Curcumin Nina Bailey BSc MSc, PhD RNutr

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Curcumin is a polyphenolic molecule extracted from the rhizome of the plant Curcuma longa, a yellow spice most commonly encountered as a traditional ingredient of curry

This natural compound has been used over centuries in Ayurvedic, Chinese and Hindu traditional medicine to treat a number of both minor and chronic conditions

Numerous studies have demonstrated that curcumin possesses anti-oxidant, anti-inflammatory and anti-cancer properties

Turmeric contains an average of 5-10% curcuminoids Curcumin (75%) Demethoxycurcumin (DMC -15%) Bis-demethoxycurcumin (BDMC – 10%)

Other components include: Volatile (essential) oils 3-7%; fibre 2-7%; mineral matter 3-7%; protein 6-8% fat

5-10%; moisture 6-13% & carbohydrates 60-70%

Average intake (India) is as much as 2-3g daily

From traditional medicine to modern medicine• Since the time of Ayurveda (around 1900 BC) numerous therapeutic activities have been

ascribed to turmeric for a wide variety of diseases and conditions

• Extensive research within the last half century has proven that most of these activities, once associated with turmeric, are due to curcumin with its structure as only determined in 1910

• Curcumin has been shown to exhibit antioxidant, anti-inflammatory, antiviral, antibacterial, antifungal and anticancer activities and thus has potential against various malignant diseases, diabetes, allergies, arthritis, Alzheimer's disease, and other chronic illnesses

• The first study on curcumin’s biological activity (according to Pubmed) as an antibacterial agent was published in 1949 in Nature and the first clinical trial was reported in The Lancet in 1937

• Although the current database indicates almost 10,000 publications on curcumin, until 1990 there were less than 100 papers published

Curcumin mechanisms• Inflammation and pro-inflammatory processes are centrally linked to several chronic human

diseases, including cancer, diabetes, obesity, arthritis, and cardiovascular and neurodegenerative diseases

• In in vitro, animal and human studies, curcumin has shown antioxidant, anti-cancer, anti-tumour, anti-arthritic, anti-amyloid, anti-ischemic and anti-inflammatory properties, as well as other benefits

• Curcumin’s multitude of health benefits are primarily (but not exclusively) attributed to its direct targeting of the transcription factor nuclear factor kappa B ( NF-κB ), also known as the inflammatory ‘master switch’

• When NF-κB is stimulated (by factors such as stress, inflammation, pathogens, lipopolysaccharides (LPS), trauma and so on), it is released from its inhibitory molecule IKB, thereby allowing its movement to the cell nucleus where it ‘switches on’ genes responsible for the production of a number of proinflammatory products, initiating an inflammatory cascade of events

• Curcumin prevents NF-κB from entering the nucleus, thereby blocking inflammation at an early stage

NF-κB in chronic disease – a target for nutritional intervention

Curcumin can modulate various types of signalling molecules including transcription factors, enzymes, growth factors, interleukins, cytokines & chemokines

Ghosh S, Banerjee S, Sil PC. The beneficial role of curcumin on inflammation, diabetes and neurodegenerative disease: A recent update. Food Chem Toxicol. 2015 Sep;83:111-24.

Pulido-Moran M, Moreno-Fernandez J, Ramirez-Tortosa C, Ramirez-Tortosa M Curcumin and Health. Molecules. 2016 Feb 25;21(3):264.

Antioxidant properties and reactive oxygen species (ROS) scavenger effects of curcumin

Sharma RA, McLelland HR, Hill KA, Ireson CR, Euden SA, Manson MM, Pirmohamed M, Marnett LJ, Gescher AJ, Steward WP. Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancer. Clin Cancer Res. 2001;7:1894–1900

Wahlstrom B, Blennow G. A study on the fate of curcumin in the rat. Acta Pharmacol Toxicol (Copenh) 1978;43:86–92.

•As curcumin has poor aqueous solubility, very little gets into the circulation and simply passes through the body via the gastrointestinal system

•In contrast, any curcumin that is absorbed undergoes extensive first-pass metabolism optimising its efficient excretion by the kidneys - thus, the majority of oral curcumin is simply excreted

•High doses of curcumin (>400 mg/kg of body weight) are required to obtain detectable tissue levels in rats

Wahlstrom et al (1978) administered curcumin at 1 g/kg to Sprague-Dawley rats and found 65–85% of the dose excreted unchanged in the faeces, with negligible amounts in the urine

Sharma et al (2001) administered Curcuma extract 440 to 2,200 mg/day (36 to 180 mg of curcumin) for up to 29 days to patients with advanced colorectal cancer and failed to detect curcumin or its metabolites in blood or urine, with considerable amounts found unchanged in the faeces

For curcumin supplements to offer significant health benefits steps must be taken to increase absorption and prevent excretion

Curcumin's benefits are hampered by its poor bioavailability

Free curcumin vs. glucuronidated curcumin

Curcumin is a lipophilic molecule that is nearly insoluble in water and the process of glucuronidation and sulfation (by the intestines and liver) renders curcumin water soluble, thereby allowing its efficient excretion via the kidneys

– Curcumin’s major metabolites are the glucuronides of tetrahydrocurcumin (THC) and hexahydrocurcumin (HHC) both of which are significantly less active than curcumin in the free form

– Free, unconjugated (unmetabolised) curcumin is, by nature, less water soluble, and therefore present for longer in the body

The focus on increasing curcumin’s bioavailability is to optimise solubility, stability, permeability and to deliver curcumin to target tissues in the free form

Pulido-Moran M, Moreno-Fernandez J, Ramirez-Tortosa C, Ramirez-Tortosa M Curcumin and Health. Molecules. 2016 Feb 25;21(3):264.

• Patients (n-25) received 8 g curcumin (900 mg curcumin, 80 mg DSM and 20 mg BDSM) for 8 weeks

• Circulating curcumin was detectable as well as glucuronide and sulfate conjugate forms, suggesting poor oral bioavailability

• Curcumin down-regulated expression of NF-kB and COX-2

• Curcumin levels peaked at 22 to 41 ng/mL with considerable inter-patient variation

The study concluded that a high dose of oral curcumin is well-tolerated and, despite limited absorption, has some biological activity in some patients with pancreatic cancer

Overcoming biovaiaibility issues would allow smaller doses to be delivered in clinical settings

Dhillon N, Aggarwal BB, Newman RA, Wolff RA, Kunnumakkara AB, Abbruzzese JL, Ng CS, Badmaev V, Kurzrock R. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res. 2008 Jul 15;14(14):4491-9

Phase II Trial of curcumin in patients with advanced pancreatic Cancer

Potent antioxidant effects– curcumin’s antioxidant mechanisms protect cells against oxidative damage

Improves liver function – curcumin regulates the activity of a number of key enzymes and antioxidants essential for optimal detoxification

Cardiovascular health – curcumin promotes cardiovascular health and function, and protects low density lipoprotein (LDL) from oxidation

Immune health – curcumin improves and supports immune function

Joint health – curcumin significantly improves joint health by reducing inflammation and promoting joint comfort and flexibility

Digestive health – curcumin stimulates bile production and promotes healthy digestive function

Anti-cancer benefits – curcumin offers protective benefits against the main hallmarks of cancer including angiogenesis, proliferation, metastasis, inflammation and apoptosis

NF-κB in chronic disease – a target for nutritional intervention

Curcumin bioavailability is dependent on a number of factors

• Solubility - curcumin must be able to ‘dissolve’ into the contents of the stomach - if it isn’t soluble, it won’t be absorbed

• Stability - curcumin is a very delicate compound that must be able to survive harsh acidic or alkaline conditions as well as glucuronidating enzymes

• Permeability - curcumin must get across the cells of the stomach or intestines and into the system to have an effect on the body’s target tissues (and to pass the blood-brain barrier to have cognitive benefits)

• Metabolism – curcumin must avoid metabolism by enzymes present in the lining of the gut and, to a greater extent, in the liver – the metabolites of curcumin are not in an active form and are easily excreted

Health benefits

If bioavailability is optimised, meaning that free form curcumin reaches therapeutic levels in plasma which are active for a sufficient length of time, the health benefits of curcumin are many!

Use of piperine to increase the bioavailability of curcuminPiperine is a compound commonly found in black pepper known to slow down hepatic and intestinal glucuronidation, which basically means elimination of different substances from the liver and gut

This is helpful in increasing the bioavailability of curcumin because it stays in the body longer and higher levels of curcumin get past the liver and stomach

•In humans (n=6), serum levels curcumin were either undetectable or very low after a dose of 2g•Concomitant administration of piperine 20 mg produced much higher concentrations from 0.25 to 1 h post drug (P < 0.01 at 0.25 and 0.5 h; P < 0.001 at 1 h), with an increase in bioavailability of 2000%•Piperine enhances the serum concentration, extent of absorption and bioavailability of curcumin in humans with no adverse effects

But……is blocking glucuronidation necessarily a good thing?

Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med. 1998 May;64(4):353-6.

KidneysMolecules excreted via

urine

Gallbladder Heavier molecules are mixed with bile and eliminated in the faeces

Processed toxins ready for elimination

Phase II DetoxificationConjugation makes molecules more water soluble for easy elimination

Phase I DetoxificationOxidise, reduce or hydrolyse toxins, to break them into smaller, electrically-

charged substances

Intermediate metabolites

Superoxide radicals

Radical oxygen intermediates

Microbial endotoxinsMetabolic byproducts

Drugs & chemicals

Secondary tissue damage

To improve the bioavailability of curcumin, numerous approaches have been undertaken, including:

• Use of adjuvant that interferes with glucuronidation Piperine (black pepper extract)• Inclusion of turmeric volatile oils

BCM-95®• Nanoformulations (liposomes, micelles, etc)

Novasol® Longvida® Curcuwin

• The use of curcumin phospholipid complex Meriva-SR®

Micelles and phospholipid complexes increase the absorption resulting in higher blood plasma concentration and lower elimination, thus increasing the bioavailability. Of these Meriva-SR® and Longvida® have shown promise in human clinical trials

Meriva vs. Longvida

Phytosome technologyMeriva (phospholipid complex)

Natural curcuminoid mixture (20%)•75% curcumin•15% DMC•10% BDMC

Phosphatidylcholine (40%)Microcrystalline cellulose (40%)

Phytosomes are more bioavailable than uncomplexed curcuminoids due to their enhanced capacity to cross the lipid membranes and to reach the systemic circulation

Phospholipid

Curcuminoid

Curcuminoid-phospholipid complex

Marczylo TH, Verschoyle RD, Cooke DN, Morazzoni P, Steward WP, Gescher AJ. Comparison of systemic availability of curcumin with that of curcumin formulated with phosphatidylcholine. Cancer Chemother Pharmacol. 2007 Jul;60(2):171-7. Epub 2006 Oct 19.

Meriva vs. standard curcumin (rodents)

These results indicate that whilst Meriva’s Phytosome technology increases the bioavailability of curcuminoids it doesn’t reduce phase II glucuronidation processes – we need to focus on raising free curcumin

• Rats received 340 mg/kg of either unformulated curcumin or curcumin formulated with phosphatidylcholine (Meriva)

• Peak plasma levels and area under the plasma concentration time curve (AUC) values for parent curcumin after administration of Meriva were fivefold higher (26.7 vs 4.8 mg min/ml) than the equivalent values seen after unformulated curcumin

• Liver levels of curcumin and curcumin metabolites were higher after administration of Meriva as compared to unformulated curcumin

Cmax (nM) Tmax (min) AUC (mg min/ml)

Standard curcuminFree curcumin 6.5 ± 4.5 30 4.8Curcumin glucoronidate 225 ± 0.6 30 200.7Curcumin sulphate 7 ± 11.5 60 15.5Meriva PhytosomeFree curcumin 33.4 ± 7.1 15 26.7Curcumin glucuronidate 4,420 ± 292 30 4,764.7Curcumin sulphate 21.2± 3.9 60 24.4

Meriva vs. standard curcumin (human study)

Cuomo J, Appendino G, Dern AS, Schneider E, McKinnon TP, Brown MJ, Togni S, Dixon BM. Comparative absorption of a standardized curcuminoid mixture and its lecithin formulation. J Nat Prod. 2011 Apr 25;74(4):664-9. doi: 10.1021/np1007262. Epub 2011 Mar 17.

• A randomised, double-blind, crossover study was carried out in nine volunteers, measuring the plasma concentrations of three curcuminoids [curcumin, DMC and BDMC] after supplementation with two dosages of Meriva and one dosage of the same batch of standard curcumin

• Doses were based on clinical studies for inflammatory conditions, where active dosages of around 1-2 g/day of standard curcumin - around 200-300 mg of curcuminoids as Meriva were used

• Subjects consumed, in random order and on separate study days, five (low-dose) or nine (high-dose) capsules of Meriva, corresponding to 209 and 376 mg total curcuminoids, or, alternatively, five capsules of the corresponding non-formulated curcuminoid mixture (reference) containing 1799 mg of total curcuminoids

• Both materials had a similar ratio of all three natural curcuminoids (75% curcumin, 15% DMC, 10% BDMC)

Meriva High dose Meriva Low dose Reference dose Free curcumin 297 165 1295DMC 68 38 369BDMC 11 6 108Total curcuminoids 376 209 1799

Meriva vs. standard curcumin (human study)

Cuomo J, Appendino G, Dern AS, Schneider E, McKinnon TP, Brown MJ, Togni S, Dixon BM. Comparative absorption of a standardized curcuminoid mixture and its lecithin formulation. J Nat Prod. 2011 Apr 25;74(4):664-9. doi: 10.1021/np1007262. Epub 2011 Mar 17.

Cmax (ng/mL) Tmax (h) AUC (ng/mL)

Meriva high doseFree curcumin 50 ± 13 3.8 538 ± 131DMC 135 ± 41 2.4 655 ± 196BDMC 25 ±8 2.2 142 ± 58Total curcuminoids 207 ± 55 2.7 1136 ± 357Meriva low doseFree curcumin 24 ± 6 4.2 272 ± 68.52DMC 39 ± 11 3.1 297 ± 107BDMC 9 ± 3 2.4 70 ± 34Total curcuminoids 69 ± 17 3.3 640 ± 198ReferenceFree curcumin 9 ± 3 6.9 123 ± 29DMC 4 ± 1 4.4 56 ± 16BDMC 2 ± 0.8 3.4 25 ± 10Total curcuminoids 14 ± 4 6.9 203 ± 54

• Phytosome delivered curcuminoids (209 mg and 376 mg) resulted in significantly higher plasma levels than a higher dose of unformulated curcuminoids (1799 mg)

• However, the major plasma curcuminoid ‘delivered’ by Meriva was DMC and not curcumin

• The marked differences in the plasma curcuminoid profile could not be accounted for by the nature of the starting materials, since Meriva capsules and the noncomplexed curcumin capsules contained very similar curcuminoid profiles

• The DMC & BDMC forms of curcumin were therefore absorbed better than free curcumin

• No information on curcumin metabolites (curcumin glucuronidate or sulphate) provided

Curcumin, the principal curcuminoid found in turmeric, is generally considered its most active constituent

Longvida technology

• Solid Lipid Curcumin Particle technology (SLCP) is a novel process based on supercritical fluid technology used for encapsulating curcumin in solid lipid particles (SLP) to yield curcumin formulations with enhanced and superior properties

• Longvida uses supercritical fluid (SCF) technology which operates under mild conditions, avoids high temperatures (curcumin is heat sensitive) and, unlike many competitor products, is also free of harsh solvents and volatile oils, and piperine (which blocks the glucuronidation of curcumin but can also therefore interfere with other essential glucuronidation involved in phase II liver detoxification processes)

Longvida optimized curcumin delivery system Longvida curcumin is able to survive the harsh digestive pH conditions and

doesn’t get destroyed by the acidic environment of the stomach

Longvida provides a unique coating (of highly purified fatty acids and phospholipids) that surrounds the curcumin molecule and enables it to be transported into the lymphatic system rather than the circulatory system

Unlike the circulatory system, the lymphatic system bypasses the liver (the major organ for metabolism) so less curcumin is exposed to metabolic enzymes and remains in a free form

The small particle size of Longvida curcumin ensures its easy passage across the intestinal cell membrane

Longvida vs. standard curcumin (human study)

650 mg Longvida curcumin

650 mg standard curcuminoids

Cmax (ng/mL) 22.43 ± 1.92 <1

Tmax (hours) 2.4 ± 0.44 na

AUC (0-t) (ng/mL-h) 95.26 ± 4.62 na

T ½ (h) 7.46 ± 2.43 na

• Healthy subjects (n=6) were given Longvida or 95% curcuminoids extract (standard curcumin) at a dose of 650 mg

• 400 mg Longvida® Optimized Curcumin, contains approximately 80 mg curcumin in a solid lipid formulation so the dose of 650mg equates to approximately 130 mg curcumin

• Plasma concentrations of curcumin were significantly higher for Longvida Cmax (22ng/mL) compared to standard curcumin (<1ng/mL) - remember – 209mg Mervia curcumin resulted in a Cmax 24ng/ (24ng/mL)

• Half life was 7.46 hours

• The tmax (time at which the maximum concentration [Cmax] is observed) was 2.4 hours

Gota VS, Maru GB, Soni TG, Gandhi TR, Kochar N, Agarwal MG: Safety and pharmacokinetics of a solid lipid curcumin particle formulation in osteosarcoma patients and healthy volunteers. Journal of agricultural and food chemistry 2010, 58:2095-2099.Shah et al. Acute human pharmacokinetics of a lipid-dissolved turmeric extract. Planta Med 2012; 78 DOI: 10.1055/s-0032-1320664

• Longvida® curcumin is highly stable and highly soluble, optimised to deliver free curcumin (the active form that is not metabolised or glucuronidated) into the bloodstream and target tissues

• Free curcumin is the only form that is proven to pass the blood-brain barrier - curcumin's symmetrical phenol groups make it more brain-permeable and able to cross the blood-brain barrier

• The concentrations of curcumin detected after dosing with 400mg (80mg curcuminoids) are in the range offering therapeutic impact in various models

• Longvida® Optimised Curcumin has a patented lipid delivery technology offering 285x greater bioavailability, 65x higher peak plasma levels and 7x longer-lasting action than standard curcumin

Gota VS, Maru GB, Soni TG, Gandhi TR, Kochar N, Agarwal MG: Safety and pharmacokinetics of a solid lipid curcumin particle formulation in osteosarcoma patients and healthy volunteers. Journal of agricultural and food chemistry 2010, 58:2095-2099.Shah et al. Acute human pharmacokinetics of a lipid-dissolved turmeric extract. Planta Med 2012; 78 DOI: 10.1055/s-0032-1320664

Longvida® Optimised Curcumin offers unprecedented bioavailability

Longvida curcumin reduces NF-κB transcriptional activity (and reduces inflammation)

Longvida curcumin significantly inhibited the transcriptional activity of NF-κB in LPS-activated macrophages at tested concentrations

NF-κB signalling pathway is the predominant upstream molecular signalling pathway that causes inflammation through enhanced cytokine, nitric oxide and prostaglandin production

Lipopolysaccharides (LPS) are endotoxins found in the outer membrane of Gram-negative bacteria, and elicit strong immune responses via NF-κB activation

LPS-induced NF-κB up-regulation accounts for a part of LPS-mediated activation of a variety of inflammatory genes

An in-vitro study to determine the dose effects of Longvida curcumin SLCP formulations on NF-κB activation in macrophages stimulated with LPS

Nahar PP, Slitt AL, Seeram NP. Anti-Inflammatory Effects of Novel Standardized Solid Lipid Curcumin Formulations. J Med Food. 2015 Jul;18(7):786-92

Placebo controlled trial showed supplementation with Longvida curcumin (400 mg/day) to significantly reduce pro-inflammatory markers of exercise-induced muscle damage including pro-inflammatory cytokines (IL-6, IL-8, IL-10, and TNF-α) and creatine kinase (CK)

Takahashi M et al., Effects of curcumin supplementation on exercise-induced oxidative stress in humans. Int J Sports Med. 2014 Jun;35(6):469-75.

Anti-inflammatory effects of Longvida curcumin

PREDay 1Day 2Day 3 Day 4PREDay 1Day 2Day 3 Day 4

Measurements were made prior to (PRE), 1, 2, 3 and 4 days following exercise-induced muscle damage

Heat map for global changes demonstrates that curcumin treatment was associated with a muted response for serum cytokines (IL-6, IL-8, IL-10, and TNF-α) and creatine kinase (CK)

Reduced muscle soreness experienced with curcumin treatment matches with the pro-inflammatory biomarkers, particularly at 2 and 4 days

The health promoting effects of Longvida curcumin in healthy individuals

Longvida curcumin Lowered -amyloid protein: a marker of brain ageing, especially in relation to

Alzheimer’s disease Lowered triglycerides: related to increased risk of poor cardiovascular

health Soluble intercellular adhesion molecule (sICAM): linked to

atherosclerosis Salivary amylase: a marker of sympathetic nervous system stress Alanine aminotransferase (ALT): a marker of liver injury

Longvida curcumin Increased Catalase activity: an antioxidant enzyme Antioxidant status: linked to lower levels of damaging free radicals

DiSilvestro RA, Joseph E, Zhao S, Bomser J. Diverse effects of a low dose supplement of lipidated curcumin in healthy middle aged people. Nutr J. 2012 Sep 26;11:79. doi: 10.1186/1475-2891-11-79.

In a 30 day, randomised placebo-controlled trial, daily supplementation with 400mg Longvida curcumin in healthy, middle-aged individuals (40-60 years) led to significant (p<0.05) improvements (versus placebo) in the following markers:

Longvida crosses the blood-brain barrier

• Longvida has been demonsrtated to deliver free curcumin across the blood-brain barrier and is able to significantly improve markers of cognitive health and brain ageing, including improved β-amyloid clearance

• Thus low dose Longvida provides the blood concentrations of free curcumin required to disaggregate β-amyloid plaques and further prevent new plaques from forming

• Longvida is one of the only curcumin dosage forms to show stability of free curcumin in the bloodstream, meaning extended release with just a single small daily dose

DiSilvestro RA, Joseph E, Zhao S, Bomser J. Diverse effects of a low dose supplement of lipidated curcumin in healthy middle aged people. Nutr J. 2012 Sep 26;11:79. doi: 10.1186/1475-2891-11-79.

Ma QL, Zuo X, Yang F, Ubeda OJ, Gant DJ, Alaverdyan M, Teng E, Hu S, Chen PP, Maiti P, Teter B, Cole GM, Frautschy SA. Curcumin suppresses soluble tau dimers and corrects molecular chaperone, synaptic, and behavioral deficits in aged human tau transgenic mice. J Biol Chem. 2013 Feb 8;288(6):4056-65.

• The blood–brain barrier is a highly selective semi-permeable membrane barrier that separates the circulating blood from the brain extracellular fluid in the central nervous system

Curcumin mechanisms (in vivo) Metals can promote amyloid-β aggregation, and the drug clioquinol, a metal chelator of copper,

zinc and iron, has been shown to dramatically reduce amyloid-β deposits

Curcumin’s chelation of both iron and copper (but not zinc) has been proposed as one mechanism potentially contributing to amyloid-β reduction in animal models

Soluble amyloid-β oligomers are more diffusible than amyloid fibrils, highly toxic and increasingly viewed as playing an important role in AD pathogenesis

Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, Chen PP, Kayed R, Glabe CG, Frautschy SA, Cole GM. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem. 2005 Feb 18;280(7):5892-901. Ono K, Hasegawa K, Naiki H, Yamada M. Curcumin has potent anti-amyloidogenic effects for Alzheimer's beta-amyloid fibrils in vitro. J Neurosci Res. 2004 Mar 15;75(6):742-50.

Curcumin can bind to plaques and block amyloid-β aggregation as well as fibril and oligomer formation

Curcumin can inhibit aggregation or promote disaggregation of amyloid plaques even at low concentrations

Curcumin treatment reduces central nervous system inducible nitric-oxide synthase, inflammatory cytokines and lipid peroxidation

Curcumin fluoresces (left) during binding to amyloid-β, versus control (no curcumin) on the right. (Ono 2004) Curcumin is an established binding agent of amyloid-β.

Longvida curcumin has been shown in animal models to reduce soluble tau and elevate heat shock proteins involved in tau clearance

Ma QL, Zuo X, Yang F, Ubeda OJ, Gant DJ, Alaverdyan M, Teng E, Hu S, Chen PP, Maiti P, Teter B, Cole GM, Frautschy SA. Curcumin suppresses soluble tau dimers and corrects molecular chaperone, synaptic, and behavioural deficits in aged human tau transgenic mice. J Biol Chem. 2013 Feb 8;288(6):4056-65.

Longvida curcumin offers benefits in Alzheimer's disease

Curcumin reduces tau by directly reducing the activation of tau kinase such as JNK and GSK3β in neurons and by reducing glial produced inflammatory cytokines that activate neuronal tau kinases Curcumin not only directly binds to and limits aggregation of the amyloid β-sheets but also restores homeostasis of the inflammatory system, boosts the heat shock system to enhance clearance of toxic aggregates, scavenges free radicals, chelates metals and induces anti-oxidant response elements!

The effect of Longvida curcumin on mood

Cox KH, Pipingas A, Scholey AB. Investigation of the effects of solid lipid curcumin on cognition and mood in a healthy older population. J Psychopharmacol. 2015 May;29(5):642-51.

ResultsOne hour after administration curcumin significantly improved performance on sustained attention and working memory tasks, compared with placebo

Working memory and mood (general fatigue and change in state calmness, contentedness and fatigue induced by psychological stress) were significantly better following chronic treatment

A significant acute-on-chronic treatment effect on alertness and contentedness was also observed

Longvida curcumin was associated with significantly reduced total and low-density (LDL) cholesterol levels

Curcumin possesses many properties which may prevent or ameliorate pathological processes underlying age-related cognitive decline, dementia or mood disorders

Randomised, double-blind, placebo-controlled trial examined the effects of 400mg Longvida curcumin on cognitive function, mood and blood biomarkers in 60 healthy adults aged 60-85

Samples taken:1 and 3 h after a single dose (acute dose)4 weeks of daily intake (chronic dose)1 and 3 h after single dose following chronic dose treatment (acute-on-chronic)

Longvida positioning

Product features

Delivers free curcumin Crosses the blood-brain barrier 285x greater bioavailability 65x higher peak plasma levels 7x longer lasting action Clinically validated to support cognitive &

general health Effective at low doses (1 x 500 mg per day) Fast onset Highly soluble Proven stability

Serving size: 1 capsule Per serving % RI*Longvida® optimised curcumin extract from turmeric root (min. 20% curcuminoids)

500 mg n/a

DIRECTIONS FOR USEAdults: take 1 capsule daily with food. For intensive support, take 2 capsules daily as a split dose. Do not exceed the dose unless advised by a healthcare practitioner.

NUTRITIONAL INFORMATION

INGREDIENTS: Longvida® optimised curcumin extract; capsule shell (emulsifier: hydroxypropyl methylcellulose); stearic acid; soy lecithin; maltodextrin; ascorbyl palmitate; silicon dioxide.

Free from: dairy, gluten, lactose, soya protein, wheat, yeast, artificial colours and flavours; not tested on animals; non-GMO; suitable for vegetarians & vegans; halal & kosher.

* % Reference Intake

Product information

Permeability SolubilityStability

Curcumin offers synergistic benefits with omega-3 fatty acids

Thota RN et al., Curcumin and long-chain Omega-3 polyunsaturated fatty acids for Prevention of type 2 Diabetes (COP-D): study protocol for a randomised controlled trial. Trials. 2016 Nov 29;17(1):565.

Lerdchai K, et al., Thai Silk Fibroin/Gelatin Sponges for the Dual Controlled Release of Curcumin and Docosahexaenoic Acid for Anticancer Treatment. J Pharm Sci. 2016 Jan;105(1):221-30.

Mirza KA et al., In vitro assessment of the combined effect of eicosapentaenoic acid, green tea extract and curcumin C3 on protein loss in C2C12 myotubes. In Vitro Cell Dev Biol Anim. 2016 Sep;52(8):838-45

Odenthal J et al., The influence of curcumin, quercetin, and eicosapentaenoic acid on the expression of phase II detoxification enzymes in the intestinal cell lines HT-29, Caco-2, HuTu 80, and LT97. Nutr Cancer. 2012 Aug;64(6):856-63.

Saw CL, et al., Synergistic anti-inflammatory effects of low doses of curcumin in combination with polyunsaturated fatty acids: docosahexaenoic acid or eicosapentaenoic acid. Biochem Pharmacol. 2010 Feb 1;79(3):421-30.

Fiala M. Curcumin and omega-3 fatty acids enhance NK cell induced apoptosis of pancreatic cancer cells but curcumin inhibits interferon-γ production: benefits of omega-3 with curcumin against cancer. Molecules. 2015 Feb 12;20(2):3020-6.

Halder RCet al., Curcuminoids and ω-3 fatty acids with anti-oxidants potentiate cytotoxicity of natural killer cells against pancreatic ductal adenocarcinoma cells and inhibit interferon γ production. Front Physiol. 2015 May 22;6:129.

Ideal to be used alongside Pharmepa RESTORE & Maintain

Potent synergistic antioxidant and anti-inflammatory health benefits

Improved insulin signalling – benefits for type II diabetes

Improved cognitive functions – benefits for neurocognitive disorders

Increasing number of studies are showing synergistic health benefits combining omega-3 EPA & DHA with curcumin

Education Technical

Sophie TullyNutrition Education Manager

sophiet@igennus.com

Dr Nina Bailey Head of Nutrition

ninab@igennus.comTwitter @DrNinaBailey

Jäger R, Lowery RP, Calvanese AV, Joy JM, Purpura M, Wilson JM. Comparative absorption of curcumin formulations. Nutr J. 2014 Jan 24;13:11.

Directly compare Meriva, BCM95, Curcuwin against curcumin was in a randomized, double-blind, crossover human study in healthy volunteers

Inclusion of turmeric volatile oilsBCM-95®

Nanoformulations (liposomes, micelles, etc) Curcuwin (similar to Lonvida)

Curcumin phospholipid complexMeriva-SR®

Jäger R, Lowery RP, Calvanese AV, Joy JM, Purpura M, Wilson JM. Comparative absorption of curcumin formulations. Nutr J. 2014 Jan 24;13:11. doi: 10.1186/1475-2891-13-11.Cuomo J, Appendino G, Dern AS, Schneider E, McKinnon TP, Brown MJ, Togni S, Dixon BM. Comparative absorption of a standardized curcuminoid mixture and its lecithin formulation. J Nat Prod. 2011 Apr 25;74(4):664-9. doi: 10.1021/np1007262. Epub 2011 Mar 17.

MethodsThe relative absorption of a curcumin phytosome formulation (CP - Meriva), a formulation with volatile oils of turmeric rhizome (CTR - BCM95) and a formulation of curcumin with a combination of hydrophilic carrier, cellulosic derivatives and natural antioxidants (CHC - Curcuwin) in comparison to a standardized curcumin mixture (CS - curcumin) was investigated in a randomized, double-blind, crossover human study in healthy volunteer

Subjects consumed optically identical 6 hard gel capsules of each of the study materials per setting yielding 376 mg of total curcuminoids for Meriva, BCM95 & Curcuwin and 1,800 mg of total curcuminoids for standard curcumin. The dose was selected based on Cuomo et al.

ResultsTotal curcuminoids appearance in the blood was 1.3-fold higher for BCM95 and 7.9-fold higher for Meriva in comparison to unformulated curcumin. CHC showed a 45.9-fold higher absorption over curcumin and significantly improved absorption over Meriva (5.8-fold) and BCM95 (34.9-fold, all p < 0.001)

ConclusionA formulation of curcumin with a combination of hydrophilic carrier, cellulosic derivatives and natural antioxidants significantly increases curcuminoid appearance in the blood in comparison to unformulated standard curcumin Meriva and BCM95

Comparative absorption of curcumin formulations

Jäger R, Lowery RP, Calvanese AV, Joy JM, Purpura M, Wilson JM. Comparative absorption of curcumin formulations. Nutr J. 2014 Jan 24;13:11. doi: 10.1186/1475-2891-13-11.

CurcuwinMerivaStandard curcumin (95%)BCM

Jäger R, Lowery RP, Calvanese AV, Joy JM, Purpura M, Wilson JM. Comparative absorption of curcumin formulations. Nutr J. 2014 Jan 24;13:11. doi: 10.1186/1475-2891-13-11.Cuomo J, Appendino G, Dern AS, Schneider E, McKinnon TP, Brown MJ, Togni S, Dixon BM. Comparative absorption of a standardized curcuminoid mixture and its lecithin formulation. J Nat Prod. 2011 Apr 25;74(4):664-9. doi: 10.1021/np1007262. Epub 2011 Mar 17.

Results in simple terms!BCM95 (376 mg of total curcuminoids) achieved curcumin plasma levels of 0.5ng/mLMeriva (376 mg of total curcuminoids) achieved curcumin plasma levels of 2.8ng/mLCurcuwin (376 mg of total curcuminoids) achieved curcumin plasma levels of 27.3ng/mLCurcumin (1800 mg of total curcuminoids) achieved curcumin plasma levels of 2.3ng/mL

Total curcuminoids(comparison to unformulated curcumin) appearance in the blood was 1.3-fold higher for BCM957.9-fold higher for Meriva45.9-fold higher for Curcuwin

Curcuwin resulted in 5.8-fold higher curcumin levels than Meriva and 34.9-fold higher curcumin levels than BCM95

Curcuwin seems superior!!

But.....lets look back at the study by Cuomo

Whilst this study gives the appearance that Curcuwin is superior 376mg raises levels to 27ng/mLWhich is less than the comparable dose reported by Cuomo which achieved levels of 50.3ng/mL

Comparative absorption of curcumin formulations

Cmax (ng/mLJäger

(Meriva)Cuomo

(Meriva)Jäger

(Cucuwin)Curcumin 2.8 50.3 27.3DMC 5.0 134.6 5.4BDMC 0.8 24.9 1.4Total curcumoids 8.6 206.9 34.9