-old spice with modem 11. Goldring MB, Goldr ing SR. tory cascade in horse leukocytes. Ital J targets. Trends Phannacol Sci Osteoarthritis. J Cell Physiol Anim Sci 2009;8:84-86.

2009;30:85-94. 2007;213:626-634. 21. Henrotin Y, Clutterbuck AL, Allaway D,

3. Jurenka JS. Anti-inflammatory 12. Krasnokutsky S, Samuels J, Abramson et al. Biological actions of curcumin on

properties of curcumin, a major SB. Osteoarthritis in 2007. Bull NYU articular chondrocytes. Osteoarthritis

constituent of Curcu1na /onga: a review 1-fosp Joint Dis 2007;65:222-228. Cartilage 2010;18:141-149.

of preclinical and clinical research. 13. Resch KL, Hill S, Ernst E. Use of 22. Kulkarni S, Dhir A, Akula KK.

A/tern Med Rev 2009;14:141-153. complirnentary therapies by individuals Potentials of curcumin as an an tide-

4. Anand P, Kunnumakkara AB, Newman with 'arthritis'. Clin Rheu1natol pressant. SdentiflcWorldJournal

RA, Aggarwal BB. Bioavailability of 1997;16:391-395. 2009;9:1233-1241.

curcumin: problems and promises. Mo/ 14. Sharif M, Shepstone L, Elson CJ, et al. 23. Deodhar SD, Sethi R, Srimal RC.

Phann 2007;4:807-818. Increased serum C reactive protein may Preliminary study on antirheumatic

5. Kidd PM. Bioavailability and activity of reflect events that precede radiographic activity of curcumin (diferuloyl

phytosome complexes from botanical progression in osteoarthritis of the 1nethane). Indian J Med Res

polyphenolics: the silymarin, curcumin, knee. Ann Rheu1n Dis 2000;59:71-74. 1980;71:632-634.

green tea, and grape seed extracts. 15. Pearle AD, Scanzello CR, George S, et al. 24. Satoskar RR, Shah SJ, Shenoy SG.

A/tern Med Rev 2009;14:226-246. Elevated high-sensitivity C-reactive Evaluation of anti-inflammatory

6. Semalty A, Semalty M, Rawat MS, protein Levels are associated with local property of curcumin (diferuloyl

Franceschi F. Supramolecular phospho- inflammatory findings in patients with methane) in patients with postopera-

lipids-polyphenolics interactions: the osteoarthritis. Osteoarthritis Cartilage tive inflamination. Int J Clin Pharmacol

PHYTOSOME® strategy to improve the 2007;15:516-523. Ther Toxico/ 1986;24:651-654.

bioavailability of phytochemicals. 16. Baron G, Tubach F, Ravaud P, et a l. 25. Kuptniratsaikul Thanakhumtorn S,

Fitoterapia 2010;81:306-314. Validation of a short form of the Chinswangwatanakul P,

7. Cuomo J, Dixon ES, Dern A. et al. Western Ontario and McMaster Wattanamongkonsil L, Thamlikitkul V.

Comparative bioavailability of unformu- Universities Osteoarthritic Index Efficacy and safety of Curcuma domes-

lated curcumin and a curcumin-phos- function subscale in hip and knee tica extracts in patients with knee

phatidylcholine co1nplex. Manuscript osteoarthritis. Arthritis Rheum osteoarthritis. J Alt Comp/ Med

submitted for publication to J Nat Prod. 2007;57:633-638. 2009;15:891-897.

8. Belcaro G, Cesarone MR, Dugall M, et al. 17. Schag CC, Heinrich RL, Ganz PA. 26. Badria FA, El-Farahaty Shabana AA,

Product evaluation registry of Meriva ·, Kamofsky performance status Hawas SA, El-Batoty F. Boswellia-

a curcumin-phosphatidylcholine revisited: reliability, validity, and curcumin preparation for treating knee

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management of osteoarthritis. 1984;2:187-193. 2002;341-348.

Panminerva Med 2010;52:55-62.


Published: March 17, 2011

Copyright r 2011 American Chemical Society andAmerican Society of Pharmacognosy 664 dx.doi.org/10.1021/np1007262 | J. Nat. Prod. 2011, 74, 664–669

ARTICLE

pubs.acs.org/jnp

Comparative Absorption of a Standardized Curcuminoid Mixture andIts Lecithin FormulationJohn Cuomo,*,† Giovanni Appendino,*,‡ Adam S. Dern,† Erik Schneider,† Toni P. McKinnon,†

Mark J. Brown,† Stefano Togni,§ and Brian M. Dixon†

†USANA Health Sciences, Inc., 3838 West Parkway Boulevard, Salt Lake City, Utah 84120, United States‡Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Universit�a degli Studi del Piemonte Orientale,Via Bovio 6, 28100, Novara, Italy§Indena S.p.A., Viale Ortles 12, 20139 Milano, Italy

Over the past few decades, preclinical and clinical evidencehas been accumulating that the pathological mechanisms

involved in chronic diseases are multifactorial and that theseconditions are therefore better addressed with a multitargetedrather than a monotargeted therapy.1�3 The promiscuous target-ing of multiple cellular end-points has therefore become atherapeutic virtue,4 and agents that can modulate multiplecellular targets, once dismissed as unselective ligands, are nowconsidered attractive research leads.4 In this context, no com-pound better than curcumin (1a) exemplifies the biomedicalrelevance of promiscuous agents.5 With over 100 moleculartargets identified and almost 3000 preclinical investigations,6

this compound is, undoubtedly, one of the best investigatednatural products to date. Curcumin features a unique blend ofMichael acceptor, metal chelating, and antioxidant propertiesthat has so far substantially eluded all attempts of dissection.7

The promiscuous binding properties of curcumin make itdifficult to explore the chemical space around the pharmaco-phore of the natural product, since analogues would have to beassayed against multiple rather than single molecular end-points.Therefore, a large share of the medicinal chemistry research oncurcumin has focused on improving the dismally low oralabsorption of the natural product by suitable formulation.8

Curcumin has a high hydrolytic instability at physiological pH9

and an inherently low intestinal absorption.8 It is therefore very

poorly bioavailable, with only conjugates being generally detect-able in plasma even after dosages as high as 12 g/day.8,10

Two major strategies have been pursued to improve thebioavailability of curcumin.8 The first is a combination withadjuvants capable of increasing the absorption of curcumin, likepiperine, quercetin, or turmeric oil.9 The curcumin�piperineformulation is the best documented and has been shown to almostdouble the human bioavailability of curcumin.11 However, it hasbeen argued that this improvement comes at the expense of anincreased potential of interaction with mainstream drugs,12 sincepiperine is an inhibitor of phase-1 and phase-2 xenobiotic meta-bolizing enzymes,13 and curcumin has also been shown to inhibitvarious classes of cytochromes (including CPYP3A4) as well asP-glycoprotein activity.12,14 The second strategy has been theinclusion of curcumin in a lipophilic matrix (liposomes, Phyto-somes, and lipid micro- and nanoparticles) or encapsulation withmicellar surfactants or casein.8 Many of these formulations haveled to dramatic improvement in the absorption of curcumin inanimal experiments,8 but little human data exist.

Commercially available natural curcumin is a mixture of threecurcuminoids: curcumin (1a, ca. 70�75%), demethoxycurcumin(1b, ca. 15�20%), and bisdemethoxycurcumin (1c, ca. 5�10%).Most published literature on curcumin does not make a clear

Received: October 11, 2010

ABSTRACT: The relative absorption of a standardized curcu-minoid mixture and its corresponding lecithin formulation(Meriva) was investigated in a randomized, double-blind, cross-over human study. Clinically validated dosages were used forboth products, and plasma levels of all three major curcumi-noids [curcumin (1a), demethoxycurcumin (1b), and bisde-methoxycurcumin (1c)] were evaluated. Total curcuminoidabsorption was about 29-fold higher for Meriva than for itscorresponding unformulated curcuminoidmixture, but only phase-2metabolites could be detected, and plasma concentrations werestill significantly lower than those required for the inhibition of most anti-inflammatory targets of curcumin. Remarkably,phospholipid formulation increased the absorption of demethoxylated curcuminoids much more than that of curcumin (1a), withsignificant differences in plasma curcuminoid profile between Meriva and its corresponding unformulated curcuminoid mixture.Thus, the major plasma curcuminoid after administration of Meriva was not curcumin (1a), but demethoxycurcumin (1b), a morepotent analogue in many in vitro anti-inflammatory assays. The improved absorption, and possibly also a better plasma curcuminoidprofile, might underlie the clinical efficacy of Meriva at doses significantly lower than unformulated curcuminoid mixtures.

665 dx.doi.org/10.1021/np1007262 |J. Nat. Prod. 2011, 74, 664–669

Journal of Natural Products ARTICLE

distinction between pure 1a (monomolecular curcumin, gener-ally obtained by synthesis) and the mixture of the three curcu-minoids obtained by extraction from turmeric. In this study, twoformulations of a mixture of natural curcuminoids, a noncom-plexed powder and a phospholipid formulation (Meriva), werecompared. Both materials had a similar ratio of all three naturalcurcuminoids (see below).15 Curcumin is sparingly soluble inboth water and lipophilic organic solvents, but has polar groupsthat make it a good candidate for phospholipid complexation viahydrogen bonding and dipole interactions with the polar headgroups of phosphatidylcholine.16 As a result, phospholipidparticles bearing curcumin at their surface can be formed,17

and curcumin has indeed been shown to strongly bind tophospholipid micelles, positioning the water-labile β-diketonemoiety into the lipid bilayer and shielding it from hydrolyticretro-Claisen fragmentation, the major mechanism of degrada-tion in water.16 Based on this previous research, a novel curcuminformulation was developed under the brand name Meriva bycombining a standardized mixture of natural curcuminoids andlecithin in a 1:2 ratio, with 2 parts of microcrystalline cellulosebeing also added to improve the physical state.18 A comparativeanalysis of the hydrolytic stability of Meriva and noncomplexedcurcumin showed a dramatic increase in stability in the pH rangeof the small intestine (pH 7�8), the major site of absorption forpolyphenolic compounds (Giori, A.; Franceschi, F.; Appendino,G. Unpublished data). Apart from hydrolytic stabilization, phos-pholipid formulation could also increase the absorption ofcurcumin in a direct way, since phospholipids can be rapidlytaken up into biomembranes by pinocytosis, shuttling their guestto cells in this process.17 These results were verified by ananimal study, which showed a >20-fold increase in absorptionof curcumin from Meriva as compared to unformulated naturalcurcumin.19 As an extension of these studies, we have nowcompared the relative human absorption of a standardized,natural curcuminoid mixture with two doses of the correspond-ing phospholipid formulation Meriva.

’RESULTS AND DISCUSSION

A randomized, double-blind, crossover study was carried outin nine volunteers, measuring the plasma concentrations ofthree curcuminoids [curcumin (1a), demethoxycurcumin (1b),and bisdemethoxycurcumin (1c)] after supplementation withtwo dosages of Meriva and one dosage of the same batch of

curcuminoid mixture used for the formulation with lecithin. Thedosages were inspired by previous clinical studies for inflamma-tory conditions, where active dosages of around 1�2 g/day ofnonformulated curcuminoid mixtures20 and around 200�300mg of curcuminoids asMeriva were used,1 while the choice of thefirst time point was done in accordance to previous data thatshowed tmax values for curcumin around 4 h.10 For this study,subjects consumed, in random order and on separate study days,five (low-dose) or nine (high-dose) capsules of Meriva, corre-sponding to 209 and 376mg total curcuminoids, or, alternatively,five capsules of the corresponding nonformulated curcuminoidmixture (reference) containing 1799 mg of total curcuminoids.The composition of the two types of capsules is listed in Table 1.

Free curcumin (1a) could not be detected in any plasmasamples, in accordance with previous studies that have mostlyfailed to detect unconjugated curcumin in human plasma evenafter the administration of megadoses of curcumin.8 Conse-quently, all plasma samples were treated with Helix pomatiaglucuronidase/sulfatase before HPLC-MS/MS analysis. Thepeak plasma total curcuminoid concentration (cmax) reachedwith the high dosage of Meriva was 206.9 ( 164.7 ng/mL, andthe corresponding time of the peak plasma curcuminoid con-centration (tmax) was reached at 2.7 ( 1 h after the administra-tion. For the low dosage, cmax was 68.9 ( 50.8 ng/mL and tmaxwas 3.3 ( 1 h. For the reference curcuminoid mixture, thesevalues were 14.4 ( 12.5 ng/mL and 6.9 ( 6.7 h. Within thecontext of curcumin human absorption, the >200 ng/mL con-centration of conjugated curcuminoids is still lower than the lowmicromolar concentration of free curcumin required for in vitrodirect activity against its various targets.7

Pharmacokinetic data for each administration were graphed,and statistical analysis was performed using GraphPad PrismVersion 5.04 software (GraphPad Software, SanDiego, CA). Theaverage of each group’s plasma analyte concentrations wereplotted against time (Figure 1). The area under the curve(AUC), the cmax, and the tmaxwere calculated for each curcuminoidand for the total curcuminoid mixture and are presented inTable 2. The AUC was calculated using the trapezoidal methodfrom time 0 to 24 h, and the values were normalized tocurcuminoid intake by dividing the observed AUC by the corre-sponding curcuminoid dosage of each administration. The result-ing normalized AUCs, expressed in ng/mL(plasma) � h/mgingested, were divided by the AUCof the reference to calculate therelative absorption values (Table 2) (for statistical details, see theExperimental Section).

From these data, the average absorption of curcumin (1a) wascalculated to be ca. 18-fold higher from Meriva than from thecorresponding unformulated mixture of curcuminoids. More-over, the overall curcuminoid absorption was about 29-foldhigher for the Phytosome formulation compared to the unfor-mulated reference, since the plasma concentrations of demethox-ycurcumin (1b) and bisdemethoxycurcumin (1c) from intake of

Table 1. Curcuminoid Content of the Study Capsules

curcuminoid

Meriva

(mg per capsule)

reference

(mg per capsule)

high dose

(mg per dose)

low dose

(mg per dose)

reference

(mg per dose)

curcumin (1a) 33 259 297 165 1295

demethoxycurcumin (1b) 8 79 68 38 396

bisdemethoxycurcumin (1c) 1 22 11 6 108

total curcuminoids 42 360 376 209 1799



Meriva were 50- to 60-fold higher than from the correspondingunformulated curcuminoid mixture. Remarkably, the majorplasma curcuminoid was demethoxycurcumin (1b) and notcurcumin (1a) with both dosages of Meriva investigated. Themarked differences in the plasma curcuminoid profile could notbe accounted for by the nature of the starting materials, sinceMeriva capsules and the noncomplexed curcumin capsulescontained very similar curcuminoid profiles. Thus, the ratio1a/1b/1c was 1/0.25/0.04 in the capsules (Table 1), but1/0.50/0.20 in the plasma samples from the reference curcuminoidmixture, and 1/1.20/0.26 in the plasma from the administrationof Meriva. These data show that demethoxylated forms ofcurcumin (1b and 1c) have a better intrinsic absorption thancurcumin (1b) and that formulation with phospholipids in-creases these differences in bioavailability.22 Interestingly,

turmeric is often used in cuisine associated with lecithin-richingredients like eggs or vegetable oils, and these observationsmight well hold also for the dietary intake of curcuminoids.

The reasons for this unexpected increase in the plasmaconcentrations of the demethoxylated curcuminoids 1b and 1cover curcumin (1a) are unknown. It is, in principle, possible thata reductive microbial metabolization of curcumin (1a) might beinvolved, in a process not unlike the one that generates enter-olactone and enterodiol from flax lignans.23 The hydrolyticstabilization of curcumin at intestinal pH might, in fact, translateinto a significant curcumin load for the gut microflora, known tobe able to reductively demethoxylate dietary phenolics.24 Thepossibility that 1b and 1c are generated from curcumin (1a)by liver metabolization seems unlikely, since dietary phenolicsare generally oxidatively O-demethylated rather than reductively

Figure 1. Pharmacokinetic data for curcumin (1a), demethoxycurcumin (1b), bisdemethoxycurcumin (1c), and total curcuminoids for each dosage.Concentrations are expressed in ng/mL and refer to enzymatically hydrolyzed plasma samples. Circles (b) represent high dosages of Meriva; squares(9) represent low-dose Meriva; and triangles (2) represent the reference material. Insets (A and C) show an expanded view of the original data. Thedata shown are baseline subtracted means ( SEM.

Table 2. Area Under the Curve (AUC), cmax, tmax, and Relative Absorption for Each Treatment of Curcuminoidsa

curcuminoid formulation AUC (ng/mL) cmax (ng/mL) tmax (h) relative absorptionb

curcumin (1a) Meriva high 538.0( 130.7 50.3( 12.7 3.8( 0.6 19.2c

Meriva low 272.6( 68.52 24.2( 5.9 4.2( 0.8 17.5c

reference 122.5( 29.3 9.0 ( 2.8 6.9( 2.2 1

demethoxycurcumin (1b) Meriva high 655.0( 195.7 134.6( 40.6 2.4( 0.3 68.3d

Meriva low 297.4( 107.3 39.1( 11.4 3.1( 0.4 55.5d

reference 55.8( 15.5 4.2 ( 1.1 4.4( 1.0 1

bisdemethoxycurcumin (1c) Meriva high 142.2( 58.2 24.9( 8.1 2.2( 0.4 56.8e

Meriva low 70.1( 34.3 8.8( 3.1 2.4( 0.6 51.3e

reference 24.6( 10.3 2.1 ( 0.8 3.4( 1.2 1

total curcuminoids Meriva high 1336.0( 357.1 206.9( 54.9 2.7( 0.3 31.5f

Meriva low 640.2( 197.7 68.9( 16.9 3.3( 0.3 27.2f

reference 202.8( 53.8 14.4 ( 4.2 6.9( 2.2 1aActual results not baseline subtracted, and errors are SEM. bAUC normalized. cAverage: 18.3. dAverage: 61.9. eAverage: 54.1. fAverage:29.4.



C-demethoxylated by liver enzymes,25 and phase-2metabolizationto conjugates is generally the primary metabolic pathway fordietary phenolics.25 The unique plasma curcuminoid profilemight play a role in the clinical efficacy of Meriva at dosagesmuch lower than those of unformulated curcumin, since de-methoxycurcumin is more potent than curcumin in manymolecular assays of anti-inflammatory activity.26 The presenceof demethoxylated curcuminoids in most “curcumin” sampleshas, surprisingly, been largely overlooked, and the fragmentarystate of our knowledge on the in vivo biological profile of thesecompounds makes it difficult to evaluate the clinical meaning ofdifferences in the plasma curcuminoid profile. However, basedon in vitro studies, a better anti-inflammatory curcuminoidprofile seems possible for Meriva compared to unformulatedcurcuminoid mixtures. This would certainly be worthy of furtherevaluation, and our data add to the growing body of informationsuggesting that curcuminoids have different biological profiles,drawing attention to their different bioavailability and to the needto specify the composition of “curcumin” whenever this com-pound is used in both cellular and clinical studies.

Curcumin has been a sort of “forbidden fruit” for biomedicalresearch,5 since its poor oral bioavailability has substantiallyhampered clinical development, despite the very promisingindications of the preclinical research.6 We have demonstratedthat formulation with phospholipids27 improves the humanabsorption of curcumin, without, however, leading to pharma-cologically active plasma concentrations and with only phase-2metabolites being detectable.23 While phase-2 metabolites mightplay a role in vivo, either as pro-drugs or as targeting agents,28 thefailure to reach pharmacologically active plasma curcuminoidconcentrations even with clinically validated dosages of Meriva21

raises the issue of how to evaluate effective dosages of multi-targeted agents whose action in vivo might be the result of thecombinatorial binding to several protein targets and/or theepigenetic modulation of their expression.29

’EXPERIMENTAL SECTION

General Experimental Procedures. Pure curcuminoid stan-dards (>98% purity by HPLC) were used (Chromadex, Irvine, CA). A95% soybean-based phospholipid�curcumin formulation (Meriva) wasprovided by Indena (Milan, Italy). Capsules of nonformulated 95%curcuminoid mixture prepared from the same batch used for the lecithinformulation were provided by USANA Health Science, Inc. β-Glucur-onidase/sulfatase (EC 3.2.1.31) fromHelix pomatiawas purchased fromSigma (St. Louis, MO).30 HPLC grade 2-propanol, formic acid, ethylacetate, and other chemicals used in the buffer system were purchasedfrom Pharmco-AAPER (Brookfield, CT). HPLC-MS/MS: AgilentHPLC system (1100 series, USA) and Agilent 6410 tandem massspectrometer with (þ) ESI, equipped with an Agilent C18 analyticalcolumn (75 mm � 4.6 mm).Chromatographic Analysis of Curcuminoids. The HPLC-

MS/MS procedure used was adapted from Liu et al.31 Concentratedstock solutions of curcumin (1a), demethoxycurcumin (1b), andbisdemethoxycurcumin (1c) were prepared by dissolving 5.0 mg ofeach compound in 200 mL of methanol to give 25 μg/mL stocksolutions. Three standard solutions were prepared by combining thestock solutions and diluting with methanol to yield final concentrationsof 0.5, 25, and 50 ng/50 μL. A calibration curve was prepared for eachsubject by spiking blank plasma from the baseline blood draw with 50 μLof the appropriate working solution to yield concentrations of 5, 250,and 500 ng/mL. These calibration standards were run multiple timesbetween samples, resulting in 18 “three-point” calibration curves that

also served as a system suitability check. Plasma spiking was used tocreate the calibration curve instead of changing the injection volume inorder to compensate for matrix effects. The analysis was carried outusing 2-propanol/0.03% formic acid (35:65, v/v) as mobile phase, withan injection volume of 10 μL, a run time of 15 min, and a flow rate of1.0 mL/min. Autosample carryover was determined by injecting themost concentrated calibration standard followed by a blank sample. Nocarryover was observed, as indicated by an inability to detect curcuminpeaks in the blank sample. The sensitivity of the multiple reactionsmonitoring (MRM) was optimized by testing with an infusion of 100ng/mL curcuminoid solution. The mass spectrometer was operatedunder MRM mode with a collision energy of 10 eV. The transitionsmonitored were m/z 369.2f 285.2 for curcumin (1a), 339.2 f 255.0for demethoxycurcumin (1b), and 309.1 f 225.0 for bisdemethoxy-curcumin (1c). The limit of detection was calculated from the signal-to-noise ratio to be 0.5 ng/mL, an order of magnitude below the loweststandard concentration used.Product Administration. The three dosages were administered

with 8 fluid oz. of water in two-piece hard-shell capsules to eight healthymale subjects and one female subject, age 35( 10 years. On each studyday, subjects were required to complete an overnight fast and donate abaseline blood sample of both serum and plasma. Next, they receivedone oral dosage of one of the three randomized treatments. Subjectsthen ate a standardized breakfast consisting of one plain bagel (99 g)with cream cheese (25 g) followed by venous blood draws at 2, 4, 8, and24 h postadministration. After the 4 h blood draw, the volunteers werefed a standardized lunch consisting of one plain bagel (99 g) with creamcheese (25 g). Subjects were released after the 8 h blood draw and wereallowed to resume their normal dietary intake but restricting foodsknown to contain curcumin. After fasting overnight, volunteers returnedthe next morning for the 24 h blood draw. After a seven-day washoutperiod, each subject returned to the clinical site to receive the nextrandomly assigned treatment. Each laboratory visit was identical to thefirst and repeated until all three treatments were administered.Sample Preparation. A 0.2 mL aliquot of plasma was transferred

to a clean microcentrifuge tube and next treated with 100 μL of asolution containing 1000 U of β-glucuronidase in 0.1 M phosphatebuffer (pH 6.86) and 50 μL of methanol. The resulting mixture was thenthoroughly vortexed and incubated at 37 �C for 1 h to hydrolyze thephase-2 conjugates of curcuminoids. After incubation, curcuminoidswere extracted with 1 mL of ethyl acetate, and the mixture was vortexedfor 1 min, followed by sonication in a water bath for 15 min. Aftercentrifugation at 15000g for 6 min, the upper organic layer wastransferred to a 2 mL microcentrifuge tube and evaporated to drynessat 30 �C under negative pressure in a centrifugal concentrator. Thisprocess was repeated for a total of two extractions. The dried extract wasreconstituted in 100 μL of methanol, and 10 μL was injected into theHPLC-MS/MS.

Table 3. Statistical Analysis [Friedman test results; numberof treatment groups = 3 (low, high, reference) for all groups]

group Friedman statistic p value

AUC curcumin (1a) 16.22 <0.0001

cmax curcumin (1a) 16.22 <0.0001

tmax curcumin (1a) 2.111 0.03285

AUC demethoxycurcumin (1b) 18 <0.0001

cmax demethoxycurcumin (1b) 18 <0.0001

AUC bisdemethoxycurcumin (1c) 12.97 0.0003

cmax bisdemethoxycurcumin (1c) 13.61 0.0002

AUC total curcuminoids 16.22 <0.0001

tmax total curcuminoids 18 <0.0001



Analysis of Capsules Used in the Study. The curcuminoidconcentration of both the reference and the Meriva capsule wasdetermined by breaking open each capsule and dissolving 5 mg of thepowder obtained in 250mL ofmethanol. The solution was shaken for 20min, and 1 μL injected into the HPLC-MS/MS, using the conditionsdescribed above.Statistical Analysis. For comparison of treatment effects, one-way

repeated measures analysis of variance by ranks (Friedman test) with aDunn’s multiple comparison post hoc test was used. Results wereconsidered significant if the p value was e0.05 relative to the referencematerial (see Table 3 for details). Statistical analysis was performed usingGraphPad Prism Version 5.04 software (GraphPad Software, San Diego,CA).

’AUTHOR INFORMATION

Corresponding Author*Tel: þ1 801 9547831 (JC); þ39 0321 375744 (GA). Fax: þ1801-954-7658 (JC); þ39 0321 375621 (GA). E-mail: [email protected] (JC); [email protected] (GA).

’ACKNOWLEDGMENT

The authors gratefully acknowledge the assistance of R. D.Strand, M.D., and thank Dr. C. Artaria (Indena S.p.A.) for thepicture of curcumin powder.

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Normolle, D. P.; Djuric, Z.; Brenner, D. E. Cancer Epidemiol. BiomarkersPrev. 2008, 17, 1411–1417. In this study, only one of the six participantswho received a 12 g/day dosage of curcuminoid mixture had plasmalevels of free curcumin that reached the detection threshold (50 ng/mL).In all the other volunteers and in the six participants who received adosage of 10 g curcumin/day, only conjugates were detected. In a recentstudy, none of the five cancer patients who received a daily dosageof 8 g curcumin had detectable plasma concentrations of unconjugatedcurcumin.Kanai, M.; Yoshimura, K.; Asada, M.; Imaizumi, A.; Suzuki, C.;Matsumoto, S.; Nishimura, T.; Mori, Y.; Masui, Tl; Kawuguchi, Y.;Yanagihara, K.; Yazumi, S.; Chiba, T.; Aggarwal, B. B. Cancer Chemother.Pharmacol. 2010in press.(11) See: http://www.bioperine.com/curcumin.html.

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(15) For sake of clarity, throughout the text curcumin refers tomonomolecular 1a, while the mixture of the three curcuminoids will bereferred to as natural curcumin or curcuminoids.

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(20) Jurenka, J. S. Altern. Med. Rev. 2009, 14, 141–153. A directcomparison between a clinical dosage of curcumin as Meriva and thesame amount of uncomplexed curcumin was not possible becauseuncomplexed curcumin does not produce consistently detectable plas-ma concentrations in humans at dosages lower than 2 g.8 On the otherhand, comparison of Meriva with very high dosages of uncomplexedcurcumin would be biased by saturation effects and by the nonlinearity ofits absorption,8 affording unrealistic values of improved absorption. The1.8 g reference dosage is a compromise between detectability and clinicalactivity of uncomplexed curcumin.Satoskar, R. R.; Shah, S. J.; Shenoy,S.G. Int. J. Clin. Pharmacol. Ther. Toxicol.1986, 24, 651–654.Kuptniratsaikul,V.; Thanakhumtorn, S.; Chinswangwatanakul, P.; Wattanamongkonsil, L.;Thamlikitkul, V. J. Compl. Altern. Med. 2009, 15, 891–897. It should bepointed out that the published clinical trials on curcumin are small, oftennonrandomized, and essentially open-label and that some of them gavenegative results, even with higher dosages (4 g/day) of curcumin than thosewe have used as reference (see ref 12).

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(22) The rate of absorption of curcuminoids increased with thedosage, and the first time point (2 h) for demethoxycurcumin (1b) andbisdemethoxycurcumin (1c) at the high dosage of Meriva was also thepeak concentration. It is, therefore, possible that the AUC of thesecompounds might, actually, be underestimated at this dosage, withthe effect of lecithin formulation being overall higher than reported. Weare grateful to one reviewer for bringing this issue to our attention. Theeffect of dosage on the rate of absorption is, undoubtedly, intriguing andwell worth further investigation.

(23) In the case of flax lignans, it is, however, the para-oxygenatedfunction that is reductively removed by gut microorganisms. Lampe,J. W. J. Nutr. 2003, 133 (Suppl. 3), 956S–964S.

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(Duke, J. A. CRCHandbook of Medicinal Spices; CRC Press: Boca Raton,FL, 2003; pp 137�144), potentially increasing the bioavailability of“dietary” curcumin.(28) (a) Roycik, M. D.; Fang, X.; Sang, Q. X.Curr. Pharm. Des. 2009,

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Complaint to TGA – Australian NaturalCare Products Curcumin · 2019. 10. 18. · Complaint to TGA...

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