No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Enhanced bioavailability and relative distribution of free (unconjugated) curcuminoids following the oral administration of a food-grade formulation with fenugreek dietary fibre: A randomised double-blind crossover study
... Curcumin-galactomannan complex (CGM) is a selfemulsifying hydrogel delivery system developed by the uniform encapsulation of curcumin within the fenugreek-derived galactomannan (soluble dietary fiber) hydrogel matrix. It has been shown to possess enhanced bioavailability of free (unconjugated) curcuminoids, improved blood-brain-barrier (BBB) permeability, brain bioavailability, and improved neuroprotective effects compared to unformulated standard curcumin complex with 95% purity (USC) (Krishnakumar et al., 2015;Kumar et al., 2016;Khanna et al., 2020). We hypothesized that CGM would be able to ameliorate the conditions of Alzheimer's disease upon continuous supplementation for longer duration. ...
... The MMSE scores and MRI scan are well-established diagnostic tools employed in the screening of subjects to confirm the stage of dementia and the onset of AD. Previous studies with CGM have shown its enhanced bioavailability of free curcuminoids, and improved BBB permeability and brain pharmacokinetics (Krishnakumar et al., 2015;Kumar et al., 2016;Khanna et al., 2020;Kannan et al., 2021). In the current study, we investigated the relative changes in cognitive and locomotive functions and serum markers, including BDNF, tau protein, Aβ42, IL-6, and TNF-α, during the study period of 6 months. ...
... The better influence of CGM can be attributed to its better free curcumin delivery and improved BBB permeability, as reported earlier (Krishnakumar et al., 2015;Khanna et al., 2020;Kannan et al., 2021). It is already known that the "free" unconjugated form of curcumin is a BBB-permeable molecule (Kumar et al., 2016;Cas and Ghidoni, 2019) and can inhibit β-sheet formation and bind with the fibrillar tau proteins to suppress soluble tau dimer formation in vitro (Rane et al., 2017;lo Cascio et al., 2019). Pathological hallmarks of AD include the deposition of amyloid β (Aβ) aggregates and the presence of neurofibrillary tangles of hyperphosphorylated tau proteins in brain tissues, leading to neuronal atrophy and death through excitotoxicity, neuroinflammation, defective calcium homeostasis, oxidative stress and energy depletion (lo Cascio et al., 2019;Silva et al., 2019). ...
Background: Although curcumin is a blood-brain-barrier permeable molecule
with the ability to bind and segregate β-amyloid plaques and neurofibrillary
tangles of hyperphosphorylated tau proteins, its poor oral bioavailability, rapid
biotransformation to inactive metabolites, fast elimination from the systemic
circulation, and hence the poor neuronal uptake has been limiting its clinical
e�cacy under neurodegenerative conditions.
Objective: We hypothesized that the highly bioavailable CurQfen-curcumin
(CGM), which has been shown to possess significant blood-brain-barrier
permeability and brain bioavailability, would ameliorate dementia in
neurodegenerative conditions.
Methods: In the present double-blinded placebo-controlled 3-arm 3-sequence
comparative study, 48 subjects characterized with moderate dementia due to the
onset of Alzheimer’s disease were randomized into three groups (N = 16/group)
and supplemented with 400 mg × 2/day of either placebo (MCC), unformulated
standard curcumin complex with 95% purity (USC), or CGM as a sachet for
six months. The relative changes in cognitive and locomotor functions and
biochemical markers were compared.
Results: Supplementation with CGMproduced significant (P < 0.05) improvement
in the Mini-Mental State Examination (MMSE) and the Geriatric Locomotive
Function Scale (GLFS) scores in both intra- and inter-group comparison by 2 ×
2 repeated measures (RM) ANOVA. Further, analysis of the serum levels of specific
biomarkers (BDNF, Aβ42, tau protein, IL-6, and TNF-α) also revealed a significant
(P < 0.05) improvement among CGM subjects as compared to placebo and the
USC groups.
Conclusion: Supplementation with CGM as sachet was found to oer significant
delay in the progress of Alzheimer’s disease, as evident from the improvements in
locomotive and cognitive functions related to dementia.
... Indeed, many authors agreed that plasma-free curcumin represents the bioactive form of curcumin and is currently the best indicator of bioavailability and bioequivalence [63][64][65]. Therefore, enzymatic hydrolysis can lead to a misreading of the results with an over-estimation of the free, bioactive curcumin at least 10-fold higher compared to non-hydrolyzed plasma samples [66]. Thus, in this review, data resulting from sample hydrolysis will be defined as "total curcumin" compared to "free curcumin" from nothydrolyzed samples. ...
... The latter are rich in galactomannan units and form a non-digestible gel hydrocolloid that undergoes fermentation in the colon, thus protecting curcumin from degradation. Moreover, the association of curcumin and soluble fiber seems to prolong the drug release [56,66]. A randomized double-blind crossover study was completed on 50 subjects who were administered 1000 mg of CurQfen ® (307 mg curcumin) or 411 mg of unformulated curcumin with similar content of curcuminoids. ...
... Beyond the dose dependency in the absorption of curcuminoids, CurQfen ® significantly increased free curcumin oral bioavailability compared to the standard formulation. From the analysis of free and conjugated metabolites ratio emerged an AUC average enhancement of 17.21%, confirming the hydrolysis-related overestimation, and the ability of fenugreek formulation to mainly provide free unconjugated curcuminoids in plasma, probably due to curcumin protection against enzymatic activity [66]. CurQfen ® effects were examined on 22 young obese men to test whether it could improve aortic stiffness and cardiovascular disease-associated blood biomarkers. ...
Curcumin possesses a plethora of interesting pharmacological effects. Unfortunately, it is also characterized by problematic drug delivery and scarce bioavailability, representing the main problem related to the use of this compound. Poor absorption, fast metabolism, and rapid systemic clearance are the most important factors contributing to low curcumin levels in plasma and tissues. Accordingly, to overcome these issues, numerous strategies have been proposed and are investigated in this article. Due to advances in the drug delivery field, we describe here the most promising strategies for increasing curcumin bioavailability, including the use of adjuvant, complexed/encapsulated curcumin, specific curcumin formulations, and curcumin nanoparticles. We analyze current strategies, already available in the market, and the most advanced technologies that can offer a future perspective for effective curcumin formulations. We focus the attention on the effectiveness of curcumin-based formulations in clinical trials, providing a comprehensive summary. Clinical trial results, employing various delivery methods for curcumin, showed that improved bioavailability corresponds to increased therapeutic efficacy. Furthermore, advances in the field of nanoparticles hold great promise for developing curcumin-based complexes as effective therapeutic agents. Summarizing, suitable delivery methods for this polyphenol will ensure the possibility of using curcumin-derived formulations in clinical practice as preventive and disease-modifying therapeutics.
... CurQfen® (CGM) is a 100 % natural and food-grade formulation of curcumin with fenugreek galactomannans (soluble dietary fiber). CGM was recognized to have high free curcuminoid absorption, enhanced BBB-permeability and better tissue distribution [30,31]. Once swell in the gastrointestinal tract, CGM has been shown to act as a self-emulsifying hydrogel with high mucoadhesive character, capable of delivering amphiphilic colloidal curcumin particles that can be absorbed quickly. ...
... CGM has already demonstrated its superior efficacy in a relatively low dosage [32][33][34], with improved brain bioavailability as revealed by its influence on brain waves [35], radioprotective [36] and neuroprotective effects [37,38]. CGM was reported to exhibit 45-fold enhancement in the bioavailability of free curcuminoids and 270-fold enhancement in the bioavailability of total curcuminoids (sum of conjugated and unconjugated), when compared to an equivalent dose of unformulated standard curcuminoids with 95 % purity [31]. CGM expressed longer circulation half-life (T 1/2 ) of 3.7 h with a sustained plasma concentration of 0.090 μg/mL even after 12 h of ingestion (C 12 ). ...
... Moreover, CGM was found to deliver significantly high levels of free curcuminoids even at a relatively low single dose of 250 mg with a maximum plasma concentration (C max ) of around 300 ng/mL. Tandem mass spectrometric measurements have further revealed high free curcuminoids to conjugated curcuminoids ratio in plasma, indicating the preferential absorption of the highly active free form of curcumin (> 60 %) [31]. Thus, CGM can be considered as the third generation bioavailable curcumin in terms of its 100 % natural status, water-based manufacturing process, organic certification, improved pharmacokinetics and 'free' curcuminoids bioavailability [31]. ...
Recently, there is a growing concern about the use of curcumin supplements owing to a few reported hepatotoxicity related adverse events among some of the long-term consumers. Even though no clear evidence was elucidated for the suspected toxicity, the addition of adjuvants that inhibits body’s essential detoxification pathways, adulteration with synthetic curcumin, and presence of contaminants including heavy metals, chromate, illegal dyes, non-steroidal anti-inflammatory agents, and pyrrole alkaloids were suggested as plausible reasons. Considering these incidences and speculations, there is a need to critically evaluate the safety of curcumin supplements for prolonged intake. The present study is an evaluation of the safety of curcumin-galactomannoside complex (CGM), a highly bioavailable curcumin formulation with demonstrated high free curcuminoids delivery. Twenty healthy human volunteers were evaluated for toxic manifestations of CGM when supplemented with 1000 mg per day (∼380 mg curcuminoids) for 90-days. CGM supplementation did not cause any adverse effects or clinically significant variations in the vital signs, hematological parameters, lipid profile and renal function markers of the volunteers, indicating its safety. Liver function enzymes aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT) and bilirubin were in the normal range after 90-day supplementation of CGM. In summary, no adverse effects were observed under the conditions of the study. CGM can be considered as a safe curcumin supplement for regular consumption and is devoid of any adulterants or contaminants.
... Numerous efforts have been made to improve the bioavailability of curcuminoids, and some of these techniques have also been applied to boswellic acids (Hüsch et al., 2013;Meins et al., 2018;Prasad, Tyagi, & Aggarwal, 2014). However, the majority of these formulations reported the availability of the total conjugated metabolites (glucuronides and sulfates) and not the bioavailability of the 'curcumin' component (Stohs et al., 2020;Szymusiak et al., 2016;Kumar et al., 2016). Various studies have shown that curcumin glucuronides (conjugated metabolite) experience poor membrane permeability and weak antioxidant, anti-inflammatory, and antiproliferative activities (Pal et al., 2014;Shoji et al., 2014;Choudhury, Raja, Mahapatra, Nagabhushanam, & Majeed, 2015;Begum et al., 2008) suggesting that these formulations may improve their bioavailability but have little impact on their efficacy. ...
... We previously reported a novel formulation for curcuminoid delivery using fenugreek (Trigonella foenum graecum) soluble dietary fiber (galactomannans) as a non-covalent water-dispersible molecular complex known as Curcumagalactomannosides (CGM; patented and registered as CurQfen®) (Krishnakumar, Ravi, Kumar, Kuttan, & Maliakel, 2012). This material was shown to significantly improve the levels of free curcuminoids in human plasma even at the relatively low dose of 250 mg and has also been shown to improve the blood-brain-barrier permeability and tissue distribution of curcuminoids (Kumar et al., 2016;Krishnakumar et al., 2015). Here, we used this fenugreek dietary fiber mediated technology (FENUMAT®) to produce a formulation that can be used as a platform for the simultaneous delivery of multiple phytonutrients (curcuminoids and boswellic acid, AKBA) from single microbeadlets. ...
... Curcuminoids and AKBA were extracted from the plasma samples and subjected to UPLC-ESI-QQQ-MS/MS analyses, as described by Kumar et al. (2016). The Agilent Jet Stream source at a capillary voltage of 3500 V was employed for the triple quadruple ESI-MS/MS analysis (6460 Mass spectrometer, Agilent India Pvt. Ltd., Bangalore, India) as described. ...
Simultaneous oral delivery of bioactive molecules with enhanced bioavailability is of great significance, especially when delivered from single beadlets. Here, we report the formulation, characterization, and pharmacokinetic properties of two poorly bioavailable lipophilic phytonutrients with synergistic effects, curcuminoids and 3-Acetyl-11-keto-β-boswellic acid (AKBA), following their co-delivery using fenugreek dietary fiber (Galactomannans)-based hydrogel beadlets (CGM-BSW). These beadlets are capable of extensive swelling and sustained-release of self-emulsified colloidal particles (150 – 200 nm) containing curcuminoids and AKBA allowing for improved absorption. The results of our double-blinded 4-way crossover, 4-sequence study (n = 14) demonstrated that a single dose of 250 mg of these beadlets enhanced the absorption of unconjugated curcuminoids (24.8-fold) and AKBA (6.9-fold) compared to their unformulated counterparts. The absorption of CGM-BSW formulated curcuminoids was also 5.6-fold higher than that of those formulated with turmerones (UCT). UPLC-ESI-QQQ-MS/MS was used to quantify both the curcuminoids and AKBA concentration in the plasma samples and this data was used to determine their pharmacokinetic characteristics.
... Various formulations that have been developed include: a liquid droplet nanomicellar formulation containing Gelucire® and polysorbate 20 (BioCurc®); micronized curcuminoids plus turmeric oil (BCM-95®; BioCurcu-max®); co-administered with piperine (Curcumin C 3 Complex®); formulated with phosphatidylcholine from soy lecithin and microcrystalline cellulose (Meriva®); a solid lipid curcumin particle (Longvida®); complexed with a hydrophobic carrier, cellulosic derivatives and natural antioxidants (CurcuWIN®); a micro-particle surface-controlled colloidal dispersion using ghatti gum and glycerin (Theracurmin®); complexed with fenugreekderived galactomannan fiber (CurQfen®); complexed with γ-cyclodextrin (Cavacurmin®); a matrix consisting of glycerol esters of fatty acids, medium chain triglycerides, hydroxymethylcellulose, sodium alginate and microcrystalline cellulose (MicroActive Curcumin); a mixture of surfactants, polar lipids and solvents (Hydro-curc™), a complex of triacetin and panodan spray-dried on porous silicon dioxide (Micronized Curcumin); a whey-protein-curcumin conjugate (CurcuminPro®), and a natural turmeric matrix formulation composed of carbohydrates, proteins, fiber and volatile oil (Acumin®/ Cureit®) [12,13,[24][25][26][27][28][29][30][31][32][33][34][35][36][37][38]. ...
... A major pitfall of most pharmacokinetic studies involving the diverse curcumin formulations has been the lack of demonstrated increase in free, bioactive curcumin in the blood [26][27][28][29][30][31][32][33][34][35][36][37][38]. With relatively few exceptions [13,24,26], plasma samples are routinely subjected to hydrolysis with the enzymes β-glucuronidase and sulfatase most commonly from Helix pomatia snail extracts to generate total curcumin [26][27][28][29][30][31][32][33][34][35][36][37][38] because curcumin glucuronide and curcumin sulfate are the predominant circulating but physiologically inactive conjugates of curcumin. ...
... A major pitfall of most pharmacokinetic studies involving the diverse curcumin formulations has been the lack of demonstrated increase in free, bioactive curcumin in the blood [26][27][28][29][30][31][32][33][34][35][36][37][38]. With relatively few exceptions [13,24,26], plasma samples are routinely subjected to hydrolysis with the enzymes β-glucuronidase and sulfatase most commonly from Helix pomatia snail extracts to generate total curcumin [26][27][28][29][30][31][32][33][34][35][36][37][38] because curcumin glucuronide and curcumin sulfate are the predominant circulating but physiologically inactive conjugates of curcumin. Thus, the resulting conclusions do not provide a clear understanding of the potential pharmacokinetic benefits of the formulations with respect to an increase in free, bioactive curcumin. ...
Background:
Numerous health benefits have been demonstrated for curcumin which is extracted from turmeric (Curcuma longa L). However, due to its poor absorption in the free form in the gastrointestinal tract and rapid biotransformation, various formulations have been developed to enhance its bioavailability. Previous studies indicate that the free form of curcumin is more bioactive than its conjugated counterparts in target tissues. Most curcumin pharmacokinetics studies in humans designed to assess its absorption and bioavailability have measured and reported total (free plus conjugated) curcumin, but not free, bioactive curcumin in the plasma because enzymatic hydrolysis was employed prior to its extraction and analysis. Therefore, the bioavailability of free curcumin cannot be determined.
Methods:
Eight human subjects (4 male, 4 female) consumed a single dose of 400 mg curcumin in an enhanced absorption formulation, and blood samples were collected over 6 h. Plasma was treated either with or without glucuronidase/sulfatase prior to extraction. Curcumin and its major metabolites were analyzed using HPLC-tandem mass spectrometry. In addition, the literature was searched for pharmacokinetic studies involving curcumin using PubMed and Google Scholar, and the reported bioavailability data were compared based on whether hydrolysis of plasma samples was used prior to sample analysis.
Results:
Hydrolysis of blood plasma samples prior to extraction and reporting the results as "curcumin" obscures the amount of free, bioactive curcumin and total curcuminoids as compared to non-hydrolyzed samples. As a consequence, the data and biological effects reported by most pharmacokinetic studies are not a clear indication of enhanced plasma levels of free bioactive curcumin due to product formulations, leading to a misrepresentation of the results of the studies and the products when enzymatic hydrolysis is employed.
Conclusions:
When enzymatic hydrolysis is employed as is the case with most studies involving curcumin products, the amount of free bioactive curcumin is unknown and cannot be determined. Therefore, extreme caution is warranted in interpreting published analytical results from biological samples involving ingestion of curcumin-containing products.
Trial registration:
ClinicalTrails.gov, trial identifying number NCT04103788 , September 24, 2019. Retrospectively registered.
... With relatively few exceptions (30,(33)(34)(35)(36)(37), plasma samples are routinely subjected to enzymatic hydrolysis due to the fact that the sulfate and glucuronide conjugates are the predominant forms of curcumin. As a consequence, these studies result in the subsequent measurement of total curcumin and not free curcumin (21)(22)(23)(24)(25)(26)(27)(28)(29)31,32,38) and do not provide a clear understanding of the potential pharmacokinetic benefits of the formulations with respect to free curcumin. ...
... An inverted dose-response effect was observed with the curcumin-galactomannan complex (CurQfen) (21). Another pharmacokinetic study should be conducted with this product to clarify the issue. ...
... When one examines the C max /mg curcumin and AUC/mg curcumin values for unformulated 95% curcumin from various studies (21,22,(25)(26)(27)(28)(29)31,32,(38)(39)(40)(41), wide variations occur in the values obtained (Table 3). Various reasons may exist for these disparate results based on differences in the analytical protocols including differences in doses given, manner of administration (with or without food), extraction procedures, analytical and quantitation methods, sample storage conditions, analytes determined, and how end-points were calculated. ...
Objective:
Curcumin exhibits many beneficial health-promoting characteristics. However, its poor oral absorption precludes its general use. This study assessed the bioavailability of a novel curcumin formulation compared to 95% curcumin and published results for various other curcumin formulations.
Methods:
A randomized, crossover, double-blind, comparator-controlled pharmacokinetic study was performed in 12 healthy adult subjects to determine the appearance of free curcumin and its metabolites curcumin sulfate and curcumin glucuronide in plasma after a single dose of a novel proprietary curcumin liquid droplet micromicellar formulation (CLDM) and unformulated 95% curcumin powder in capsule form. An equivalent 400-mg dose of each product was administered. The 95% curcumin contained 323 mg curcumin, and the CLDM contained 64.6 mg curcumin. Blood samples were drawn and plasma was analyzed for curcumin and its 2 conjugates without enzymatic hydrolysis by liquid chromatography-tandem mass spectroscopy.
Results:
Plasma levels of curcumin sulfate and curcumin glucuronide after 1.5 hours from CLDM were approximately 20 and 300 ng/mL, respectively, whereas the levels for 95% curcumin were near baseline. Free curcumin reached a maximum level of 2 ng/mL for CLDM and 0.3 ng/mL for 95% curcumin at 1.5 hours. For the CLDM, a small secondary free curcumin peak occurred at 12 hours and a tertiary 1.5-ng/mL peak occurred at 24 hours. The total curcumin absorbed as represented by the area under the curve (AUC)/mg administered curcumin for CLDM was 522 times greater than for the 95% curcumin.
Conclusions:
The novel CLDM formulation facilitates absorption and produces exceedingly high plasma levels of both conjugated and total curcumin compared to 95% curcumin. A comparison of the Cmax/mg curcumin and AUC/mg of administered curcumin for CLDM with data from pharmacokinetic studies of various enhanced absorption formulations indicate that the greatest absorption and bioavailability are produced with the novel CLDM formulation.
... However, large doses of curcumin (>300 mg) are required to achieve effectiveness. Since curcurmin is liposoluble, its use in coadministration with phospholipids (soja lecithines) improves its absorption by the organism [8,9,15,18,19]. From the different previous investigations,it comes out that the combination of curcumin with other substances increases the bioavailability of curcumin in vitro. Yet, only little is known about the mechanism of this effect. ...
... Likewise equations (18) and (19) in (21): ...
Why this miraculous and amphiphic compound, curcumin, which has a very extraordinary therapeutic potential (because can react with many targets in the organism), has a weak bioavailability in the organism and is metabolized in compoumds having very weak activity or inactive compounds? How to improve substantially its bioavailability and therefore its absorption in the organism in order to allow its incorporation in making of pharmaceuticals regardless of its nanoparticles of which the obtention is furthermore hardworking? It seems indicated to search the response in the kinetic and thermodynamic behavior of this compound or in its co-administration with the other compounds (more soluble in water) in vitro in order to understand how to increase its absorption in vivo. So our objective is to make better our understanding of the absorption of natural curcuminoids in the organism without resorting to their chemical transformation in nanoparticles that is additionally hardworking. In this paper, curcumin was examined in the presence of cafein in ethanol with the aim to deepen the knowledge of the interaction between them. The study has revealed the presence of two complexes A6B4 and AB9 (A = curcumin, B = cafein), evidenced by the Job's method (continuous variations method) whose complexation constants have been calculated and the value of (1.12 10 32) is higher than the value of (2.7 10-10) suggesting the great stability of .
... Several of these enhanced-absorption preparations are commercially available under different registered brand names. Bioavailabilities of curcumin in human studies of example branded products are presented in Table 3 [19,22,42], [45,46,47,48,49], [49,50,51,52,53,54,55,56],. ...
... CurQfen® is a combination of curcumin and a galactomannan-rich fiber extract from fenugreek seeds. It has been shown to boost curcumin bioavailability by 45.5-fold [53]. Longvida® uses particle-based technology for preparing curcumin with a mixture of lecithin and phospholipids from soy. ...
Curcumin, from the rhizome of turmeric (Curcuma longa L.), has a wide variety of biological activities. Unfortunately, its poor water-solubility greatly limits its bioavailability. The purpose of this study was to evaluate CUMINUP60®, a novel preparation utilizing a solvent-free, co-grinding method designed to improve curcumin’s bioavailability. We performed a single-center crossover experiment to compare the new product with standard 95% curcumin in the blood plasma of twelve healthy adults (10 males, 2 females). Total bioavailability of curcumin and its sulfate and glucuronide conjugates from the test product, measured by their areas under the curve over 12 h (AUC0-T), showed a combined increase of 178-fold over standard curcumin and its conjugates from the reference product. The new product represents a significant improvement for providing greater bioavailability of curcumin, as compared with several other branded preparations. It therefore has broad applications for preparing curcumin as a more effective health ingredient in functional foods, beverages, and nutraceuticals.
... Several successful technologies have been developed to improve the bioavailability and ultimately the therapeutic efficacy of curcumin and its curcuminoids [14,16,17]. A food-grade technology, with curcuminoids encapsulated in a fenugreek dietary fiber, showed enhanced bioavailability of free curcuminoids as well as safety in healthy individuals [18,19]. This bioavailable form also showed that supplementation using a low dose (400 mg once daily) significantly reduced pain and stiffness, and improved physical function in individuals with knee osteoarthritis [20]. ...
... Improvements in the bioavailability have resulted in clinical trials with lower doses. The curcumin provided in this study was a highly bioavailable curcumin supplement (CGM), which was developed through the encapsulation of the curcuminoids in a fenugreek galactomannan fiber, resulting in a higher bioavailability and relative distribution of free (unconjugated) curcuminoids [18,31]. These free curcuminoids are understood to be driver for the biological activity and this was demonstrated using a low dose of the highly bioavailable CGM in subsequent clinical studies [32,33]. ...
Background
Acute inflammation is the body’s immediate and well-coordinated response to injury, which if not resolved can lead to a state of chronic inflammation and is an important component of aging-associated pathologies and chronic diseases. Resolution of inflammation has been shown to be highly regulated by several endogenous specialized pro-resolving mediators which are metabolized from dietary omega-3 and -6 fatty acids. The aim of this pilot study was to validate the use of a combination of a specialized pro-resolving (SPM) enriched marine oil supplement and a highly bioavailable curcumin supplement to reduce pain/discomfort in healthy adults.
Methods
This was a virtual (remote), single-arm open-label study in healthy adults with mild to moderate pain. Twenty-nine individuals were provided with an SPM-enriched marine oil supplement (enriched for three SPM precursors) and a highly bioavailable curcumin supplement to be taken daily for 60 days. The Short-Form McGill Pain Questionnaire (SF-MPQ), Short-Form 36 (SF-36) Health Survey and Medical Symptoms Questionnaire (MSQ) were used to evaluate safety, tolerability and efficacy in reducing pain/discomfort of inflammation.
Results
The SF-MPQ showed significant improvement in all aspects of the questionnaire, especially in total pain, pain intensity and pain severity within 30 days of supplementation. Significant improvements were also observed in the physical health domain of the SF-36 health survey, particularly in the areas of pain and physical functioning at both days 30 and 60. No adverse events related to the study materials were reported during the study.
Conclusion
In conclusion, the combination of anti-inflammatory and pro-resolving supplements may provide a complementary approach for targeting pain/discomfort associated with inflammation.
Trial registration
ClinicalTrials.gov, NCT04819646. Registered 29 March 2021 – Retrospectively registered.
... Curcumagalactomannosides, (CGM), a selfemulsifying formulation of curcumin with fenugreek galactomannan hydrogel scaffold as a water-dispersible non-covalent curcumingalactomannan molecular complex. CGM is one such oral delivery form developed to address the bioavailability issues of curcumin [26,27]. It has been shown to exhibit high bioavailability of free (unconjugated) form of curcuminoids in human volunteers than the parent compound (45.5-fold), and several preclinical and clinical trials have suggested its physiologically relevant effects [26,27] and safety [28]. ...
... CGM is one such oral delivery form developed to address the bioavailability issues of curcumin [26,27]. It has been shown to exhibit high bioavailability of free (unconjugated) form of curcuminoids in human volunteers than the parent compound (45.5-fold), and several preclinical and clinical trials have suggested its physiologically relevant effects [26,27] and safety [28]. However, the influence of CGM on global gene expression has not been studied. ...
Background:
Chronic diseases or non-communicable diseases are a major burden worldwide due to the lack of highly efficacious treatment modalities and the serious side effects associated with the available therapies.
Purpose/study design:
A novel self-emulsifying formulation of curcumin with fenugreek galactomannan hydrogel scaffold as a water-dispersible non-covalent curcumin-galactomannan molecular complex (curcumagalactomannosides, CGM) has shown better bioavailability than curcumin and can be used for the prevention and treatment of chronic diseases. However, the exact potential of this formulation has not been studied, which would pave the way for its use for the prevention and treatment of multiple chronic diseases.
Methods:
The whole transcriptome analysis (RNAseq) was used to identify differentially expressed genes (DEGs) in the liver tissues of mice treated with LPS to investigate the potential of CGM on the prevention and treatment of chronic diseases. Expression analysis using DESeq2 package, GO, and pathway analysis of the differentially expressed transcripts was performed using UniprotKB and KEGG-KAAS server.
Results:
The results showed that 559 genes differentially expressed between the liver tissue of normal mice and CGM treated mice (100 mg/kg b.wt. for 14 days), with adjusted p-value below 0.05, of which 318 genes were significantly upregulated and 241 were downregulated. Further analysis showed that 33 genes which were upregulated (log2FC > 8) in the disease conditions were significantly downregulated, and 32 genes which were downregulated (log2FC < -8) in the disease conditions were significantly upregulated after the treatment with CGM.
Conclusion:
Overall, our study showed CGM has high potential in the prevention and treatment of multiple chronic diseases.
... The delineation of free curcumin versus total curcumin minimizes translational concerns, namely that the assessed bioavailability advantage of a curcuminoid formulation over C-95 is not exaggerated. [27,28,30] Stohs and colleagues in their 2019 study enumerated this, assessing a 31-fold increase in total curcumin after enzymatic hydrolysis. [31] Total curcumin analysis is an exogenous deconjugation step assessing for the sum of free and (formally) conjugated curcumin. ...
... [33,34] free curcumin analysis on the other hand evaluates for curcumin absorbed intact into the bloodstream, by assaying for curcumin directly from the plasma sample (i.e., no deconjugation step). [30] Many confounding factors weigh in on the likelihood of an in vitro process of a curcumin-conjugate hydrolysis process translating to what happens in a live system, [31] including the extent of involvement of neutrophils and macrophagessuch as with inflammation, pH, and starting concentration of conjugates. [35][36][37] Whereas curcumin is identified as bioactive, curcumin conjugates as inactive [37] and exogenous curcumindeconjugation as "variable", we conclude that the differential assessment of free curcumin separate from total curcumin adds further value to current best practice analyses. ...
Background:
Curcuminoids have been widely studied for human health and disease applications, yet bioavailability remains a hurdle to actualizing all the benefits ascribed to them. The lack of standardization in analysis method, confusion about what constitutes an ideal analyte, and conflicting thoughts around dosing strategies have made it difficult to draw parity between bioavailability and bioactivity and establish a baseline for formulation comparisons.
Methods:
This randomized double-blinded, 2-way cross over, single oral dose, comparative bioavailability study differentially evaluates curcumin at the time of its absorption and along various biotransformation pathways, to include free curcumin, the readily usable form of curcumin; individual and composite totals of curcumin and its analogues as exogenously cleaved conjugates, for example, total curcumin, total demethoxycurcumin (DMC), total bisdemethoxycurcumin (BDMC), and total curcuminoids respectively; and the bioactive metabolite of curcumin, total tetrahydrocurcumin (THC). As a primary study objective, the relative bioavailability of CURCUGEN, a novel dispersible, 50% curcuminoids-concentrated turmeric extract was compared to the standard curcumin reference product, curcuminoids 95% standardized extract (C-95), using the maximum concentration (Cmax), and area under the curve (AUC0-t) of free curcumin, total curcumin, total DMC, total BDMC and the curcumin active metabolite, as total THC.
Results:
The evaluation of free curcumin demonstrated that the Cmax and AUC0-t of the CURCUGEN was 16.1 times and 39 times higher than the Cmax and AUC0-t of C-95. Furthermore, total curcumin, total DMC, total BDMC, and total curcuminoids resulted in AUC0-t of the CURCUGEN at 49.5-, 43.5-, 46.8-, and 52.5-fold higher than C-95, respectively. The relative bioavailability of CURCUGEN for total THC was found to be 31 times higher when compared to C-95.
Conclusion:
As the first human pharmacokinetics study to apply best-practice recommendations and pharmaceutically-aligned guidance in the comprehensive evaluation of a novel curcuminoids formulation, we have established the novelty of said formulation while better standardizing for the common variances and discrepancies between curcuminoids and their derivatives in the literature and commercial marketing, alike.
... But, the poor oral bioavailability and lack of cellular uptake contributed by the insolubility and rapid biotransformation of curcuminoids to relatively low bioactive and impermeable glucuronide conjugated metabolites have been identified as its major limitation in clinical practices (13). Though various bioavailable formulations with enhanced bioavailability of conjugated curcumin metabolites (glucuronides and sulfates) have been reported, formulations capable of delivering significantly high levels of bioactive free (unconjugated) curcuminoids have recently emerged as more efficient forms of curcumin (14,15). Thus, the present study employed CGM, a food-grade formulation of curcumin with fenugreek galactomannans, that has been shown to deliver significant levels of free (unconjugated) curcuminoids at the cellular level to investigate the comparative radioprotective efficacy in irradiated mice and hence to delineate the efficacy of curcuminoids with bioavailability (14,16). ...
... Though various bioavailable formulations with enhanced bioavailability of conjugated curcumin metabolites (glucuronides and sulfates) have been reported, formulations capable of delivering significantly high levels of bioactive free (unconjugated) curcuminoids have recently emerged as more efficient forms of curcumin (14,15). Thus, the present study employed CGM, a food-grade formulation of curcumin with fenugreek galactomannans, that has been shown to deliver significant levels of free (unconjugated) curcuminoids at the cellular level to investigate the comparative radioprotective efficacy in irradiated mice and hence to delineate the efficacy of curcuminoids with bioavailability (14,16). ...
Purpose: The present study investigated the role of free curcuminoids bioavailability on the relative radioprotective efficacy of natural unformulated curcuminoids.
Materials and Methods: A food-grade bioavailable formulation of curcuminoids as curcumagalactomannosides (CGM) and unformulated curcuminoids (UC) were employed for the study. Swiss albino mice were randomized into Normal control, Radiation control, Radiation + UC, and Radiation + CGM groups and irradiated with γ-radiation of 6, 8, 10 and 12 Gy. Survival rate, hematological and biochemical parameters, bone marrow cellularity, chromosomal aberrations and histopathology of intestine were followed as a measure of the relative efficacy.
Results and Discussion: Oral administration with both UC and CGM at 100 mg/kg. b.wt. produced significant radioprotective effect over the untreated control group of animals. However, CGM treatment was found to provide better clastogenic and genotoxic potential as compared to UC. Further, the histopathology analysis of intestine confirmed the better protective effect of CGM over UC-treated animals.
Conclusion: The present study demonstrated the positive role of the bioavailability of curcuminoids in the amelioration of radiation-induced damages in mice since CGM treatment exerted better survival rate and radioprotective effect as compared with UC, despite the relatively low concentrations of curcuminoids in CGM (39% w/w).
... A number of formulations have utilized various techniques to decrease particle size as incorporation of curcumin in: liquid droplet nano-micelles containing lauroyl polyoxy 32-glycerides (Gelucire ® ) and polysorbate 20 (BioCurc ® ) [15]; fenugreek-derived galactomannan fiber (CurQfen ® ) [28]; liquid droplets containing Gelucire ® and caprylocaproyl polyoxyglycerides (Labrasol ® ), a BioCurc ® formulation [29]; colloidal dispersions using ghatti gum and glycerin (Theracurmin ® ) [30][31][32][33]; a matrix of glycerol esters of fatty acids, medium chain triglycerides, hydroxymethylcellulose and sodium alginate (MicroActive Curcumin®) [34]; a proprietary mixture of surfactants, polar lipids and solvents (HydroCurc ® ) [35]; solid lipid curcumin particles composed of docosahexaenoic acid (DHA), soy lecithin, stearic acid and vitamin C esters (Longvida ® ) [36]; a blend of sodium caseinate and Tween 20 [37]; proprietary microcapsules (Curcushine™); and a complex with acacia gum, quillaia (high in saponins) and sunflower oil (TurmiPure ® ). ...
... Various pharmacokinetic studies have compared absorption between a formulated product and unformulated curcumin [15,[24][25][26][27][28]30,31,33] where enzymatic hydrolysis of plasma samples was employed, and therefore total curcumin but not free, bioactive curcumin was reported. Under these conditions, some indication of enhanced absorption is provided as a result of the product designed to enhance bioavailability. ...
Curcumin exerts a wide range of beneficial physiological and pharmacological activities, including antioxidant, anti-amyloid, anti-inflammatory, anti-microbial, anti-neoplastic, immune-modulating, metabolism regulating, anti-depressant, neuroprotective and tissue protective effects. However, its poor solubility and poor absorption in the free form in the gastrointestinal tract and its rapid biotransformation to inactive metabolites greatly limit its utility as a health-promoting agent and dietary supplement. Recent advances in micro- and nano-formulations of curcumin with greatly enhanced absorption resulting in desirable blood levels of the active forms of curcumin now make it possible to address a wide range of potential applications, including pain management, and as tissue protective. Using these forms of highly bioavailable curcumin now enable a broad spectrum of appropriate studies to be conducted. This review discusses the formulations designed to enhance bioavailability, metabolism of curcumin, relationships between solubility and particle size relative to bioavailability, human pharmacokinetic studies involving formulated curcumin products, the widely used but inappropriate practice of hydrolyzing plasma samples for quantification of blood curcumin, current applications of curcumin and its metabolites and promising directions for health maintenance and applications.
... But the poor absorption, rapid biotransformation into various metabolites of relatively low activity, and lack of cellular uptake have been recently identified as the major problems for its therapeutic efficacy [36]. Thus, the present study employed a highly bioavailable form of curcumin, CGM, that has been shown to deliver bioactive forms of free (unconjugated) curcuminoids into plasma with significant cellular uptake when administered orally [37,38]. It was hypothesized that formulations capable of delivering significant levels of free curcuminoids over conjugated curcumin metabolites would alleviate the earliest responses of chronic ethanol exposure such as elevation in liver function markers. ...
... Considering the earlier human bioavailability study of CGM at 250 mg dose and its favorable pharmacokinetics with regard to the maximum absorption (C max ), elimination halflife (T 1/2 ), and area under curve (AUC) of free curcuminoids over relatively less reactive curcumin glucuronide metabolites [38], the present study employed a convenient dosage of (250 mg × 2)/day of CGM. Despite various in vitro and in vivo reports on hepatoprotective effects of curcumin, the present investigation is the first attempt to investigate its efficacy among alcohol induced fatty liver subjects. ...
Considering the recent interest in free (unconjugated) curcuminoids delivery, the present study investigated the efficacy of a novel food-grade free-curcuminoids delivery system (curcumin-galactomannoside complex; CGM) in improving the hepatic function markers (inflammation and oxidative stress) in chronic alcoholics. The double-blinded, placebo-controlled study randomized 48 subjects with elevated serum transaminases and gamma-glutamyl transferase (GGT) levels, who were allocated to two groups (n=24) and to receive either placebo or CGM at (250 mg × 2)/day for 8 weeks. While liver function markers (transaminases and GGT) in the placebo group showed an increase (~ 9.5%), CGM group indicated a significant decrease in transaminases (31%) and GGT (29%) from the baseline levels. The beneficial effect of CGM was also clear from the significant increase (p <0.001) in endogenous antioxidants (GSH, SOD, and GPx) and decrease in inflammatory markers (IL-6 and CRP) levels (p <0.001) as compared to both the baseline and placebo group. To summarize, the nutritional intervention of CGM-curcumin was found to offer a significant hepatoprotective effect to attenuate the alcohol induced alterations to hepatic function markers. The Indian Medical Council and Drug Controller General of India approved Clinical Trial Registry No. CTRI/2018/03/012385.
... Fenugreek soluble fibre was characterized as galactomannans and has been clinically shown to possess hypoglycemic, hypolipidemic and gastroprotective effects [13,14]. Earlier we had reported enhanced bioavailable formulations of curcumin using fenugreek galactomannans [15]. ...
... The values are expressed as mean ± SD for six animals in each group, where ** p < 0.01 and *** p < 0.001, when treated group compared with that of control. reported as a good natural polymer suitable for oral delivery formulations [15]. Relatively high fibre content and also water based process without using any synthetic excipients or organic solvents make it suitable for nutraceutical and food applications. ...
Albeit the fact that asafotida is a popular kitchen spice and Indian folklore medicine for gut disorders, its consumption at physiologically relevant dosage is greatly challenged by the unpleasant flavor characteristics. Herein we report a green approach to derive stable powder formulations of asafoetida gum with minimized taste and odor suitable for dietary applications and gut health-related disorders. Employing a water based ultrasound mediated gel-phase dispersion of asafoetida gum on fenugreek derived soluble galactomannan fibre matrix, microencapsulated particles (1±0.3μm) of asafoetida was prepared as water dispersible free flowing powder (Asafin). Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), accelerated stability and in vitro dissolution studies confirmed the stability, sustained release and microencapsulated structure of Asafin. Further investigations revealed significant (p<0.01) reduction in acetic acid-induced writings and inhibition of ethanol-induced ulcer (94.1%) in rats orally administered with Asafin at 250mgkg⁻¹ b.w. Asafin also exhibited anti-inflammatory effects (p<0.01), in acute and chronic paw edema mice models. It was also found to be safe upon acute toxicity studies at 4gkg⁻¹ b.w. and upon 28days of sub-acute toxicity studies at 2.0gkg⁻¹ b.w.
... We anticipated that the technology will help the delivery of our phytonutrient trio complex (curcumin, resveratrol, carnosic acid) with improved bioavailability of the bioactive (unconjugated) and BBB-permeable forms of these phytonutrients, allowing the neuronal uptake or active compounds to reach brain regions directly [23]. The selection of delivery technology was based on the previous studies on a similar self-emulsifying hydrogel formulation of curcumin as Curcuma galactomannosides (CGM) using FenuMat technology which was shown to deliver significantly high levels of 'free' (unconjugated) forms of curcuminoids over the relatively weak conjugated glucuronide and sulfate metabolites [24,25]. The presence of blood brain barrier lowers the delivery efficiency to the brain [26]. ...
Repeated traumatic brain injury has grown in importance as sports-related injuries have increased. Repetitive mild TBI (rmTBI) increases the risk of developing neurodegenerative diseases such as Alzheimer’s and Parkinson's diseases, as well as chronic comorbidities like PTSD, depression, substance abuse and neuroendocrine functions. However, no effective therapeutic strategies have been reported for the effective management of TBI. Herein, we examined the effectiveness of co-delivery of the phytonutrients curcumin, trans-resveratrol, and carnosic acid as a bioavailable complex (CGM+) in managing rmTBI in the rodent model. The rats were randomly assigned to sham, rmTBI, and CGM+ (300 mg/kg b.wt.) groups for a total of 21 days. On Days 6 and 7, all animals, except those in the sham group, were subjected to repeated mild traumatic brain injury (rmTBI). The CGM+ group received supplementation throughout the 21 days, while the other groups received a vehicle. Neurological severity score (NSS) was assessed 24 h after the last injury, and behavioral tests were completed within 14 days post-injury. Samples for the biochemical analysis were collected after euthanasia. CGM+ supplementation significantly decreased the sensory-motor deficits associated with rmTBI. Following TBI, the CGM+ group demonstrated enhanced memory and low-stress levels. Furthermore, CGM+ has been shown to modulate neurotransmitter levels and promote neurogenesis. The biochemical and molecular analysis revealed that CGM+ promotes recovery following rmTBI by modulating mitochondrial bioenergetics and BDNF pathways. The findings indicate that CGM+ can be used to manage cognitive and sensory-motor defects caused by rmTBI, such as in the case of sports injuries.
... To meet its effectiveness, high doses of >1 g per day may be required that has raised the compliance issues [10][11][12][13] . To increase the end user compliance, various research strategies have come up to bring several formulations by addressing the bioavailability issue [14][15][16][17][18] . As mentioned by Manish et al., 2023, Maxicuma is one such product with bioavailability of 172 folds high compared to regular/generic extract developed by patent pending LIMAN (Lipid Matrix Nanotechnology) technology [19][20][21] . ...
Curcumin is well known for its diverse health benefits based on the traditional and current scientific evidence. The aim of the present study was to evaluate the safety of Maxicuma ® made by using proprietary LIMAN technology that involves encapsulation of 40% curcuminoids with lipid matrix. The safety profile was studied with single dose and repeated dose oral administration of Maxicuma ® in both rodents and non-rodents. The toxicity study was conducted at a range of 0.5 to 10 gm curcumin equivalent to human dose per day. None of the tested doses in any of the species produced treatment related clinical signs of toxicity with respect to haematology and blood chemistry parameters and mortality. Moreover gross and histopathological findings did not show any remarkable and treatment related changes. The treated animals exhibited normal weight gain and comparable feed intake. Based on the obtained results Maxicuma ® up to 220 mg/kg oral dose could be considered as safe, tolerated and no observed adverse effect level (NOAEL) dose in rabbits.
... Other curcumin formulations exist on the market with different bioavailabilities [2,[6][7][8][9]]. ...
Background: Why this miraculous and amphiphilic compound, the curcumin, which has a very extraordinary therapeutic potential (because can react with many targets in the organism), has a weak bioavailability in the organism and is metabolized in compounds having very weak activity or Original Research Article Kunyima et al.; Asian J. Chem. Sci., vol. 12, no. 3, pp. 15-30, 2022; Article no.AJOCS.93273 16 inactive compounds?. How to improve substantially its bioavailability and therefore its absorption in the organism in order to allow its incorporation in making of pharmaceuticals regardless of its nanoparticles of which obtention is furthermore hardworking? Aim: It seems indicated to search the response in the kinetic and thermodynamic behavior of this compound or in its co-administration with the other compounds in vitro in order to understand how to increase its absorption in vivo because bioavailability entails hydrosolubility (hydrophile) of curcuminoids of which the molecules are naturally hydrophobes. Objective: So our objective is to make better our understanding of the absorption of natural curcuminoids in the organism without resorting to chemical transformation in nanoparticles that is additionally hardworking. Methodology: In this paper, kinetic and thermodynamic study of extraction of oleoresin containing curcuminoids from Turmeric (Curcuma Longa L.), using KUNYIMA's first law, has been performed in acetone that can be reduced in propan-2-ol which is water-like solvent by catalytic hydrogenating (H 2 ,Ni) or by chemical reduction (LiAlH 4). Results: The weak global kinetic constant of extraction of oleoresin containing curcuminoids has been determined at 250 rpm (round per minute) and found the same at 500 rpm (k= 0.1520 ± 0.0005) min-1 for temperature of 27,5°C and constant pressure in acetone in closed system. Conclusion: Kunyima's first law has made possible the kinetic and thermodynamic study of extraction of oleoresin containing curcuminoids from Turmeric. Kinetic constant is a measure of solubility of oleoresin containing curcuminoids and therefore a measure of solubility of curcuminoids in a given solvent, ethanol and acetone being concerned in this paper as solvents. Results show that kinetic constant is inversely proportional to solubility of solvent and it can be a parameter abling the determination of the endothermic or exothermic behavior of extraction of curcuminoids. The endothermic behavior of curcuminoids hereby determined in ethanol and acetone in vitro, increased by magnetic stirring, suggests their weak bioavailability and therefore the weak bioavailability of curcumin. The challenge of this actual research is to improve our understanding of kinetics and thermodynamics of extraction of oleoresin containing curcuminoids from Turmeric in vitro in order to presage their bioavailability still weak for an efficient validated action. The increase of bioavailability will be done whether through improved formulations of curcumin or through new pathways of administration. The conception of curcumin analogous is also a way to promote its effects. More the phenomenon is exothermic in water-like solvents, more the involved chemical compound is bioavailable. The study revealed the predominance of keto form of curcumin in acetone and the lack of bioavailability of curcumin (curcuminoids) through the endothermic behavior of extraction of oleoresin containing curcuminoids and through the weak global kinetic constant. The variation of entropy in acetone has shown without surprise the disturbance of the system after extraction. The values of kinetic constants in acetone and ethanol as water-like solvents have been compared and showed the great solubility of curcuminoids in acetone evidenced by the weak kinetic constant compared to that in ethanol. Curcumin predicts anyway hopeful future.
... Accurately dosing the CoQ 10 and pressing it into tablets might be difficult, due to the poor rheology and low melting point of a CoQ 10 (Abdel-Hamid and Betz, 2012;Nakamura et al., 2016). Therefore, attempts should be made in order to overcome these limitations and improve the solubility, oral bioavailability, and stability of CoQ 10 formulations (Kumar et al., 2016). ...
Our study aimed to develop a self-microemulsifying drug delivery system for the poorly aqueous-soluble drug Coenzyme Q10, to improve the dissolution and the oral bioavailability. Excipients were selected based on their Coenzyme Q10 solubility, and their concentrations were set for the optimization of the microemulsion by using a D-optimal mixture design to achieve a minimum droplet size and a maximum solubility of Coenzyme Q10 within 15 min. The optimized formulation was composed of an oil (omega-3; 38.55%), a co-surfactant (Lauroglycol® 90; 31.42%), and a surfactant (Gelucire® 44/14; 30%) and exhibited a mean droplet size of 237.6 ± 5.8 nm and a drug solubilization (at 15 min) of 16 ± 2.48%. The drug dissolution of the optimized formulation conducted over 8 h in phosphate buffer medium (pH 6.8) was significantly higher when compared to that of the Coenzyme Q10 suspension. A pharmacokinetic study in rats revealed a 4.5-fold and a 4.1-fold increase in the area under curve and the peak plasma concentration values generated by the optimized formulation respectively, as compared to the Coenzyme Q10 suspension. A Coenzyme Q10 brain distribution study revealed a higher Coenzyme Q10 distribution in the brains of rats treated with the optimized formulation than the Coenzyme Q10 suspension. Coenzyme Q10-loaded self microemulsifying drug delivery system was successfully formulated and optimized by a response surface methodology based on a D-optimal mixture design and could be used as a delivery vehicle for the enhancement of the oral bioavailability and brain distribution of poorly soluble drugs such as Coenzyme Q10.
... However, it must be emphasized that all formulations are not bioequivalent. Indeed, it has been reported that the relative bioavailability of curcumin is 20-or 2fold that of curcumin alone when it is administered (2 g) with piperine (20 or 5 mg) [30], 24.8-fold when CurQfen™ (97.7 mg of curcuminoids) is compared to the same dose of unformulated curcuminoids [31], 27.6-fold when Theracurmin™ (30 mg) is compared to the same dose of curcumin [32], and 27.2-fold [ratio of normalized Area Under the Curve (AUC)] when a curcumin-phosphatidylcholine phytosome complex of soy lecithin, microcrystalline cellulose and curcuminoids (Meriva®) (209 mg of curcuminoids) is compared to curcumin (1799 mg) [33]. The values for the increase of bioavailability with Longvida® formulations are heterogeneous, from 95-to 285-fold. ...
Due to the numerous potential health benefits of Curcuma, turmeric dietary supplements (DS) are among the top selling products. To assess the quality of these formulations, thirty Curcuma DS along with five standard Curcuma rhizomes were analyzed with UHPLC-MS and ¹H NMR. The chemometric treatment of the UHPLC-MS spectra showed a significant variability of their chemical composition that was confirmed by ¹H NMR which allowed the absolute quantification of the Curcuma major bioactive components, i.e. curcuminoids (curcumin, demethoxycurcumin and bisdemethoxycurcumin), and turmerones (aryl-, α- and β-) as well as piperine, a commonly associated curcumin bioavailability enhancer: respectively 3.5-556, 0-8.6, 0.18-8.1 mg/capsule or tablet. The comparison of the actual and claimed quantities of curcuminoids and piperine showed that 58% of the DS contained the expected amounts of actives.
... These include nanoparticulate preparations, formulations with micelles, liposomes or gelatin, or as combinations with other herbal extracts and polysaccharide complexes of curcumin. [5,[22][23][24] However, only a few studies have systematically characterized the PK of curcuminoids for achieving comparable bioavailability with lower doses. In this study, we compared the PK characteristics of the WDTE60N formulation with those of STE95. ...
Objectives
The therapeutic utility of turmeric (Curcuma longa L., Zingiberaceae) is limited due to low bioavailability of its active principal curcuminoids. This study evaluates the pharmacokinetic characteristics of a natural, water-dispersible turmeric extract containing 60% curcuminoids (TurmXtra 60N), referred to as WDTE60N, compared to standard turmeric extract 95% (STE95).
Methods
This open-label, two-way crossover, single oral dose, comparative pharmacokinetic study, randomized 14 subjects to receive one capsule of WDTE60N (150 mg curcuminoids) or three capsules of STE95 (500 mg curcuminoids each). The resulting dose ratio of actives for WDTE60N:STE95 was 1:10.
Key findings
Peak plasma levels of free curcumin, total curcuminoids, tetrahydrocurcumin and demethoxycurcumin were similar (P > 0.05). Cmax of total curcumin was higher (P = 0.0253) for WDTE60N at a 10-fold lower dose compared to STE95 (43.5 ± 28.5 vs. 21.3 ± 10.7 ng/ml). Mean AUC0-t was higher (P < 0.001) for free curcumin and comparable for total curcumin and total curcuminoids with WDTE60N than with STE95. Five adverse events were reported in three subjects (mild in severity) and were unrelated to study products.
Conclusion
WDTE60N showed higher absorption and comparable exposure for free curcumin, total curcumin and total curcuminoids at a 10-fold lower dose than STE95.
... Both extracts were used in weight-calculated doses corresponding to human doses. CurQfen extract is better absorbed and reaches many times greater concentrations in plasma compared to Standard extract (KRISHNAKUMAR et al., 2015;KUMAR et al., 2016). Therefore, we believe that its effect is superior to the effect of Standard extract. ...
... Recently, novel technologies have been used for robust and efficient separation of curcuminoids, including a fused-core technology in HPLC column from turmeric extracts (Osorio-Tobó n et al., 2016). Since lower bioavailability of curcuminoids is a major concern for their usability and exploitation of their various biological properties, different formulations have been proposed, including a food-grade formulation of curcumin with fenugreek dietary fiber as curcumagalactomannosides (CGM), which supplied more than 70% of absorbed curcuminoids in unconjugated form (Kumar et al., 2016). For enhancing the solubility in aqueous media, encapsulation methods have been described recently, which include the usage of polyethylene glycol (PEG) for the formation of encapsulated particles of curcuminoids (Perko et al., 2015). ...
... These findings may be related to the highly bioavailable curcumin in the formula. 39,40 Neutrophil apoptosis has been demonstrated to be delayed in patients with IBD and curcumin has exhibited the ability to induce neutrophil apoptosis both in vitro and in vivo. 15,18 Churchill et al. reported that curcumin increased small intestinal mucosal CD4þ T lymphocytes and B lymphocytes in mice that were treated for nearly 11 weeks. ...
Background:
Due to the high prevalence of nutrient deficiencies in patients with inflammatory bowel disease (IBD), routine monitoring of nutrient status and supplementation are recommended.
Objective:
This preliminary study was implemented to prospectively identify potential effects of a nutrition support formula on blood nutrient parameters in adults with IBD.
Methods:
Ten adults with Crohn's disease or ulcerative colitis were recruited from the Portland, Oregon, metropolitan area into a single-arm, open-label pilot study. Participants consumed a nutrition support beverage twice daily for 12 weeks. The formula contained a mixture of micronutrients (including methylated forms of folate and vitamin B12), macronutrients, and phytonutrients (including curcumin, xanthohumol, ginger compounds, and quercetin). Primary measures were the following parameters: folate, vitamin B12, red blood cell (RBC) count, hemoglobin, hematocrit, electrolytes, and albumin. Exploratory measures included a food frequency questionnaire, circulating blood cell counts, and inflammatory markers.
Results:
Nine participants completed the study and one withdrew. Adherence was 98%. Serum folate increased 48.7% (P = .029), serum vitamin B12 increased 17.4% but did not reach statistical significance (P = .053), and red cell distribution width (RDW) decreased 9.2% (P = .012) over the 12-week study period. There were minimal shifts in total white blood cell (WBC) counts (-1.0%, P = .845), but percent neutrophils decreased 10.4% (P = .042) and absolute lymphocyte count increased 18.6% (P = .048). RBC count, hemoglobin, hematocrit, electrolytes, albumin, and inflammatory markers did not change significantly. Post hoc analysis demonstrated that neutrophil-lymphocyte ratio (NLR) decreased 18.4% (not significant, P = .061).
Conclusion:
Serum folate and RDW improved in adults with IBD after 12 weeks. Modulation of leukocyte subtypes was also observed, including a decrease in neutrophils and an increase in lymphocytes, with no change in total WBC count. A randomized, controlled study to further examine effects of the nutrition support formula will be initiated to follow up on this promising, but preliminary investigation.
... With few exceptions [13,18,19], plasma samples are routinely subjected to enzymatic hydrolysis with β-glucuronidase and sulfatase to yield total curcumin [20][21][22][23][24][25][26][27][28][29][30][31][32]. Therefore, most pharmacokinetic studies involving curcumin formulations have not demonstrated an increase in free, bioactive curcumin in the blood. ...
... Hooda and Jood (2005) formed biscuits from different combinations (0, 5, 10, 15 and 20%) of raw, dripping and sprouted fenugreek seed flours. Bread made from wheat flour supplemented with fenugreek seed powder flour has improved physicochemical, nutritional and rheological properties (Kumar et al., 2016;Sharma, 1986). *Author for correspondence; E-mail: m.farhan.chughtai@ ...
In current study nutritional constituents of fenugreek seeds Trigonella foenum graecum and antioxidant potential was determined. Rheological aspects of fenugreek supplemented flour were evaluated. Total phenolic contents (TPC) were quantified by using spectrophotometer. TPC content was higher in ethanol extract as compared to methanol extract, accounted for 9.11mg GAE/g, and 7.82mg GAE/g, respectively. High pressure liquid chromatography was used to analyze the individual phenolic acids. Chlorogenic acid was found in higher quantity accounted for 167. 9 μg/g and sinapic acid with lowest amount 8.6 μg/g. Composite flours with treatments T1, T2, T3 and T4 of fenugreek seed powder with wheat flour were prepared and their rheological properties revealed the T4 with best and healthy results. Physicochemical and sensory analysis of cookies depicted that T1 was best as compared to rest of the treatments.
... Despite various reports on the improved bioavailable formulations of curcumin, the systemic oral bioavailability of unconjugated curcumins remains a challenge. The formulation of curcumin with fenugreek galactomannans as curcumagalactomannosides improved the oral bioavailability by 45 times with improved pharmacokinetics [59]. ...
Background:
This is a short review on the most recent studies on curcumin and its analogs, including the studies from the laboratories of authors. The diverse medicinal properties of curcumin itself reported in the recent years are reviewed. Although curcumin has shown great potential in treating various diseases, it has not been approved as a clinical drug candidate because of its poor pharmacokinetics.
Method:
The recent methods developed to solve this problem are briefly described.
Conclusion:
The biological and other properties of synthetic curcumin analogs (diarylheptanoids and diarylpentanoid monocarbonyl derivatives) reported in the recent literature are also presented.
Green formulations of phytonutrients with enhanced solubility and bioavailability are of great significance in nutrition therapy. In the present contribution, we hypothesized that the collagen peptides could be a safe, natural, food-grade, and cost-effective functional agent for the surface decoration and stabilization of liposomes in powder form and hence a "green" solution for the oral delivery of phytonutrients. The present study reports a two-stage supramolecular self-assembly-directed process for the preparation of collagen peptide-decorated liposomal complexes of curcumin (CCL) [10% (w/w)] as microspheres (125 ± 25 μm) with improved solubility (1.46 × 105-fold) and sustained-release properties under gastrointestinal pH conditions. The molecular self-assembly of collagen peptides around the lipid bilayers and the various noncovalent interactions and conformational changes leading to the supramolecular assembly to act as a matrix for the encapsulation of lipid vesicles of curcumin were clear from the spectroscopic studies (UV-vis, fluorescence, FTIR, and circular dichroism). Further investigation of pharmacokinetics following a randomized double-blinded controlled trial on healthy volunteers (n = 15) demonstrated that the oral administration of 2.5 g of CCL sachet (250 mg of curcumin) enhanced the plasma concentration (Cmax: 118 vs. 4.3 ng/mL), the elimination half-life (4.2 vs. 0.7 h), and bioavailability as per the area under the curve over 12 h [AUC0-12h (CCL) = 506·8 vs. AUC0-12h (C95) = 9.47 (53-fold)], when the plasma concentration of curcumin was estimated with triple quadruple tandem mass spectrometry (UPLC-ESI-MS/MS).
The golden spice turmeric with its main bioactive component curcumin is one of the most popular and extensively studied nutraceuticals. Despite numerous preclinical studies reporting positive pharmacodynamics of turmeric extracts and curcumin, the main issues in translating the pharmacological effects to clinical efficacy have been to overcome its poor pharmacokinetics and to deliver significant amounts of the biologically relevant forms of the actives to various tissues. This review is aimed at providing a first critical evaluation of the current published literature with the novel curcumagalactomannoside (CGM) formulation of curcumin using fenugreek galactomannan dietary fiber, specifically designed to address curcumin poor pharmacokinetics. We describe CGM and its technology as a food-grade formulation to deliver 'free' unconjugated curcuminoids with enhanced bioavailability and improved pharmacokinetic properties. The therapeutic relevance of improving bioavailability of 'free' curcuminoids and some of the technical challenges in the measurement of the 'free' form of curcuminoids in plasma and tissues are also discussed. A total of 26 manuscripts are reviewed here, including 14 preclinical and 12 clinical studies that have investigated CGM pharmacokinetics, safety, and efficacy in various animal models and human conditions. Overall current scientific evidence suggests CGM formulation has improved bioavailability and tissue distribution of the biologically relevant unconjugated forms of turmeric actives called "free" curcuminoids that may be responsible for the superior clinical outcomes reported with CGM treatments in comparison with unformulated standard curcumin across multiple studies.
The poor oral bioavailability, rapid biotransformation to less active metabolites, and fast elimination from systemic circulation have been identified as the major limitations responsible for the clinical insignificance of many drug candidates and phytonutrients. Despite the technological advancements in the nanoformulations of synthetic drugs, there exist many challenges for nutritional therapy, due to the regulatory issues, use of high levels of synthetic emulsifiers and polymers, low stability, low loading levels, mainly liquid state, etc. Herein, we report the characterization and human pharmacokinetics of a natural self-emulsifying hybrid-hydrogel formulation of trans-resveratrol prepared by uniformly impregnating resveratrol micelles into the fenugreek galactomannan hydrogel scaffold to form a water-soluble micelle/hydrogel composite in powder form (RF-20). Fourier transform infrared spectroscopy (FTIR), powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), particle size analysis by dynamic light scattering (DLS), and transmission electron microscopy (TEM) demonstrated the uniform impregnation of resveratrol micelles within the galactomannan hydrogel matrix to form a soluble (average particle size of 172.0 ± 10.4 nm and -21.0 ± 2.5 mV zeta potential) and amorphous powder form with smooth and translucent surface morphology for RF-20, with no chemical alterations. Upon pharmacokinetic studies on healthy human subjects (n = 16) following a randomized, double-blinded, placebo-controlled, 2-arm, 4-sequence crossover design and tandem mass spectrometry (UPLC-ESI-MS/MS), 80 mg of trans-resveratrol from RF-20 provided enhanced free resveratrol bioavailability and pharmacokinetic properties compared to the unformulated resveratrol with 98% purity. The enhancement in bioavailability was more when supplemented in sachet (12.98-fold) form than the capsule (10.48-fold) with improved absorption (C max = 50.97 ± 15.82 ng/mL), circulation half-life (t 1/2 = 7.01 ± 1.44 h), and sustained delivery (T max = 4.71 ± 0.73 h), as compared to the unformulated form (C max = 15.07 ± 5.10 ng/mL; t 1/2 = 1.58 ± 0.65 h; T max = 1.21 ± 0.42 h).
Neuroinflammation is characterized by reactive microglia and astrocytes (collectively called gliosis) in the central nervous system and is considered as one of the main pathological hallmarks in different neurodegenerative diseases such as Alzhei-mer's disease, age-related dementia, and multiple sclerosis. Upon activation, glia undergoes structural and morphological changes such as the microglial cells swell in size and astrocytes become bushy, which play both beneficial and detrimental roles. Hence, they are unable to perform the normal physiological role in brain immunity. Curcumin, a cytokine suppressive anti-inflammatory drug, has a high proven pre-clinical potency and efficacy to reverse chronic neuroinflammation by attenuating the activation and morphological changes that occur in the microglia and astrocytes. This review will highlight the recent findings on the tree structure changes of microglia and astrocytes in neuroinflammation and the effects of curcumin against the activation and morphology of glial cells.
Neuroinflammation is characterized by reactive microglia and astrocytes (collectively called gliosis) in the central nervous system and is considered as one of the main pathological hallmarks in different neurodegenerative diseases such as Alzheimer’s disease, age-related dementia, and multiple sclerosis. Upon activation, glia undergoes structural and morphological changes such as the microglial cells swell in size and astrocytes become bushy, which play both beneficial and detrimental roles. Hence, they are unable to perform the normal physiological role in brain immunity. Curcumin, a cytokine suppressive anti-inflammatory drug, has a high proven pre-clinical potency and efficacy to reverse chronic neuroinflammation by attenuating the activation and morphological changes that occur in the microglia and astrocytes. This review will highlight the recent findings on the tree structure changes of microglia and astrocytes in neuroinflammation and the effects of curcumin against the activation and morphology of glial cells.
Intestinal delivery with enhanced bioavailability is of great significance for stomach irritating and pungent bioactive molecules. The present study reports the development of a pungency-masked food-grade microbeadlets for the sustained-intestinal delivery of red chili extracted capsaicinoids using fenugreek galactomannans. Capsaicinoids encapsulated microbeads (CapF) of about 250 to 400 µm were prepared by a gel-phase homogenization, fluid-bed granulation followed by galactomannan coating, and characterized by NMR, FTIR, DSC, PXRD, and SEM as stable, directly compressible, free flowing amorphous beadlets with a tap density of 0.64 ± 0.2 g/mL. Swelling studies, in vitro release kinetics and particle size analysis indicated the intestinal delivery of soluble capsaicinoids. Pharmacokinetic studies on Wistar rats revealed enhanced bioavailability (19-fold) of CapF when the area under plasma concentration verses time was compared with that of unformulated capsaicinoids. CapF was safe upon gastric mucosa irritation test and demonstrated significant (P < 0.05) anti-obesity effect in high fat diet-induced hypercholesteremic rats.
Today, due to the prevalence of various diseases such as the novel coronavirus (SARS-CoV-2), diabetes, central nervous system diseases, cancer, cardiovascular disorders , and so on, extensive studies have been conducted on therapeutic properties of natural and synthetic agents. A literature review on herbal medicine and commercial products in the global market showed that curcumin (Cur) has many therapeutic benefits compared to other natural ingredients. Despite the unique properties of Cur, its use in clinical trials is very limited. The poor biopharmaceutical properties of Cur such as short half-life in plasma, low bioavailability, poor absorption, rapid metabolism , very low solubility (at acidic and physiological pH), and the chemical instability in body fluids are major concerns associated with the clinical applications of Cur. Recently, nanoformulations are emerging as approaches to develop and improve the therapeutic efficacy of various drugs. Many studies have shown that Cur nanoformulations have tremendous therapeutic potential against various diseases such as SARS-CoV-2, cancer, inflammatory, osteoporosis, and so on. These nanoformulations can inhibit many diseases through several cellular and molecular mechanisms. However, successful long-term clinical results are required to confirm their safety and clinical efficacy. The present review aims to update and explain the therapeutic potential of Cur nanoformulations. K E Y W O R D S bioavailability, biological applications, commercial nanoproducts, Curcumin, nanoformulations, therapeutic mechanisms
Background:
Curcuminoids from turmeric rhizome have significant health benefits but low bioavailability.
Objectives:
To assess the pharmacokinetics of a novel natural turmeric dried colloidal suspension compared with 4 other turmeric formulations (including a standardized extract) at their respective recommended dosages.
Methods:
Thirty healthy men and women (18 to 45 y old) were enrolled in a randomized, open-labeled, crossover trial, and sequentially consumed single oral doses of standard turmeric extract (1500 mg), liquid micellar preparation (1000 mg), piperine-curcuminoid combination (1515 mg), phytosome formulation (1000 mg), or the dried colloidal suspension (300 mg). Eleven blood samples were obtained over 24 h, plasma was extracted with or without deconjugation with β-glucuronidase or sulfatase, and ultra-high-pressure liquid chromatography/tandem MS was used to quantify the 3 parent curcuminoids and 12 metabolites. Classical pharmacokinetics parameters were derived.
Results:
The total AUC values of unconjugated curcuminoids were highly variable within participants, with no significant differences between formulations. However, the AUC values for total curcuminoids (including all metabolites) showed significant product effects. Indeed, the micellar preparation delivered higher levels of total curcuminoids than any other formulation (8540 ng·h/mL), reaching significance when compared with the dried colloidal suspension and standard extract (6520 and 5080 ng·h/mL, respectively). After dose normalization, both micellar and dried colloidal formulations showed significantly higher AUC levels than the standard extract (respectively 136 and 72.9, compared with 3.7 ng·h/mL/mg). Total curcuminoid absorption levels were also significantly higher for the dried colloidal suspension when compared with either piperine or phytosome formulations. Interestingly, no significant differences were observed between the piperine-curcuminoid combination and the standard extract. No serious adverse events were reported.
Conclusions:
The administration of a low dose of the novel natural dried colloidal suspension provided high unconjugated and conjugated curcuminoid absorption, with significant beneficial differences when compared with the high dose of standard extract.This trial was registered at clinicaltrials.gov as NCT03621865.
Objective:
Though a number of bioavailable formulations of curcuminoids have been reported and available commercially as nutraceuticals for brain health, systematic informations on their blood-brain-barrier permeability and brain tissue distribution have not been reported. The present study was aimed to investigate the brain regional pharmacokinetics of curcuminoids following both single dose and repeated dose oral administration of a self-emulsifying food-grade formulation of curcuminoids using fenugreek galactomannan hydrogel scaffold as 'curcumagalactomannosides' (CGM), and its influence on cognitive functions in comparison with unformulated natural curcuminoids (NC) in Wistar rats.
Methods:
CGM was given to animals in single dose (100 mg curcuminoids/kg b. wt.) and repeated dose (100 mg curcuminoids/kg b. wt. for 28 days) and the concentration of total curcuminoids at various parts of brain was evaluated at different time points using Ultra-performance liquid chromatography/electrospray ionization triple quadruple tandem mass spectroscopy (UPLC-ESI-MS/MS) system. Another set of animals were also fed with CGM at single dose (100 mg curcuminoids/kg b. wt.) and repeated dose (100 mg curcuminoids/kg b. wt. for 28 days) and the behavioural studies were conducted using open field test and radial arm maze.
Results:
UPLC-ESI-MS/MS analyses of plasma revealed significant absorption of unconjugated (free) curcuminoids upon both single and repeated dose administration of CGM with maximum concentrations of 173.34 ± 27.12 ng/mL and 223.22 ± 32.73 ng/mL, respectively. Further analysis of brain tissues demonstrated significant blood-brain-barrier permeability. Brain regional pharmacokinetics (AUC, Cmax and t1/2) indicated a relative distribution order of hippocampus > striatum > cerebellum > cerebral cortex > brain stem. Supplementation of CGM for 28 days also offered significant (p < 0.05) improvement in locomotor activity and reduction in spatial memory errors as compared to NC. The NC treatment also improved the behaviour better than the vehicle-treated group.
Conclusion:
CGM could distribute significant amount of free curcuminoids, in brain especially in the hippocampus at both single and repeated dose administration with an elimination half-life of 2.6 h. CGM also showed a positive impact in behaviour of animals in comparison with normal unformulated curcuminoids.
A 6‐week, randomized, open‐label, active‐controlled clinical trial was conducted to evaluate the influence of a low‐dose curcumagalactomannosides (CGM) (400 mg once daily) in OA subjects. The treatment was compared with a standard combination of 500 mg glucosamine hydrochloride (GLN) and 415 mg chondroitin sulphate (CHN), supplied as a single oral dose twice a day. Out of 84 subjects randomized, 72 subjects who have completed the study were evaluated for the safety and efficacy of the treatments at baseline and subsequent visits (day 28 and 42), by measuring walking performance, VAS, KPS, and WOMAC scores. CGM exhibited 47.02, 21.43, and 206% improvement in VAS, KPS, and walking performance, respectively, compared to the baseline. Similarly, there was 31.17, 32.93, 36.44, and 35% improvement in the pain, stiffness, physical function, and total WOMAC scores. CGM also caused a substantial reduction in the serum inflammatory marker levels. The results indicate that a short‐term supplementation of a low dosage CGM exerted superior beneficial effects than a high‐dosage CHN–GLN combination in alleviating the pain and symptoms of OA subjects. Further clinical trials of extended duration in a larger population is required to substantiate the efficacy of CGM in the long‐term management of OA.
Turmeric belongs to the family Zingiberaceae and is a yellow spice of high economic importance due to its medicinal value. Cultivated in tropical and sub-tropical regions around the world, it is used extensively as a colouring, flavouring and preserving agent. In recent years, several drugs derived from natural products have been developed and current drug research is actively investigating the possible therapeutic roles of many Ayurvedic medicines, most notable among those being examined is turmeric. The wide range of pharmacological activities attributed to turmeric come mainly from curcuminoids and two related compounds, demethoxycurcumin and bisdemethoxycurcumin.
This comprehensive book brings together the research carried out on constituents obtained from turmeric and highlights their chemical and biological activities. Comprising 17 chapters, each written by experts in their respective field and curated by authorities, it will be invaluable to all those who are involved in the production, processing, marketing, and the use of turmeric. Appealing to researchers and professionals in natural products, nutraceuticals and food chemists, this book is exposing some of the myths and showing areas for possible future use.
Turmeric belongs to the family Zingiberaceae and is a yellow spice of high economic importance due to its medicinal value. Cultivated in tropical and sub-tropical regions around the world, it is used extensively as a colouring, flavouring and preserving agent. In recent years, several drugs derived from natural products have been developed and current drug research is actively investigating the possible therapeutic roles of many Ayurvedic medicines, most notable among those being examined is turmeric. The wide range of pharmacological activities attributed to turmeric come mainly from curcuminoids and two related compounds, demethoxycurcumin and bisdemethoxycurcumin.
This comprehensive book brings together the research carried out on constituents obtained from turmeric and highlights their chemical and biological activities. Comprising 17 chapters, each written by experts in their respective field and curated by authorities, it will be invaluable to all those who are involved in the production, processing, marketing, and the use of turmeric. Appealing to researchers and professionals in natural products, nutraceuticals and food chemists, this book is exposing some of the myths and showing areas for possible future use.
Overview
A novel highly bioavailable curcumin-galactomannan (CGM) formulation was shown to have improved blood-brain-barrier (BBB) permeability of free curcuminoids in animal models; however, this has not been established in humans. The present study was conducted to determine the functional effects of CGM on brain waves in healthy individuals, owing to its BBB permeability.
Methods
A total of 18 healthy volunteers aged 35–65 were randomly assigned to consume 500 mg CGM, Unformulated curcumin (UC) or Placebo capsules twice daily for 30 days. Electroencephalogram (EEG) measurements, audio-visual reaction time tests and a working memory test were conducted at baseline and after 30 days.
Results
Supplementation of CGM resulted in a significant increase in α- and β-waves (p < 0.05) as well as a significant reduction in α/β ratio in comparison with unformulated curcumin and placebo groups. Furthermore, the CGM showed significant reduction in the audio-reaction time (29.8 %; p < 0.05) in comparison with placebo and 24.6% (p < 0.05) with unformulated curcumin. The choice-based visual-reaction time was also significantly decreased (36%) in CGM as compared to unformulated curcumin and placebo which produced 15.36% and 5.2% respectively.
Conclusion
The observed increase in α and β waves and reduction in α/β ratio in the CGM group suggest that CGM can influence the brain waves in healthy subjects in a manner consistent with penetration of the blood-brain-barrier. The EEG results correlated with improved audio-visual and working memory tests which further support the role of CGM on memory improvements and fatigue reduction.
Objective:
A combination of curcumagalactomannosides (CGM) (400 mg) with glucosamine hydrochloride (GLN) (500 mg) was evaluated against a standard dietary supplement combination chondroitin sulfate (CHN) (415 mg)/GLN (500 mg) for their effectiveness in alleviating the pain and symptoms among osteoarthritic subjects.
Design:
Randomized, double-blinded and active-controlled study.
Settings/Location:
The study was conducted in a hospital-based research center in Vadodara, Gujarat, India.
Subjects:
Eighty subjects (38 males and 42 females), with confirmed osteoarthritis (OA) (Class I-III), were randomized into two parallel groups designated as Group I (CGM-GLN) and Group II (CHN-GLN).
Interventions:
All the study subjects were supplemented with their corresponding intervention capsules (ether CGM along with GLN or CHN along with GLN), as a single oral dose twice a day, once in the morning 10-15 min before breakfast and again in the evening before dinner, for 84 days.
Outcome measures:
A validated treadmill uphill walking protocol was used for the study, and the efficiency of supplementation was evaluated using visual analogue scale (VAS) score, Karnofsky Performance Scale (KPS) score, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire at the baseline, 28th, and 84th day following the treatment. Mechanism of action of CGM-GLN combination was analyzed by measuring the levels of serum inflammatory markers interleukin 1 beta (IL-1β), interleukin 6 (IL-6), and soluble vascular cell adhesion molecule-1 (sVCAM) at the baseline and 84th day.
Results:
CGM-GLN was found to offer significant beneficial effects to pain, stiffness, and physical function of OA subjects compared with CHN-GLN, which was evident from the improvement in walking performance, VAS score, KPS score, and WOMAC score. The efficiency of CGM-GLN was almost double compared with the CHN-GLN by the end of the study (84th day). A significant reduction of inflammatory serum marker levels was observed among CGM-GLN subjects compared with CHN-GLN subjects. Compared with the baseline, CGM-GLN produced 54.52%, 59.08%, and 22.03% reduction in IL-1β, IL-6, and sVCAM levels, respectively. Whereas CHN-GLN group of subjects expressed only 23.17%, 21.38%, and 6.82% reduction in IL-1β, IL-6, and sVCAM levels, respectively.
Conclusions:
In conclusion, the present study demonstrated the potential benefits of CGM-GLN supplements in alleviating the symptoms and function of OA subjects compared with the standard CHN-GLN treatment. The augmented efficacy of CGM-GLN combination could be attributed to the enhanced anti-inflammatory effect of CGM.
Alcoholic liver diseases are classified as one of the major reasons for worldwide morbidity and mortality. Curcuminoids exhibit a wide range of pharmacological activities that are beneficial for health, including hepatoprotective effects, but its clinical significance is limited due to poor oral bioavailability. In the present study, a novel formulation of curcumin as curcumin‐galactomannosides (CGM) with enhanced oral bioavailability alleviated alcohol‐induced liver damage in wistar rats with an increased potency compared to the unformulated natural curcuminoids (CM). Ethanol administration significantly elevated liver toxicity markers, lipid peroxidation and inflammatory markers with a simultaneous reduction in antioxidant defenses. Supplementation of CGM reversed all of the pathological effects of alcohol administration, almost close to the normal level, when compared with CM. Histopathology of liver tissue also confirmed the better protective effect of CGM, indicating the enhancement in antioxidant and anti‐inflammatory effects as a function of bioavailability.
Toxicity of the pesticide carbofuran (CF) can be alleviated by curcumin, if not for its poor bioavailability. Hence, we investigated the effect of a bioavailable curcumin-galactomannan complex (CGM) on CF-induced neurotoxicity in rats in comparison to that of unformulated standard curcumin (CS). The CF (5 mg/kg b.wt/day) treatment for 90 days produced chronicity model which were treated with either CS or CGM (100 mg/kg b.wt and 250 mg/kg b.wt/day) for another 30 days. Improvement in CF-induced behaviour was evident in endurance, motor co-ordination and pain response on both CS (p < 0.01) and CGM (p < 0.001) supplementation. Amelioration of CF-induced toxicity parameters, oxidative stress, and mitochondrial dysfunction on CS (p < 0.01) and CGM (p < 0.001) supplementation was further confirmed by histopathology of brain and liver tissues. But, CGM was more effective in mitigating CF toxicity, with results comparable to that of normal. Hence, CGM might be superior in toxicity management against CF.
A turmeric-and-black-pepper-based hydrolysate (HTBP) was developed. The polyphenolic compounds content, antioxidant activity [1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and ferric reducing antioxidant power (FRAP)] and antimicrobial activity [minimal inhibitory concentration (macro-dilution method) and minimum bactericidal concentration (inoculating the surfaces of agar plates)] were evaluated. Furthermore, the best solvent for extraction of the polyphenolic compounds and curcumin, the main bioactive in turmeric flour (TF), was established. In addition, the tautomeric conformation of curcumin (present in TF and HTBP) was determined by using Fourier-transform infrared spectroscopy (FT-IR). The HTBP was obtained by complete hydrolysis of the starch to dextrose and showed the same curcumin content as TF, suggesting that the starch hydrolysis allowed the release of curcumin from the starch matrix. The antioxidant results indicated that curcumin was responsible for reducing the ferric ion, in the FRAP assay. The presence of piperine in HTBP was confirmed by FT-IR. The ethanol extracts of TF and HTBP showed antibacterial activity against Staphylococcus aureus, Bacillus cereus, Escherichia coli, Klebsiella pneumoniae, Salmonella Enteritidis, Salmonella Typhi and Pseudomonas aeruginosa.
Curcumin (diferuloylmethane) is a yellow pigment present in the spice turmeric (Curcuma longa) that has been associated with antioxidant, anti-inflammatory, anticancer, antiviral, and antibacterial activities as indicated by over 6,000 citations. In addition, over one hundred clinical studies have been carried out with curcumin. One of the major problems with curcumin is perceived to be the bioavailability. How curcumin should be delivered in vivo, how bioavailable is it, how well curcumin is absorbed and how it is metabolized, is the focus of this review. Various formulations of curcumin that are currently available are also discussed.
The potential health benefits of curcumin are limited by its poor solubility, low absorption from the gut, rapid metabolism and rapid systemic elimination. The purpose of this study was the comparative measurement of the increases in levels of curcuminoids (curcumin, demethoxycurcumin, bisdemethoxycurcumin) and the metabolite tetrahydrocurcumin after oral administration of three different curcumin formulations in comparison to unformulated standard.
The relative absorption of a curcumin phytosome formulation (CP), a formulation with volatile oils of turmeric rhizome (CTR) and a formulation of curcumin with a combination of hydrophilic carrier, cellulosic derivatives and natural antioxidants (CHC) in comparison to a standardized curcumin mixture (CS) was investigated in a randomized, double-blind, crossover human study in healthy volunteers. Samples were analyzed by HPLC-MS/MS.
Total curcuminoids appearance in the blood was 1.3-fold higher for CTR and 7.9-fold higher for CP in comparison to unformulated CS. CHC showed a 45.9-fold higher absorption over CS and significantly improved absorption over CP (5.8-fold) and CTR (34.9-fold, all p < 0.001).
A 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 CS, CTR and CP.
Curcumin revealed various health-beneficial properties in numerous studies. However its bioavailability is low due to its limited intestinal uptake and rapid metabolism. The aim of our project was to develop novel curcumin formulations with improved oral bioavailability and to study their safety as well as potential sex-differences.
In this crossover study, healthy subjects (13 women, 10 men) took, in random order, a single oral dose of 500 mg curcuminoids as native powder, micronized powder, or liquid micelles. Blood and urine samples were collected for 24 h and total curcuminoids and safety parameters were quantified. Based on the area under the plasma concentration-time curve (AUC), the micronized curcumin was 14-, 5-, and 9-fold and micellar curcumin 277-, 114-, and 185-fold better bioavailable than native curcumin in women, men, and all subjects, respectively. Thus, women absorbed curcumin more efficiently than men. All safety parameters remained within the reference ranges following the consumption of all formulations.
Both, the micronized powder and in particular the liquid micellar formulation of curcumin significantly improved its oral bioavailability without altering safety parameters and may thus be ideally suited to deliver curcumin in human intervention trials. The observed sex differences in curcumin absorption warrant further investigation.
Background:
A growing number of preclinical studies have demonstrated that curcumin could be a promising anticancer drug; however, poor bioavailability has been the major obstacle for its clinical application. To overcome this problem, we developed a new form of curcumin (Theracurmin) and reported high plasma curcumin levels could be safely achieved after a single administration of Theracurmin in healthy volunteers. In this study, we aimed to evaluate the safety of repetitive administration of Theracurmin in cancer patients.
Methods:
Pancreatic or biliary tract cancer patients who failed standard chemotherapy were eligible for this study. Based on our previous pharmacokinetic study, we selected Theracurmin containing 200 mg of curcumin (Level 1) as a starting dose, and the dose was safely escalated to Level 2, which contained 400 mg of curcumin. Theracurmin was orally administered every day with standard gemcitabine-based chemotherapy. In addition to safety and pharmacokinetics data, NF-κB activity, cytokine levels, efficacy, and quality-of-life score were evaluated.
Results:
Ten patients were assigned to level 1 and six were to level 2. Peak plasma curcumin levels (median) after Theracurmin administration were 324 ng/mL (range, 47-1,029 ng/mL) at Level 1 and 440 ng/mL (range, 179-1,380 ng/mL) at Level 2. No unexpected adverse events were observed and 3 patients safely continued Theracurmin administration for >9 months.
Conclusions:
Repetitive systemic exposure to high concentrations of curcumin achieved by Theracurmin did not increase the incidence of adverse events in cancer patients receiving gemcitabine-based chemotherapy.
The mechanisms underlying Tau-related synaptic and cognitive deficits and the interrelationships between Tau species, their clearance pathways, and synaptic impairments remain poorly understood. To gain insight into these mechanisms, we examined these interrelationships in aged non-mutant genomic human Tau mice, with established Tau pathology and neuron loss. We also examined how these interrelationships changed with an intervention by feeding mice either a control diet or one containing the brain permeable beta-amyloid and Tau aggregate binding molecule curcumin. Transgene-dependent elevations in soluble and insoluble phospho-Tau monomer and soluble Tau dimers accompanied deficits in behavior, hippocampal excitatory synaptic markers, and molecular chaperones (heat shock proteins (HSPs)) involved in Tau degradation and microtubule stability. In human Tau mice but not control mice, HSP70, HSP70/HSP72, and HSP90 were reduced in membrane-enriched fractions but not in cytosolic fractions. The synaptic proteins PSD95 and NR2B were reduced in dendritic fields and redistributed into perikarya, corresponding to changes observed by immunoblot. Curcumin selectively suppressed levels of soluble Tau dimers, but not of insoluble and monomeric phospho-Tau, while correcting behavioral, synaptic, and HSP deficits. Treatment increased PSD95 co-immunoprecipitating with NR2B and, independent of transgene, increased HSPs implicated in Tau clearance. It elevated HSP90 and HSC70 without increasing HSP mRNAs; that is, without induction of the heat shock response. Instead curcumin differentially impacted HSP90 client kinases, reducing Fyn without reducing Akt. In summary, curcumin reduced soluble Tau and elevated HSPs involved in Tau clearance, showing that even after tangles have formed, Tau-dependent behavioral and synaptic deficits can be corrected.
Background: Various types of Tau aggregates in AD brains may differentially impact neurodegeneration.
Results: Curcumin selectively suppresses soluble Tau dimers and corrects molecular chaperone, synaptic, and behavioral deficits.
Conclusion: A drug increasing HSPs involved in Tau clearance reduced Tau dimers and improved cognition.
Significance: Curcumin that reduced Tau dimers and increased molecular chaperones was efficacious without altering insoluble Tau.
Extensive research over the past half century has shown that curcumin (diferuloylmethane), a component of the golden spice turmeric (Curcuma longa), can modulate multiple cell signaling pathways. Extensive clinical trials over the past quarter century have addressed the pharmacokinetics, safety, and efficacy of this nutraceutical against numerous diseases in humans. Some promising effects have been observed in patients with various pro-inflammatory diseases including cancer, cardiovascular disease, arthritis, uveitis, ulcerative proctitis, Crohn's disease, ulcerative colitis, irritable bowel disease, tropical pancreatitis, peptic ulcer, gastric ulcer, idiopathic orbital inflammatory pseudotumor, oral lichen planus, gastric inflammation, vitiligo, psoriasis, acute coronary syndrome, atherosclerosis, diabetes, diabetic nephropathy, diabetic microangiopathy, lupus nephritis, renal conditions, acquired immunodeficiency syndrome, β-thalassemia, biliary dyskinesia, Dejerine-Sottas disease, cholecystitis, and chronic bacterial prostatitis. Curcumin has also shown protection against hepatic conditions, chronic arsenic exposure, and alcohol intoxication. Dose-escalating studies have indicated the safety of curcumin at doses as high as 12 g/day over 3 months. Curcumin's pleiotropic activities emanate from its ability to modulate numerous signaling molecules such as pro-inflammatory cytokines, apoptotic proteins, NF-κB, cyclooxygenase-2, 5-LOX, STAT3, C-reactive protein, prostaglandin E(2), prostate-specific antigen, adhesion molecules, phosphorylase kinase, transforming growth factor-β, triglyceride, ET-1, creatinine, HO-1, AST, and ALT in human participants. In clinical trials, curcumin has been used either alone or in combination with other agents. Various formulations of curcumin, including nanoparticles, liposomal encapsulation, emulsions, capsules, tablets, and powder, have been examined. In this review, we discuss in detail the various human diseases in which the effect of curcumin has been investigated.
Curcumin is a polyphenol that is commonly used for its perceived health benefits. However, the absorption efficacy of curcumin is too low to exhibit beneficial effects. We have successfully developed a highly absorptive curcumin dispersed with colloidal nano-particles, and named it THERACURMIN. The absorption efficacy of THERACURMIN was investigated and compared with that of curcumin powder. The area under the blood concentration-time curve (AUC) after the oral administration of THERACURMIN was found to be more than 40-fold higher than that of curcumin powder in rats. Then, healthy human volunteers were administered orally 30 mg of THERACURMIN or curcumin powder. The AUC of THERACURMIN was 27-fold higher than that of curcumin powder. In addition, THERACURMIN exhibited an inhibitory action against alcohol intoxication after drinking in humans, as evidenced by the reduced acetaldehyde concentration of the blood. These findings demonstrate that THERACURMIN shows a much higher bioavailability than currently available preparations. Thus, THERACURMIN may be useful to exert clinical benefits in humans at a lower dosage.
Curcumin and Alzheimer Disease: This Marriage Is Not to Be Performed
• Cesare Mancuso¹,
• Raffaella Siciliano and
• Eugenio Barone
• Institute of Pharmacology, Catholic University School of Medicine, Largo Francesco Vito, 1–00168 Roma, Italy
• 1E-mail: cmancuso{at}rm.unicatt.it
The therapeutic use of curcumin in the treatment of Alzheimer disease (AD) proposed by Zhang et al. (1) was contradicted by clinical evidence. In a randomized clinical trial, curcumin (1–4 g/day for 6 months) failed to improve cognitive performance in mild-to-moderate AD patients and did not have any beneficial effect on pro-inflammatory biomarkers such as serum amyloid-β peptide and isoprostanes (2). This lack of effect could be attributable to the low bioavailability of oral curcumin. The oral administration of 450–3600 mg of curcumin/day for 1 week to patients affected by colorectal cancer produced a plasma concentration of ∼3 nm (3). However, plasma levels up to 160 nm were obtained in healthy volunteers exposed to oral curcumin at supra-therapeutic doses (10–12 g/day) (4). These low plasma concentrations did not depend on the acute regimen of treatment. Indeed, chronic administration of curcumin (1–4 g/day for 6 months per os) initiated plasma concentrations in the range 60–270 nm (2). Considering the presence of the blood-brain barrier, it is plausible to conclude that brain curcumin concentration in humans could be even lower than that found in plasma. Therefore, the inhibition of amyloid precursor protein maturation by 1–20 μm curcumin found by Zhang et al. (1) in human and rat cells is unlikely to occur in AD subjects. Finally, curcumin is not safe since it initiates several toxic effects including diarrhea, iron-deficient anemia, potential harmful interactions with drug-metabolizing enzymes, and DNA damage, which could be even more severe in elderly individuals such as those suffering from AD (5).
• © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.
References
• 1.↵
• Zhang C.,
• Browne A.,
• Child D.,
• Tanzi R. E.
(2010) J Biol. Chem. 285, 28472–28480
Abstract/FREE Full Text
• 2.↵
• Baum L.,
• Lam C. W.,
• Cheung S. K.,
• Kwok T.,
• Lui V.,
• Tsoh J.,
• Lam L.,
• Leung V.,
• Hui E.,
• Ng C.,
• Woo J.,
• Chiu H. F.,
• Goggins W. B.,
• Zee B. C.,
• Cheng K. F.,
• Fong C. Y.,
• Wong A.,
• Mok H.,
• Chow M. S.,
• Ho P. C.,
• Ip S. P.,
• Ho C. S.,
• Yu X. W.,
• Lai C. Y.,
• Chan M. H.,
• Szeto S.,
• Chan I. H.,
• Mok V.
(2008) J. Clin. Psychopharmacol. 28, 110–113
Medline Google Scholar
• 3.↵
• Garcea G.,
• Jones D. J.,
• Singh R.,
• Dennison A. R.,
• Farmer P. B.,
• Sharma R. A.,
• Steward W. P.,
• Gescher A. J.,
• Berry D. P.
(2004) Br. J. Cancer 90, 1011–1015
CrossRef Medline Google Scholar
• 4.↵
• Lao C. D.,
• Ruffin M. T.,
• Normolle D.,
• Heath D. D.,
• Murray S. I.,
• Bailey J. M.,
• Boggs M. E.,
• Crowell J.,
• Rock C. L.,
• Brenner D. E.
(2006) BMC Complement Altern. Med. 6, 10
CrossRef Medline Google Scholar
• 5.↵
• Burgos-Moron E.,
• Calderon-Montano J. M.,
• Salvador J.,
• Robles A.,
• Lopez-Lazaro M.
(2009) Int. J. Cancer 126, 1771–1775
Google Scholar
Curcumin is the active ingredient of turmeric powder, a natural spice used for generations in traditional medicines. Curcumin's broad spectrum of antioxidant, anticarcinogenic, antimutagenic, and anti-inflammatory properties makes it particularly interesting for the development of pharmaceutical compounds. Because of curcumin's various effects on the function of numerous unrelated membrane proteins, it has been suggested that it affects the properties of the bilayer itself. However, a detailed atomic-level study of the interaction of curcumin with membranes has not been attempted. A combination of solid-state NMR and differential scanning calorimetry experiments shows curcumin has a strong effect on membrane structure at low concentrations. Curcumin inserts deep into the membrane in a transbilayer orientation, anchored by hydrogen bonding to the phosphate group of lipids in a manner analogous to cholesterol. Like cholesterol, curcumin induces segmental ordering in the membrane. Analysis of the concentration dependence of the order parameter profile derived from NMR results suggests curcumin forms higher order oligomeric structures in the membrane that span and likely thin the bilayer. Curcumin promotes the formation of the highly curved inverted hexagonal phase, which may influence exocytotic and membrane fusion processes within the cell. The experiments outlined here show promise for understanding the action of other drugs such as capsaicin in which drug-induced alterations of membrane structure have strong pharmacological effects.
Alzheimer's disease (AD) involves amyloid beta (Abeta) accumulation, oxidative damage, and inflammation, and risk is reduced with increased antioxidant and anti-inflammatory consumption. The phenolic yellow curry pigment curcumin has potent anti-inflammatory and antioxidant activities and can suppress oxidative damage, inflammation, cognitive deficits, and amyloid accumulation. Since the molecular structure of curcumin suggested potential Abeta binding, we investigated whether its efficacy in AD models could be explained by effects on Abeta aggregation. Under aggregating conditions in vitro, curcumin inhibited aggregation (IC(50) = 0.8 microM) as well as disaggregated fibrillar Abeta40 (IC(50) = 1 microM), indicating favorable stoichiometry for inhibition. Curcumin was a better Abeta40 aggregation inhibitor than ibuprofen and naproxen, and prevented Abeta42 oligomer formation and toxicity between 0.1 and 1.0 microM. Under EM, curcumin decreased dose dependently Abeta fibril formation beginning with 0.125 microM. The effects of curcumin did not depend on Abeta sequence but on fibril-related conformation. AD and Tg2576 mice brain sections incubated with curcumin revealed preferential labeling of amyloid plaques. In vivo studies showed that curcumin injected peripherally into aged Tg mice crossed the blood-brain barrier and bound plaques. When fed to aged Tg2576 mice with advanced amyloid accumulation, curcumin labeled plaques and reduced amyloid levels and plaque burden. Hence, curcumin directly binds small beta-amyloid species to block aggregation and fibril formation in vitro and in vivo. These data suggest that low dose curcumin effectively disaggregates Abeta as well as prevents fibril and oligomer formation, supporting the rationale for curcumin use in clinical trials preventing or treating AD.
Curcumin is the major yellow pigment extracted from turmeric, a commonly-used spice in India and Southeast Asia that has broad anticarcinogenic and cancer chemopreventive potential. However, few systematic studies of curcumin's pharmacology and toxicology in humans have been performed.
A dose escalation study was conducted to determine the maximum tolerated dose and safety of a single dose of standardized powder extract, uniformly milled curcumin (C3 Complextrade mark, Sabinsa Corporation). Healthy volunteers were administered escalating doses from 500 to 12,000 mg.
Seven of twenty-four subjects (30%) experienced only minimal toxicity that did not appear to be dose-related. No curcumin was detected in the serum of subjects administered 500, 1,000, 2,000, 4,000, 6,000 or 8,000 mg. Low levels of curcumin were detected in two subjects administered 10,000 or 12,000 mg.
The tolerance of curcumin in high single oral doses appears to be excellent. Given that achieving systemic bioavailability of curcumin or its metabolites may not be essential for colorectal cancer chemoprevention, these findings warrant further investigation for its utility as a long-term chemopreventive agent.
Studies in vitro and in animal models of colorectal and hepatocellular cancers suggest that curcumin is an effective chemopreventive agent. In this pilot trial, we investigated whether oral administration of curcumin results in concentrations of the agent in normal and malignant human liver tissue, which are sufficient to elicit pharmacological activity. In total, 12 patients with hepatic metastases from colorectal cancer received 450-3600 mg of curcumin daily, for 1 week prior to surgery. Levels of curcumin and its metabolites were measured by HPLC in portal and peripheral blood, bile and liver tissue. Curcumin was poorly available, following oral administration, with low nanomolar levels of the parent compound and its glucuronide and sulphate conjugates found in the peripheral or portal circulation. While curcumin was not found in liver tissue, trace levels of products of its metabolic reduction were detected. In patients who had received curcumin, levels of malondialdehyde-DNA (M(1)G) adduct, which reflect oxidative DNA changes, were not decreased in post-treatment normal and malignant liver tissue when compared to pretreatment samples. The results suggest that doses of curcumin required to furnish hepatic levels sufficient to exert pharmacological activity are probably not feasible in humans.
Curcumin can reduce inflammation and neurodegeneration, but its chemical instability and metabolism raise concerns, including whether the more stable metabolite tetrahydrocurcumin (TC) may mediate efficacy. We examined the antioxidant, anti-inflammatory, or anti-amyloidogenic effects of dietary curcumin and TC, either administered chronically to aged Tg2576 APPsw mice or acutely to lipopolysaccharide (LPS)-injected wild-type mice. Despite dramatically higher drug plasma levels after TC compared with curcumin gavage, resulting brain levels of parent compounds were similar, correlating with reduction in LPS-stimulated inducible nitric-oxide synthase, nitrotyrosine, F2 isoprostanes, and carbonyls. In both the acute (LPS) and chronic inflammation (Tg2576), TC and curcumin similarly reduced interleukin-1beta. Despite these similarities, only curcumin was effective in reducing amyloid plaque burden, insoluble beta-amyloid peptide (Abeta), and carbonyls. TC had no impact on plaques or insoluble Abeta, but both reduced Tris-buffered saline-soluble Abeta and phospho-c-Jun NH(2)-terminal kinase (JNK). Curcumin but not TC prevented Abeta aggregation. The TC metabolite was detected in brain and plasma from mice chronically fed the parent compound. These data indicate that the dienone bridge present in curcumin, but not in TC, is necessary to reduce plaque deposition and protein oxidation in an Alzheimer's model. Nevertheless, TC did reduce neuroinflammation and soluble Abeta, effects that may be attributable to limiting JNK-mediated transcription. Because of its favorable safety profile and the involvement of misfolded proteins, oxidative damage, and inflammation in multiple chronic degenerative diseases, these data relating curcumin dosing to the blood and tissue levels required for efficacy should help translation efforts from multiple successful preclinical models.
Curcumin is a polyphenol, found in the spice turmeric, that has promising anticancer properties, but previous studies suggest that absorption of curcumin may be limited.
This study examined the pharmacokinetics of a curcumin preparation in healthy human volunteers 0.25 to 72 h after a single oral dose. Curcumin was administered at doses of 10 g (n = 6) and 12 g (n = 6). Subjects were randomly allocated to dose level for a total of six subjects at each dose level. Serum samples were assayed for free curcumin, for its glucuronide, and for its sulfate conjugate. The data were fit to a one-compartment absorption and elimination model.
Using a high-performance liquid chromatography assay with a limit of detection of 50 ng/mL, only one subject had detectable free curcumin at any of the 14 time points assayed, but curcumin glucuronides and sulfates were detected in all subjects. Based on the pharmacokinetic model, the area under the curve for the 10 and 12 g doses was estimated (mean +/- SE) to be 35.33 +/- 3.78 and 26.57 +/- 2.97 mug/mL x h, respectively, whereas C(max) was 2.30 +/- 0.26 and 1.73 +/- 0.19 mug/mL. The T(max) and t(1/2) were estimated to be 3.29 +/- 0.43 and 6.77 +/- 0.83 h. The ratio of glucuronide to sulfate was 1.92:1. The curcumin conjugates were present as either glucuronide or sulfate, not mixed conjugates.
Curcumin is absorbed after oral dosing in humans and can be detected as glucuronide and sulfate conjugates in plasma.
Curcumin, a natural polyphenolic compound derived from turmeric (Curcuma longa L), has proven to be a modulator of multiple intercellular signalling pathways linked to inflammation, to proliferation, growth, invasion, drug sensitivity, angiogenesis and metastasis of cancer cells. Although curcumin has shown significant efficacy in cell culture studies, it has shown limited efficacy in clinical studies when administered in conventional oral formulations. This discrepancy is largely attributed to its poor oral bioavailability, which may result from its poor solubility, its poor pharmacokinetic profile, or a combination of both. To circumvent these barriers, alternative drug delivery strategies and systems should be explored. In this article, after a brief review of the physicochemical properties and pharmacokinetic profiles of curcumin, recent advances in curcumin oral delivery systems are discussed.
The aim of the present study was to study the oral bioavailability of seven different formulations of curcumin (CRM). CRM formulations viz. aqueous suspension, micronized suspension, nanosuspension, amorphous solid dispersion, hydroxypropyl-β-cyclodextrin (HP-β-CD) inclusion complex, combination with piperine, and spray-dried CRM–milk composite were compared for oral bioavailability in male Sprague–Dawley rats at a CRM dose of 250 mg/kg body weight using a validated high-performance liquid chromatography method. Aqueous suspension provided a C
max and AUC(0 − t) of 28.9 ng/ml and 26.9 ng h/ml, respectively. In comparison, statistically significant increase in the oral bioavailability was obtained with the nanosuspension, HP-β-CD inclusion complex, and amorphous solid dispersion with 251%, 567%, and 446% increase in terms of AUC(0 − t) and 405%, 415%, and 270% in terms of C
max. However, no significant increase in AUC(0 − t) and C
max was observed with piperine and micronized suspension. The milk composite reduced the oral bioavailability of CRM (10% and 37% in terms of AUC(0 − t) and C
max). A statistically significant increase in the T
max was observed with piperine and in HP-β-CD complex, while the T
max was reduced for nanosuspension. The results provide interesting insights into the role of solubility enhancement and metabolism inhibition, for improving the oral bioavailability of CRM.
To exert its activity a drug must reach its pharmacological site(s) of action(s) within the body. One of the current approaches to achieve site specific delivery utilises the use of a carrier. This review focuses on the physicochemical and biological properties of polymeric particulate carriers in the nanometre size range surface modified by poly(ethylene oxide) (PEO). Such systems are able to bypass the normal physiological defence processes occurring after the intravenous injection of particulates and, depending on the particle size and PEO layer properties, remain for a prolonged period of time in the systemic circulation, or have a degree of selectivity for sites of deposition within the body.
Curcumin has considerable neuro-protective and anti-cancer properties but is rapidly eliminated from the body. By optimizing the HPLC method for analysis of curcumin, this study evaluates how the ability of curcumin to penetrate organs and different regions of the brain is affected by nanoparticulation to increase curcumin circulation time in the body. Curcumin-loaded PLGA nanoparticles (C-NPs) were prepared by the high-pressure emulsification-solvent evaporation method. The mean particle size and entrapment efficiency were 163nm and 46.9%, respectively. The release profile of C-NPs was an initial burst effect followed by sustained diffusion. In distribution studies, curcumin could be detected in the evaluated organs, including liver, heart, spleen, lung, kidney and brain. C-NPs were found mainly in the spleen, followed by the lung. Formulation significantly raised the curcumin concentration in these organs with increases in the AUC, t(1/2) and MRT of curcumin, though this was not apparent in the heart. Curcumin and C-NPs could cross the blood-brain barrier (BBB) to enter brain tissue, where it was concentrated chiefly in the hippocampus. Nanoparticulation significantly prolonged retention time of curcumin in the cerebral cortex (increased by 96%) and hippocampus (increased by 83%). These findings provide further understanding for the possible therapeutic effects of curcumin and C-NPs in further pre-clinical and clinical research.
The relative absorption of a standardized curcuminoid mixture and its corresponding lecithin formulation (Meriva) was investigated in a randomized, double-blind, crossover human study. Clinically validated dosages were used for both products, and plasma levels of all three major curcuminoids [curcumin (1a), demethoxycurcumin (1b), and bisdemethoxycurcumin (1c)] were evaluated. Total curcuminoid absorption was about 29-fold higher for Meriva than for its corresponding unformulated curcuminoid mixture, but only phase-2 metabolites could be detected, and plasma concentrations were still 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), with significant 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 more potent analogue in many in vitro anti-inflammatory assays. The improved absorption, and possibly also a better plasma curcuminoid profile, might underlie the clinical efficacy of Meriva at doses significantly lower than unformulated curcuminoid mixtures.
Although mucoadhesive drug carriers for the gastro-intestinal tract (GIT) have been reported, the mucoadhesive property and drug release characteristics have never been evaluated separately, whilst the adherence of the carriers to the surface of GIT has not been directly visualized. Here, a monopolymeric carrier made from ethylcellulose (EC) and a dipolymeric carrier made from a blend of methylcellulose (MC) and EC (ECMC) were easily fabricated through a self-assembling process and yielded the highest reported curcumin loading of ~48-49%. Both curcumin loaded ECMC (C-ECMC) and curcumin loaded EC (C-EC) particles showed an in vitro free radical scavenging activity and a dose-dependent in vitro cytotoxic effect towards MCF-7 human breast adenocarcinoma and HepG2 hepatoblastoma cells in tissue culture. The in vivo evaluation of their adherence to stomach mucosa and their ability to release curcumin into the circulation were carried out through quantification of curcumin levels in the stomach tissue and in blood of mice orally administered with the two spheres. Direct evidence of the adherence of the C-EC and C-ECMC particles along the mucosal epithelia of the stomach is also presented for the first time through SEM images. The mucoadhesive property of self-assembled C-EC nanoparticles is discussed.
Curcumin is the lipid-soluble antioxidant compound obtained from the rhizome of Curcuma longa Linn, also known as turmeric. Curcumin targets multiple chemotherapeutic and inflammatory pathways and has demonstrated safety and tolerability in humans, supporting its potential as a therapeutic agent; however, the clinical literature lacks conclusive evidence supporting its use as a therapeutic agent due to its low bioavailability in humans. The purpose of this study was to quantify plasma levels of free curcumin after dosing of a solid lipid curcumin particle (SLCP) formulation versus unformulated curcumin in healthy volunteers and to determine its tolerability and dose-plasma concentration relationship in late-stage osteosarcoma patients. Doses of 2, 3, and 4 g of SLCP were evaluated in 11 patients with osteosarcoma. Plasma curcumin levels were measured using a validated high-performance liquid chromatography method. The limit of detection of the assay was 1 ng/mL of curcumin. In healthy subjects, the mean peak concentration of curcumin achieved from dosing 650 mg of SLCP was 22.43 ng/mL, whereas plasma curcumin from dosing an equal quantity of unformulated 95% curcuminoids extract was not detected. In both healthy individuals and osteosarcoma patients, high interindividual variability in pharmacokinetics and nonlinear dose dependency was observed, suggesting potentially complex absorption kinetics. Overall, good tolerability was noted in both healthy and osteosarcoma groups.
The plasma concentrations of free (unconjugated) and conjugated silybin after intake of a single oral dose of a lipophilic silybin-phospatidylcholine complex (silipide, 80 mg expressed as silybin equivalents) were evaluated in 12 healthy volunteers by using a sensitive and specific HPLC method. Free silybin concentrations reached a peak of 141 +/- 31 ng/ml (mean +/- SEM) at 2.4 hours after dosing and declined thereafter with a half-life of about 2 hours. Peak concentrations of conjugated silybin were greater (255 +/- 35 ng/ml) and occurred at a later time (about 3.8 hours). The elimination of conjugated drug tended to be slower than that of free drug. AUC values for conjugated sylibin were about three-fold greater than those of free drug. It is concluded that after oral intake of silipide, silybin undergoes extensive conversion to conjugated derivative(s) which are retained in the circulation at relatively large concentrations.
Curcumin is a polyphenol derived from the herbal remedy and dietary spice turmeric. It possesses diverse anti-inflammatory and anti-cancer properties following oral or topical administration. Apart from curcumin's potent antioxidant capacity at neutral and acidic pH, its mechanisms of action include inhibition of several cell signalling pathways at multiple levels, effects on cellular enzymes such as cyclooxygenase and glutathione S-transferases, immuno-modulation and effects on angiogenesis and cell-cell adhesion. Curcumin's ability to affect gene transcription and to induce apoptosis in preclinical models is likely to be of particular relevance to cancer chemoprevention and chemotherapy in patients. Although curcumin's low systemic bioavailability following oral dosing may limit access of sufficient concentrations for pharmacological effect in certain tissues, the attainment of biologically active levels in the gastrointestinal tract has been demonstrated in animals and humans. Sufficient data currently exist to advocate phase II clinical evaluation of oral curcumin in patients with invasive malignancy or pre-invasive lesions of the gastrointestinal tract, particularly the colon and rectum.
Curcumin, a component of turmeric (Curcuma longa), has been shown to exhibit chemopreventive activity. Whether analogs of curcumin (Cur), such as demethoxycurcumin (DMC), bisdemethoxycurcumin (BDMC), tetrahydrocurcumin (THC) and turmerones, modulate inflammatory signaling and cell proliferation signaling to same extent as curcumin was investigated. The results indicate that the relative potency for suppression of tumor necrosis factor (TNF)-induced nuclear factor-kappaB (NF-kappaB) activation was Cur > DMC > BDMC; thus suggesting the critical role of methoxy groups on the phenyl ring. THC, which lacks the conjugated bonds in the central seven-carbon chain, was completely inactive for suppression of the transcription factor. Turmerones also failed to inhibit TNF-induced NF-kappaB activation. The suppression of NF-kappaB activity correlated with inhibition of NF-kappaB reporter activity and with down-regulation of cyclooxygenase-2, cyclin D1 and vascular endothelial growth factor, all regulated by NF-kappaB. In contrast to NF-kappaB activity, the suppression of proliferation of various tumor cell lines by Cur, DMC and BDMC was found to be comparable; indicating the methoxy groups play minimum role in the growth-modulatory effects of curcumin. THC and turmerones were also found to be active in suppression of cell growth but to a much lesser extent than curcumin, DMC and BDMC. Whether suppression of NF-kappaB or cell proliferation, no relationship of any of the curcuminoid was found with reactive oxygen species (ROS) production. Overall, our results demonstrated that different analogs of curcumin present in turmeric exhibit variable anti-inflammatory and anti-proliferative activities, which do not correlate with their ability to modulate the ROS status.
Curcumin possesses anti-inflammatory activity and is a potent inhibitor of reactive-oxygen-generating enzymes such as lipoxygenase/cyclooxygenase, xanthine dehydrogenase/oxidase, and inducible nitric oxide synthase (iNOS); it is an effective inducer of heme oxygenase-1. Curcumin is also a potent inhibitor of protein kinase C (PKC), EGF-receptor tyrosine kinase, and IkappaB kinase. Subsequently, curcumin inhibits the activation of NF-KB and the expressions of oncogenes including c-jun, c-fos, c-myc, NIK, MAPKs, ERK, ELK, PI3K, Akt, CDKs, and iNOS. It is considered that PKC, mTOR, and EGFR tyrosine kinase are the major upstream molecular targest for curcumin intervention, whereas the nuclear oncogenes such as c-jun, c-fos, c-myc, CDKs, FAS, and iNOS might act as downstream molecular targets for curcumin actions. It is proposed that curcumin might suppress tumor promotion through blocking signal transduction pathways in the target cells. The oxidant tumor promoter TPA activates PKC by reacting with zinc thiolates present within the regulatory domain, whereas the oxidized form of cancer chemopreventive agent such as curcumin can inactivate PKC by oxidizing the vicinal thiols present within the catalytic domain. Recent studies indicated that proteasome-mediated degradation of cell proteins play a pivotal role in the regulation of several basic cellular processes, including differentiation, proliferation, cell cycling, and apoptosis. It has been demonstrated that curcumin-induced apoptosis is mediated through the impairment of the ubiquitin-proteasome pathway.
Curcumin, a polyphenolic compound derived from dietary spice turmeric, possesses diverse pharmacologic effects including anti-inflammatory, antioxidant, antiproliferative and antiangiogenic activities. Phase I clinical trials have shown that curcumin is safe even at high doses (12 g/day) in humans but exhibit poor bioavailability. Major reasons contributing to the low plasma and tissue levels of curcumin appear to be due to poor absorption, rapid metabolism, and rapid systemic elimination. To improve the bioavailability of curcumin, numerous approaches have been undertaken. These approaches involve, first, the use of adjuvant like piperine that interferes with glucuronidation; second, the use of liposomal curcumin; third, curcumin nanoparticles; fourth, the use of curcumin phospholipid complex; and fifth, the use of structural analogues of curcumin (e.g., EF-24). The latter has been reported to have a rapid absorption with a peak plasma half-life. Despite the lower bioavailability, therapeutic efficacy of curcumin against various human diseases, including cancer, cardiovascular diseases, diabetes, arthritis, neurological diseases and Crohn's disease, has been documented. Enhanced bioavailability of curcumin in the near future is likely to bring this promising natural product to the forefront of therapeutic agents for treatment of human disease.
Assessing the proliferative activity against human cell lines
- Curcuminglucuronides
Curcuminglucuronides: Assessing the proliferative activity
against human cell lines. Bioorganic and Medicinal Chemistry,
22, 435-439.
Biotransformation of curcumin through reduction and glucuronidation in mice. Drug Metabolism and Disposition: The Biological Fate of Chemicals
- M H Pan
- T M Huang
- J K Lin
Pan, M. H., Huang, T. M., & Lin, J. K. (1999). Biotransformation of
curcumin through reduction and glucuronidation in mice.
Drug Metabolism and Disposition: The Biological Fate of Chemicals,
27, 486-494.