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Highly bioavailable curcumin (Theracurmin): its development and clinical application
Accepted Manuscript Title: Highly bioavailable curcumin (Theracurmin): its development and clinical application Author: Atsushi Imaizumi PII: DOI: Reference:
S2213-4344(15)30003-7 http://dx.doi.org/doi:10.1016/j.phanu.2015.08.002 PHANU 68
To appear in: Received date: Accepted date:
20-8-2015 20-8-2015
Please cite this article as: Atsushi Imaizumi, Highly bioavailable curcumin (Theracurmin): its development and clinical application, PharmaNutrition http://dx.doi.org/10.1016/j.phanu.2015.08.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Highly bioavailable curcumin (Theracurmin): Its development and clinical application Atsushi Imaizumi* [email protected] *
Corresponding author at: Tokyo University of Pharmacy and Life Sciences, 1432-1
Horinouchi Hachioji, Tokyo 192-0355, Japan, Theravalues Corporation, 3-12 Kioicho Chiyoda-ku, Tokyo 102-0094, Japan,TEL: 81-3-3234-7677, FAX: 81-3-3234-7680.
Highlights 1. Development of highly bioavailable curcumin (Theracurmin) 2. Effect of curcumin on cancer 3. Effect of curcumin on cardiovascular disease 4. Effect of curcumin supplementation and aerobic exercise training on arterial compliance 5. Effect of curcumin supplementation on exercise-induced oxidative stress, inflammation, and muscle damage
Abstract Curcumin is a polyphenol with antioxidant and anti-inflammatory properties. It is highly lipophilic and sparingly soluble in water and very little is absorbed when it is ingested; therefore, improving its absorbability is a major priority. We developed a highly bioavailable curcumin called Theracurmin using submicron particle formation and surface controlled technology. In human study, the area under the blood concentration–time curve (AUC) after oral administration of Theracurmin was 27-fold higher than that of commercially available curcumin. Preclinical safety tests were conducted and no adverse effects were confirmed. The effects of Theracurmin on cancer (lung, pancreatic, and prostate), cardiovascular disease (heart disease), vascular function (arterial stiffness and central blood pressure), and bone and cartilage (knee osteoarthritis) were evaluated by collaborating with universities and medical institutions. In this paper, 1
we present the development of Theracurmin and its effects in an animal model as well as in human clinical studies. Keywords: highly bioavailable curcumin; antioxidant; anti-inflammatory; Theracurmin
1. Development of highly bioavailable curcumin (Theracurmin) Low oral bioavailability is one of the major reasons why curcumin has been unsuccessful in achieving therapeutic outcomes, despite its pleiotropic pharmacological properties [1]. To increase its absorption through the intestinal membrane, a higher concentration at the membrane surface is essential. Many curcumin delivery methods with increased solubility and stability or accessibility, in or to the GI tract, have been reported [2]. A number of attempts have been made to improve the absorption of curcumin using technologies such as submicron suspensions [3], phosphatidylcholine complexes [4], and solid lipid nanoparticles [5]. A submicron crystal solid dispersion of curcumin, Theracurmin, was prepared as follows; first, gum ghatti, mainly consists of polysaccharides, obtained from the exudation of ghatti trees, was dissolved in water to make gum ghatti solution. Curcumin powder was mixed into this solution, and water was added to adjust the weight. This mixture was ground by a wet grinding mill (DYNO-MILL® KDL, Willy A Bachofen AG), and then, dispersed by a high-pressure homogenizer. After this procedure, stable THERACURMIN was obtained. THERACURMIN consisted of 10 w/w% of curcumin, 2% of other curcuminoids such as demethoxycurcumin and isdemethoxycurcumin, 4% of gum ghatti, and 84% of water. When curcumin in Theracurmin was orally administered to rats at doses of 5 mg/kg and 30 mg/kg, Cmax was 764 ng/ml (Tmax = 1 h) and 1697 ng/ml (Tmax = 2 h), respectively. A 30-mg dose of Theracurmin or conventional curcumin was administered to healthy human volunteers. The area under the blood concentration–time curve (AUC) for Theracurmin was 27-fold higher than that for curcumin for food additive as pigment offered commercially, and Cmax was 30 ng/ml (Tmax = 1 h). Curcumin in Theracurmin at higher doses of 150 mg and 210 mg were also tested, and the Cmax values were 189 ng/ml (Tmax = 4 h) and 275 ng/ml (Tmax = 2 h), respectively. In these studies, plasma curcumin was assayed after hydrolysis with glucuronidase [3]. 2
Recently, many curcumin products with increased bioavailability have been introduced in the market [4, 5]. However, it is difficult to compare the literature in terms of the absorption efficiency because of the different conditions of experiments, dosages, and analytical methods. Table 1 and Figure 1 show the comparison of the products BCM-95, Meriva, and Theracurmin (Curcuminoids 83–88%, Curcumin 79–84%) in a double-blinded, three-way crossover study [6]. Among several attempts that have been made to improve absorption of curcumin, Theracurmin has been shown to be one of the most promising. 2. Effect of curcumin on cancer Resistance to erlotinib in lung cancer may be related to the activation of nuclear factor kappa B (NFkappaB)-related pathways in association with a decrease in ikappaB levels. Therefore, the effects of coadministration of erlotinib and curcumin on lung cancer cells (PC9) were evaluated [7]. Expression of ikappaB was elevated in PC9 cells by curcumin administration, and pretreatment with siRNAs for ikappaB significantly attenuated the decrease in cell viability after coadministration of erlotinib and curcumin (Fig. 2). Coadministration of erlotinib and/or Theracurmin on the growth of PC9 tumors in mice was then investigated. The body weight of the animals did not significantly differ between any of the treatment groups during the experiment (n = 5 in each group). The general behavior of the animals also appeared to be similar in all groups. Coadministration of erlotinib and/or Theracurmin decreased the growth of PC9 tumors in mice, and statistically significant reduction was achieved only by coadministration of erlotinib and Theracurmin (Fig. 3). Histological studies of these tumors showed that the region of necrosis was significantly increased in the coadministered group in comparison with the control group. Based on the results of these findings, safety evaluation of the coadministration of erlotinib and Theracurmin in non-small cell lung cancer patients is now underway (University Hospital Medical Information Network in Japan (UMIN) 000013424). In 2014, Masashi Kanai published a review in the World Journal of Gastroenterology [8] titled “Therapeutic applications of curcumin for patients with pancreatic cancer.” He mentioned that many papers have reported the anticancer effects of curcumin against pancreatic cancer in vitro and in vivo as well as in clinical trials in patients with pancreatic cancer. Several investigators have tested plasma curcumin levels in clinical trials, and 3
most studies have reported that plasma curcumin levels remained at low (ng/mL) levels, despite multi-gram doses of curcumin [9-11]. Kanai highlighted Theracurmin as a curcumin product with improved bioavailability. To verify the improved bioavailability of Theracurmin in human subjects, dose-escalation and pharmacokinetics studies were conducted. Six healthy human volunteers were recruited and given Theracurmin via a single oral dose of curcumin 150 mg. Following an interval of 2 weeks, the same subjects were given Theracurmin via a single oral dose of curcumin 210 mg. The Cmax values for curcumin in Theracurmin for 150 and 210 mg doses were 189 and 275 ng/ml, respectively. No toxicity associated with Theracurmin intake was observed in this study [12]. These results indicate that Theracurmin can lead to higher plasma curcumin levels than those achieved with conventional curcumin (C3 complex, Sabinsa Corporation, Piscataway, NJ, USA). The authors then conducted a phase I study testing the safety of Theracurmin in patients with pancreatic cancer. A total of 16 patients (14 patients with pancreatic cancer and two patients with biliary tract cancer) who had failed standard gemcitabine-based chemotherapy were enrolled in the study. Based on their previous pharmacokinetic study, the authors chose to use Theracurmin containing 200 mg curcumin (Level 1) as the starting dose. Theracurmin was orally administered every day in combination with standard gemcitabine-based chemotherapy. Ten patients were assigned to the level 1 group and six to the level 2 group (Theracurmin containing 400 mg curcumin). Peak plasma curcumin levels (median) following Theracurmin administration were 324 ng/ml (range 47–1029 ng/ml) for level 1 and 440 ng/ml (range 179–1380 ng/ml) for level 2. These values were significantly higher than the median value (85 ng/ml) observed in the authors’ previous study using 8-g doses of conventional curcumin powder [11]. With respect to safety, the toxicity was comparable with that for gemcitabine-based chemotherapy alone, and repetitive exposure to high concentrations of curcumin did not cause any unexpected serious adverse events nor did they increase the incidence of adverse events in patients with pancreatic cancer receiving gemcitabine-based chemotherapy. Fatigue and functioning-associated quality of life (QOL) scores as scaled by EORTC QOL-C30 significantly improved following Theracurmin administration (Table 2). In five patients, the fatigue score improved by >20, which was interpreted as a significant and clinically relevant change [13]. Improved QOL has been demonstrated to contribute 4
to better outcomes in cancer patients; therefore, we speculate that Theracurmin may prolong the overall survival of patients with pancreatic cancer through QOL improvements. A randomized phase II trial using highly bioavailable curcumin (Theracurmin) in patients with unresectable advanced pancreatic cancer (UMIN000010326) is now underway to verify this hypothesis. Prostate cancer is the most common neoplasm in Caucasian men, while its incidence in Asians has been relatively low. Observational studies have suggested that diet is one of the most contributing factors for the lower observed incidence and mortality of prostate cancers in Asia [14]. Among the most often cited dietary factors thought to play a role in protection against prostate cancer are green tea catechins, lycopene, soy isoflavones, pomegranate phenolics, selenium, vitamins E and D, resveratrol, and curcumin [15]. Epidemiological and laboratory data suggest that dietary modifications that enrich one’s intake of these substances may have chemopreventive effects against prostate cancer. Sustained chronic inflammation in the prostate promotes prostate carcinogenesis. Ide et al. [16] reported the combined inhibitory effects of isoflavones and curcumin on prostate-specific antigen (PSA). The authors observed that the production of PSA was markedly decreased by combined treatment of isoflavones and curcumin in the prostate cancer cell line LNCaP. The expression of androgen receptor was also suppressed by this treatment. In clinical trials, 85 participants were randomized to take a supplement containing isoflavones and curcumin or placebo daily in a double-blind study. The results showed that PSA levels decreased in the patient group with PSA ≥10 treated with the supplement containing isoflavone and curcumin (P = 0.01) [16]. The author then starts to investigate a randomized, double-blind, placebo-controlled, preventative study is now underway to postoperatively examine the effects of curcumin on PSA elevation in prostate cancer patients using Theracurmin. 3. Effect of curcumin on cardiovascular disease Curcumin is an inhibitor of p300 histone acetyltransferase activity, which is associated with heart failure [17]. Sunagawa et al. reported that at a dosage of 50-mg/kg native curcumin prevented deterioration of the systolic function in rat models of heart failure [18]. To achieve more efficient oral pharmacological effects against heart failure using curcumin, the authors estimated the dose effects of Theracurmin in the same rat models of heart failure. At a dosage of 0.5 mg/kg curcumin in Theracurmin, but not native curcumin 5
(Wako, Osaka, Japan), restored left ventricular (LV) fractional shortening in postmyocardial infarction rats. A 100× lower dose of Theracurmin was required when compared with native curcumin to restore LV fractional shortening in a postmyocardial infarction model of rats [19]. The authors then hypothesized that highly absorbable curcumin improves LV function in hypertensive patients. Treatment of hypertensive patients using 60 mg/day of Theracurmin (60 mg of curcumin) for 24 weeks significantly improved the ratio of E/E’, which is a parameter of diastolic function, as assessed by Doppler echocardiography. However, systolic and diastolic blood pressures (BP) were unchanged (UMIN000003851). These results suggest that Theracurmin improves left ventricular diastolic function independent of blood pressure in hypertensive patients. Arterial pressure in the central region (e.g., aorta and carotid artery) is mainly composed of the incident wave from the heart and the reflected wave from the periphery. Age-related aortic stiffening and impaired endothelial function may result in the early return (in late systole) of the augmented reflection wave from the periphery, and thereby increase LV afterload [20]. An increase in LV afterload potentiates a corresponding increase in LV mass, which is an independent risk for heart failure and coronary heart disease mortality ; therefore, central arterial hemodynamics has emerged as an important factor underlying the pathophysiology of cardiovascular disease [21-23]. Sugawara et al. aimed to test the hypothesis that regular endurance exercise combined with daily Theracurmin ingestion lowers the age-related increase in LV afterload to a greater extent than either intervention alone in postmenopausal women in a randomized, double-blind, placebo-controlled study [24]. Forty-five women were randomly assigned to four groups: placebo only, Theracurmin only, exercise training with placebo ingestion, and exercise training with Theracurmin ingestion. Theracurmin (curcumin: 150 mg/day) or matching placebo were administered for 8 weeks. Aortic BP and augmentation index (Alx), an index of LV afterload, were evaluated by pulse wave analysis from tonometrically measured radial arterial pressure waveforms. There were no significant differences in baseline hemodynamic variables among the four groups. After these interventions, brachial systolic BP (SBP) significantly decreased in both exercise-training groups, whereas aortic SBP only significantly decreased in the combined-treatment (e.g., Theracurmin and exercise) group. Heart rate (HR)-corrected Alx significantly decreased in the combined-treatment group only (Fig. 4). These findings suggest that regular endurance exercise combined with daily curcumin ingestion 6
may reduce LV afterload to a greater extent than intervention alone in postmenopausal women. 4. Effect of curcumin supplementation and aerobic exercise training on arterial compliance A reduction in arterial compliance due to aging is a risk factor for cardiovascular and cerebrovascular diseases. To overcome these risks, increased physical activity and habitual exercise in daily life may help prevent or inhibit arterial stiffness. Arterial stiffness has been shown to be lower in middle-aged and older people who regularly exercise such as by jogging, walking, or cycling than in those who do not [25]. These findings are not limited to merely fit middle-aged individuals because habitual aerobic exercise-induced decreases in arterial stiffness have also been noted in both the young and elderly as well as in the obese [26-29]. Lifestyle modification, particularly aerobic exercise and dietary modification, has a favorable effect on vascular aging. Curcumin exhibits known anti-inflammatory and antioxidative effects. Therefore, it is plausible to hypothesize that curcumin improves arterial compliance. Maeda et al. investigated the effects of curcumin (Theracurmin) ingestion alone and in combination with aerobic exercise training on arterial compliance in postmenopausal women. A total of 51 postmenopausal women were assigned to four groups: placebo, Theracurmin, exercise and placebo (EX + placebo), and exercise and Theracurmin (EX + Theracurmin). Theracurmin or placebo was orally ingested for 8 weeks. The exercise groups underwent moderate aerobic exercise training for 8 weeks [30]. As shown in Figures 5, carotid arterial compliance significantly increased in the Theracurmin, EX + placebo, and EX + Theracurmin groups, whereas no such changes were observed in the placebo group. The magnitude of the increase in carotid compliance was the greatest in the EX + Theracurmin group. The percent change in carotid arterial compliance was significantly greater in the Ex + Theracurmin group than in the placebo group (Fig. 6). On the other hand, the percent change in the Theracurmin group or the Ex + placebo group statistically did not differ compared with the placebo group. These results suggest that Theracurmin improves carotid arterial compliance like aerobic exercise training. In addition, Theracurmin and exercise training improved vascular endothelial function in postmenopausal women as measured by flow-mediated dilation [31]. 7
5. Effect of curcumin supplementation on exercise-induced oxidative stress, inflammation, and muscle damage Curcumin has beneficial effects on conditions such as injured skeletal muscles. It has been shown that curcumin reduces inflammatory cytokine concentration in skeletal muscles after downhill running [32]. In addition, Kawanishi et al. observed that curcumin attenuates oxidative stress following downhill-running–induced muscle damage. They reported that hydrogen peroxide concentration and NADPH-oxidase mRNA in downhill-running mice were significantly higher than in the resting mice; however, these variables were significantly attenuated by Theracurmin administration in the downhill-running mice. In addition, mRNA expression levels of inflammation cytokines such as MCP-1 and CXCL14 in the downhill-running mice were significantly higher than in the resting mice. However, MCP-1 mRNA expression was not significantly changed by Theracurmin administration in the downhill-running mice [33]. Takahashi et al. [34] investigated the effects of curcumin supplementation on exercise-induced oxidative stress in humans. Their findings indicate that curcumin supplementation can attenuate exercise-induced oxidative stress by increasing blood antioxidant capacity. Recently, Sciberras et al. [35] reported the effect of curcumin supplementation on cytokine and inflammatory marker responses following 2 h of endurance cycling in humans. In addition, Huang et al. [36] reported the effect of curcumin supplementation on physiological fatigue and physical performance in mice, and concluded that curcumin supplementation results in significant benefits for physiological indicators after exercise by increasing muscle glycogen content; exercise performance was improved, including grip strength and endurance. In addition, the results also showed beneficial effects on body composition and biochemistry in terms of lipid profiles and liver and renal parameters. Regarding toxicity, curcumin was determined to be safe in relevant observations. Therefore, curcumin could help ameliorate exercise-induced fatigue and safely contribute to health promotion. 6. Effects of highly bioavailable curcumin on knee osteoarthritis Osteoarthritis, also referred to as degenerative joint disease, is a slow, destructive process in joints that affects millions of people worldwide. Although the exact biochemical cause of osteoarthritis remains unknown, the process usually begins when the joint structures 8
are abnormal or the stress placed on joint surfaces is unusually high. Knee osteoarthritis is a chronic inflammatory condition that is usually treated with analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs); however, these drugs can cause serious adverse GI and cardiovascular events, particularly with long-term use [37, 38]. Thus, there is a need for disease-modifying agents that not only decrease joint pain but also slow the progression of the condition. Nakagawa et al. [39] determined the clinical effects of orally administered Theracurmin in patients with knee osteoarthritis in a randomized, double-blind, placebo-controlled prospective study. Fifty patients with knee osteoarthritis of Kellgren–Lawrence grades II or III and who were >40 years of age were enrolled in this clinical study. Placebo or Theracurmin containing 180 mg/day of curcumin were orally administered every day for 8 weeks. To monitor adverse events, blood biochemistry analyses were performed before and after the 8-week intervention. The patients’ knee symptoms were evaluated at 0, 2, 4, 6, and 8 weeks by the Japanese Knee Osteoarthritis Measure, a knee pain visual analog scale (VAS); the knee scoring system of the Japanese Orthopedic Association; and the need for NSAIDs. At 8 weeks after treatment initiation, knee pain VAS scores were significant lower in the Theracurmin group than in the placebo group (Fig. 7). Theracurmin decreased celecoxib dependence significantly more than placebo after 8 weeks (Fig. 8). No major side effects were observed with Theracurmin treatment. 7. Conclusion Low oral bioavailability is one of the major reasons why curcumin has been unsuccessful in achieving therapeutic outcomes, despite its pleiotropic pharmacological properties. Among these pharmacological properties, inhibition of NF-kB activation is a major benefit against age-related chronic inflammatory conditions such as cancer, cardiovascular disease, Alzheimer’s disease, and bone and cartilage diseases. To increase its absorption through the intestinal membrane, a higher concentration at the membrane surface is essential. Curcumin delivery methods with increased solubility and stability or accessibility to the GI tract have been investigated. The methods that have already been tested in clinical research include microsuspensions [3], phosphatidylcholine complexes [4], and solid lipid nanoparticles [5]. Their bioavailability is much improved compared with that of conventional curcumin powder. In future, with the application of other methods, curcumin with better bioavailability could potentially be developed. Many 9
beneficial effects of Theracurmin on age-related chronic inflammation have been demonstrated, not only in conditions such as cancer, cardiovascular disease, and bone and cartilage diseases but also in vascular function and exercise-related QOL in humans. As reviewed in this article, many studies, ranging from basic studies to clinical studies, have been conducted on curcumin and its clinical applications in treating various diseases. Given its range of effects, curcumin alone may be useful in treating and preventing a number of diseases; however, completely establishing its potential will require further research into its clinical applications. Highly bioavailable curcumin (Theracurmin) is proposed to be a useful tool to elucidate the potential effects of curcumin.
References [1] Yang K-Y, Lin L-C, Tseng T-Y, Wang S-C, Tsai T-H.;1; Oral bioavailability of curcumin in rat and the herbal analysis from Curcuma longa by LC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci 2007;853:183–9. doi:10.1016/j.jchromb.2007.03.010. [2] Kurita T, Makino Y. ;1; Novel Curcumin Oral Delivery Systems. Anticancer Res 2013;33:2807–21. [3] Sasaki H, Sunagawa Y, Takahashi K, Imaizumi A, Fukuda H, Hashimoto T, et al.;1; Innovative preparation of curcumin for improved oral bioavailability. Biol Pharm Bull 2011;34:660–5. [4] Cuomo J, Appendino G, Dern AS, Schneider E, McKinnon TP, Brown MJ, et al.;1; Comparative absorption of a standardized curcuminoid mixture and its lecithin formulation. J Nat Prod 2011;74:664–9. doi:10.1021/np1007262. [5] Gota VS, Maru GB, Soni TG, Gandhi TR, Kochar N, Agarwal MG. ;1; Safety and pharmacokinetics of a solid lipid curcumin particle formulation in osteosarcoma patients and healthy volunteers. J Agric Food Chem 2010;58:2095–9. doi:10.1021/jf9024807.
10
[6] Sunagawa Y, Hirano S, Katanasaka Y, Miyazaki Y, Funamoto M, Okamura N, et al.;1; Colloidal submicron-particle curcumin exhibits high absorption efficiency: A double-blind, 3-way crossover study. J Nutr Sci Vitaminol 2015:61:37–44. [7] Yamauchi Y, Izumi Y, Yamamoto J, Nomori H. ;1; Coadministration of erlotinib and curcumin augmentatively reduces cell viability in lung cancer cells. Phytother Res 2014;28:728–35. doi:10.1002/ptr.5056. [8] Kanai M. ;1; Therapeutic applications of curcumin for patients with pancreatic cancer. World J Gastroenterol 2014;20:9384–91. doi:10.3748/wjg.v20.i28.9384. [9] Lao CD, Ruffin MT, Normolle D, Heath DD, Murray SI, Bailey JM, et al.;1; Dose escalation of a curcuminoid formulation. BMC Complement Altern Med 2006;6:9. doi:10.1186/1472-6882-6-10. [10] Sharma RA, Euden SA, Platton SL, Cooke DN, Shafayat A, Hewitt HR, et al. Phase I ;1; Clinical Trial of Oral Curcumin Biomarkers of Systemic Activity and Compliance. Clin Cancer Res 2004;10:6847–54. doi:10.1158/1078-0432.CCR-04-0744. [11] Kanai M, Yoshimura K, Asada M, Imaizumi A, Suzuki C, Matsumoto S, et al.;1; A phase I/II study of gemcitabine-based chemotherapy plus curcumin for patients with gemcitabine-resistant pancreatic cancer. Cancer Chemother Pharmacol 2011;68:157–64. doi:10.1007/s00280-010-1470-2. [12] Kanai M, Imaizumi A, Otsuka Y, Sasaki H, Hashiguchi M, Tsujiko K, et al.;1; Dose-escalation and pharmacokinetic study of nanoparticle curcumin, a potential anticancer agent with improved bioavailability, in healthy human volunteers. Cancer Chemother Pharmacol 2012;69:65–70. doi:10.1007/s00280-011-1673-1. [13] Kanai M, Otsuka Y, Otsuka K, Sato M, Nishimura T, Mori Y, et al.;1; A phase I study investigating the safety and pharmacokinetics of highly bioavailable curcumin (Theracurmin) in cancer patients. Cancer Chemother Pharmacol 2013;71:1521–30. doi:10.1007/s00280-013-2151-8. 11
[14] Hebert JR, Hurley TG, Olendzki BC, Teas J, Ma Y, Hampl JS. ;1; Nutritional and socioeconomic factors in relation to prostate cancer mortality: a cross-national study. J Natl Cancer Inst 1998;90:1637–47. [15] Bemis DL, Katz AE, Buttyan R. ;1; Clinical trials of natural products as chemopreventive agents for prostate cancer. Expert Opin Investig Drugs 2006;15:1191–200. doi:10.1517/13543784.15.10.1191. [16] Ide H, Tokiwa S, Sakamaki K, Nishio K, Isotani S, Muto S, et al.;1; Combined inhibitory effects of soy isoflavones and curcumin on the production of prostate-specific antigen. Prostate 2010;70:1127–33. doi:10.1002/pros.21147. [17] Morimoto T, Sunagawa Y, Kawamura T, Takaya T, Wada H, Nagasawa A, et al.;1; The dietary compound curcumin inhibits p300 histone acetyltransferase activity and prevents heart failure in rats. J Clin Invest 2008;118:868–78. doi:10.1172/JCI33160. [18] Sunagawa Y, Morimoto T, Wada H, Takaya T, Katanasaka Y, Kawamura T, et al.;1; A natural p300-specific histone acetyltransferase inhibitor, curcumin, in addition to angiotensin-converting enzyme inhibitor, exerts beneficial effects on left ventricular systolic function after myocardial infarction in rats. Circ J 2011;75:2151–9. [19] Sunagawa Y, Wada H, Suzuki H, Sasaki H, Imaizumi A, Fukuda H, et al.;1; A novel drug delivery system of oral curcumin markedly improves efficacy of treatment for heart failure after myocardial infarction in rats. Biol Pharm Bull 2012;35:139–44. [20] Brown DW, Giles WH, Croft JB. ;1; Left ventricular hypertrophy as a predictor of coronary heart disease mortality and the effect of hypertension. Am Heart J 2000;140:848–56. doi:10.1067/mhj.2000.111112. [21] Roman MJ, Devereux RB, Kizer JR, Okin PM, Lee ET, Wang W, et al.;1; High central pulse pressure is independently associated with adverse cardiovascular outcome
12
the strong heart study. J Am Coll Cardiol 2009;54:1730–4. doi:10.1016/j.jacc.2009.05.070. [22] Safar ME, Blacher J, Pannier B, Guerin AP, Marchais SJ, Guyonvarc’h P-M, et al. ;1; Central pulse pressure and mortality in end-stage renal disease. Hypertension 2002;39:735–8. [23] Safar ME, Levy BI, Struijker-Boudier H. ;1; Current perspectives on arterial stiffness and pulse pressure in hypertension and cardiovascular diseases. Circulation 2003;107:2864–9. doi:10.1161/01.CIR.;1; 0000069826.36125.B4. [24] Sugawara J, Akazawa N, Miyaki A, Choi Y, Tanabe Y, Imai T, et al.;1; Effect of endurance exercise training and curcumin intake on central arterial hemodynamics in postmenopausal women: pilot study. Am J Hypertens 2012;25:651–6. doi:10.1038/ajh.2012.24. [25] Tanaka H, Dinenno FA, Monahan KD, Clevenger CM, DeSouza CA, Seals DR. ;1; Aging, habitual exercise, and dynamic arterial compliance. Circulation 2000;102:1270–5. [26] Kakiyama T, Sugawara J, Murakami H, Maeda S, Kuno S, Matsuda M. ;1; Effects of short-term endurance training on aortic distensibility in young males. Med Sci Sports Exerc 2005;37:267–71. [27] Yoshizawa M, Maeda S, Miyaki A, Misono M, Choi Y, Shimojo N, et al.;1; Additive beneficial effects of lactotripeptides and aerobic exercise on arterial compliance in postmenopausal women. Am J Physiol Heart Circ Physiol 2009;297:H1899–903. doi:10.1152/ajpheart.00433.2009. [28] Maeda S, Tanabe T, Otsuki T, Sugawara J, Ajisaka R, Matsuda M. ;1; Acute exercise increases systemic arterial compliance after 6-month exercise training in older women. Hypertens Res 2008;31:377–81. doi:10.1291/hypres.31.377.
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[29] Miyaki A, Maeda S, Yoshizawa M, Misono M, Saito Y, Sasai H, et al.;1; Effect of habitual aerobic exercise on body weight and arterial function in overweight and obese men. Am J Cardiol 2009;104:823–8. doi:10.1016/j.amjcard.2009.04.057. [30] Akazawa N, Choi Y, Miyaki A, Tanabe Y, Sugawara J, Ajisaka R, et al.;1; Effects of curcumin intake and aerobic exercise training on arterial compliance in postmenopausal women. Artery Research 2013;7:67–72. doi:10.1016/j.artres.2012.09.003. [31] Akazawa N, Choi Y, Miyaki A, Tanabe Y, Sugawara J, Ajisaka R, et al.;1; Curcumin ingestion and exercise training improve vascular endothelial function in postmenopausal women. Nutr Res 2012;32:795–9. doi:10.1016/j.nutres.2012.09.002. [32] Davis JM, Murphy EA, Carmichael MD, Zielinski MR, Groschwitz CM, Brown AS, et al.;1; Curcumin effects on inflammation and performance recovery following eccentric exercise-induced muscle damage. Am J Physiol Regul Integr Comp Physiol 2007;292:R2168–73. doi:10.1152/ajpregu.00858.2006. [33] Kawanishi N, Kato K, Takahashi M, Mizokami T, Otsuka Y, Imaizumi A, et al.;1; Curcumin attenuates oxidative stress following downhill running-induced muscle damage. Biochemical and Biophysical Research Communications 2013;441:573–8. doi:10.1016/j.bbrc.2013.10.119. [34] Takahashi M, Suzuki K, Kim HK, Otsuka Y, Imaizumi A, Miyashita M, et al.;1; Effects of curcumin supplementation on exercise-induced oxidative stress in humans. Int J Sports Med 2014;35:469–75. doi:10.1055/s-0033-1357185. [35] Sciberras JN, Galloway SD, Fenech A, Grech G, Farrugia C, Duca D, et al.;1; The effect of turmeric (Curcumin) supplementation on cytokine and inflammatory marker responses following 2 hours of endurance cycling. J Int Soc Sports Nutr 2015;12:5. doi:10.1186/s12970-014-0066-3.
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[36] Huang W-C, Chiu W-C, Chuang H-L, Tang D-W, Lee Z-M, Wei L, et al.;1; Effect of curcumin supplementation on physiological fatigue and physical performance in mice. Nutrients 2015;7:905–21. doi:10.3390/nu7020905. [37] Smalley WE, Ray WA, Daugherty JR, Griffin MR. ;1; Nonsteroidal anti-inflammatory drugs and the incidence of hospitalizations for peptic ulcer disease in elderly persons. Am J Epidemiol 1995;141:539–45. [38] Felson DT, Lawrence RC, Hochberg MC, McAlindon T, Dieppe PA, Minor MA, et al.;1; Osteoarthritis: new insights. Part 2: treatment approaches. Ann Intern Med 2000;133:726–37. [39] Nakagawa Y, Mukai S, Yamada S, Matsuoka M, Tarumi E, Hashimoto T, et al.;1; Short-term effects of highly-bioavailable curcumin for treating knee osteoarthritis: a randomized, double-blind, placebo-controlled prospective study. J Orthop Sci 2014;19:933–9. doi:10.1007/s00776-014-0633-0.
Figure Captions Fig. 1. Change in plasma concentration of curcumin in healthy volunteers ●, Theracurmin; ♦, BCM-95; ▲, Meriva. Each point and bar represents the mean ± SD (n = 9). * P < 0.05 vs. BCM-95. # P < 0.05 vs. Meriva. Sample preparation and measurement of plasma curcumin levels: Each plasma sample was incubated with beta-glucuronidase to hydrolyze the curcumin conjugates. After extraction with chloroform, the dried extracts were reconstituted in 50% MeOH and injected into a chromatographic system. Plasma concentrations of curcumin were measured using the HPLC-MS/MS system. Adapted from Sunagawa Y, et al. [6]. Colloidal submicron-particle curcumin exhibits high absorption efficiency: A double-blind, 3-way crossover study. J Nutr Sci Vitaminol 2015:61:37–44. Fig. 2. IkappaB expression was elevated in PC9 cells by curcumin administration. 15
(A) Administration of curcumin at 25 µM (cur group, n = 4), or coadministration of erlotinib and curcumin (elt + cur group, n = 4) significantly elevated ikappaB expression in comparison to control (cont group, n = 4) (* P = 0.019, ** P < 0.001 between the indicated groups). (B) Pretreatment with siRNAs for ikappaB (siRNA elt + cur) attenuated the elevation of ikappaB expression by erlotinib and curcumin administration (elt + cur). The figure is representative of three independent experiments. Adapted from Yamauchi Y, et al. [7]. Coadministration of erlotinib and curcumin augmentatively reduces cell viability in lung cancer cells. Phytother Res 2014;28:728–35. Fig. 3. Coadministration of erlotinib and/or curcumin attenuated the growth of PC9 tumors in mice; however, statistically significant attenuation was achieved only by coadministration of erlotinib and curcumin. Macroscopically, no metastases were observed in any of the animals at the time of sacrifice, (* P < 0.01 between the indicated groups). pad: post administration days; cont: DMSO; elt: erlotinib 25 mg/kg; Thera: Theracurmin 100 mg/kg; elt + Thera: erlotinib 25 mg/kg + Theracurmin 100 mg/kg. n = 5 in each group. Adapted from Yamauchi Y, et al. [7]. Coadministration of erlotinib and curcumin augmentatively reduces cell viability in lung cancer cells. Phytother Res 2014;28:728–35. Fig. 4. Changes in aortic augmented pressure (AP75) and augmentation index (AIx75) normalized for a heart rate of 75 bpm. Data are mean ± SEM. bpm: beats per minute; Cur: curcumin; Ex + Cur: exercise training + curcumin; Ex + Pla: exercise training + placebo; Pla: placebo. Adapted from Sugawara J, et al. [24]. Effect of endurance exercise training and curcumin intake on central arterial hemodynamics in postmenopausal women: pilot study. Am J Hypertens 2012;25:651–6. Fig. 5. Carotid arterial compliance before and after intervention. Data are expressed as mean ± SE. * P < 0.05 before vs. after intervention.
16
Adapted from Akazawa N, et al. [30]. Effects of curcumin intake and aerobic exercise training on arterial compliance in postmenopausal women. Artery Research 2013;7:67–72. Fig. 6. Percentage changes in arterial compliance in response to intervention. Data are expressed as mean ± SE. * P < 0.05 placebo vs. exercise + curcumin (Ex + curcumin). Adapted from Akazawa N, et al. [30]. Effects of curcumin intake and aerobic exercise training on arterial compliance in postmenopausal women. Artery Research 2013;7:67–72. Fig. 7. The improved VAS scores in the two groups are presented as means ± SD. The two-sample one-sided t test was used to perform the statistical analysis of the VAS, JKOM, and JOA scores. The chi-square test was used to analyze the need for celecoxib. The level of statistical significance was set to a P value of <0.05. Except for the patients with initial VAS scores of 0.15 or less, the VAS scores were significantly improved in the Theracurmin group in comparison to the placebo group at 8 weeks (P = 0.023). VAS: visual analog scale. Adapted from Nakagawa Y, et al. [39]. Short-term effects of highly-bioavailable curcumin for treating knee osteoarthritis: a randomized, double-blind, placebo-controlled prospective study. J Orthop Sci 2014;19:933–9. Fig. 8. NSAID necessity in the two groups. At 8 weeks only, the ratio of patients who needed celecoxib was significantly lower in the Theracurmin group than in the placebo group (P = 0.0252). NSAID: nonsteroidal anti-inflammatory drugs. Adapted from Nakagawa Y, et al. [39]. Short-term effects of highly-bioavailable curcumin for treating knee osteoarthritis: a randomized, double-blind, placebo-controlled prospective study. J Orthop Sci 2014;19:933–9.
17
Fig. 1
Fig. 2
18
Fig. 3
Fig. 4
19
Fig. 5
Fig. 6
20
Fig. 7
Fig. 8
21
Tables Table 1 Composition of each curcumin capsule Dosage used in Measured Manufacturing Sample
Curcumin this study Ingredients
value
method
content
(number of (mg) capsules)
Theracurmin (Dextrin, Maltose, Curcuma longa extract (Curcuminoids 83–88%, Curcumin dispersed Curcumin 79–84%) , Gum
30 mg/
180 mg
182.4 ±
(6 capsules)
6.0
260 mg/
260 mg
279.3 ±
capsule
(1 capsule)
10.7
75 mg/
150 mg (2
152.5 ±
capsules)
20.3
Theracurmin with colloidal ghatti, Citric acid), Cornstarch, capsule submicron-particles Silicon dioxide, Calcium stearate, Hydroxypropyl methylcellulose (capsule) Curcuma longa extract with Curcumin complex Essential Oils of Turmeric with essential oils of BCM-95
Rhizome, Rice flour, Vegetable the turmeric cellulose (capsule), Vegetable rhizome stearate, Silica Curcuma longa extract (root) / Curcumin complex Phosphatidylcholine complex), with
Hypromellose (capsule),
Meriva phosphatidylcholine Leucine, Calcium citratelaurate, capsule from soy lecithin
Silicon dioxide, Microcrystalline cellulose
22
Table 2 Changes in QOL scores after Theracurmin administration Best score during Baseline
Mean change
P valuec
curcumin intake Fatigue score
38.0 ± 13.2
24.8 ± 14.3
–13.2
0.004
Functional scorea,b
82.8 ± 11.9
90.7 ± 8.1
8.0
0.001
Diarrhea
15.0 ± 27.6
5.6 ± 12.4
–9.4
0.006
Financial difficulties
16.7 ± 25.5
2.8 ± 9.2
–13.9
0.027
Appetite loss
38.9 ± 26.6
22.2 ± 28.3
–16.7
0.026
Insomnia
13.9 ± 16.4
8.3 ± 14.4
–5.6
0.083
Pain
22.2 ± 19.6
16.7 ± 18.0
–5.5
0.083
Nausea
6.9 ± 10.7
2.8 ± 4.2
–4.1
0.096
Constipation
19.4 ± 21.3
11.1 ± 20.8
–8.3
0.214
Dyspnea
25.0 ± 27.6
16.7 ± 21.5
–8.3
0.215
Global healthb
56.3 ± 18.7
63.2 ± 20.0
6.9
0.101
Complete EORTC QLQ-C30 scores on day 1 of the first treatment cycle (baseline) and on day 1 of the second or later treatment cycles were available in 12 patients. Three patients could not submit the score sheet after Theracurmin administration because of withdrawal or DLTs, and one failed to complete the score sheet. a. Five functional scores (emotional, role, cognitive, physical, and social functions) were pooled together b. Higher scores indicate better symptoms; otherwise, a lower score indicates a better symptom c. P < 0.005 indicates significance for multiple comparisons
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S2213-4344(15)30003-7 http://dx.doi.org/doi:10.1016/j.phanu.2015.08.002 PHANU 68
To appear in: Received date: Accepted date:
20-8-2015 20-8-2015
Please cite this article as: Atsushi Imaizumi, Highly bioavailable curcumin (Theracurmin): its development and clinical application, PharmaNutrition http://dx.doi.org/10.1016/j.phanu.2015.08.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Highly bioavailable curcumin (Theracurmin): Its development and clinical application Atsushi Imaizumi* [email protected] *
Corresponding author at: Tokyo University of Pharmacy and Life Sciences, 1432-1
Horinouchi Hachioji, Tokyo 192-0355, Japan, Theravalues Corporation, 3-12 Kioicho Chiyoda-ku, Tokyo 102-0094, Japan,TEL: 81-3-3234-7677, FAX: 81-3-3234-7680.
Highlights 1. Development of highly bioavailable curcumin (Theracurmin) 2. Effect of curcumin on cancer 3. Effect of curcumin on cardiovascular disease 4. Effect of curcumin supplementation and aerobic exercise training on arterial compliance 5. Effect of curcumin supplementation on exercise-induced oxidative stress, inflammation, and muscle damage
Abstract Curcumin is a polyphenol with antioxidant and anti-inflammatory properties. It is highly lipophilic and sparingly soluble in water and very little is absorbed when it is ingested; therefore, improving its absorbability is a major priority. We developed a highly bioavailable curcumin called Theracurmin using submicron particle formation and surface controlled technology. In human study, the area under the blood concentration–time curve (AUC) after oral administration of Theracurmin was 27-fold higher than that of commercially available curcumin. Preclinical safety tests were conducted and no adverse effects were confirmed. The effects of Theracurmin on cancer (lung, pancreatic, and prostate), cardiovascular disease (heart disease), vascular function (arterial stiffness and central blood pressure), and bone and cartilage (knee osteoarthritis) were evaluated by collaborating with universities and medical institutions. In this paper, 1
we present the development of Theracurmin and its effects in an animal model as well as in human clinical studies. Keywords: highly bioavailable curcumin; antioxidant; anti-inflammatory; Theracurmin
1. Development of highly bioavailable curcumin (Theracurmin) Low oral bioavailability is one of the major reasons why curcumin has been unsuccessful in achieving therapeutic outcomes, despite its pleiotropic pharmacological properties [1]. To increase its absorption through the intestinal membrane, a higher concentration at the membrane surface is essential. Many curcumin delivery methods with increased solubility and stability or accessibility, in or to the GI tract, have been reported [2]. A number of attempts have been made to improve the absorption of curcumin using technologies such as submicron suspensions [3], phosphatidylcholine complexes [4], and solid lipid nanoparticles [5]. A submicron crystal solid dispersion of curcumin, Theracurmin, was prepared as follows; first, gum ghatti, mainly consists of polysaccharides, obtained from the exudation of ghatti trees, was dissolved in water to make gum ghatti solution. Curcumin powder was mixed into this solution, and water was added to adjust the weight. This mixture was ground by a wet grinding mill (DYNO-MILL® KDL, Willy A Bachofen AG), and then, dispersed by a high-pressure homogenizer. After this procedure, stable THERACURMIN was obtained. THERACURMIN consisted of 10 w/w% of curcumin, 2% of other curcuminoids such as demethoxycurcumin and isdemethoxycurcumin, 4% of gum ghatti, and 84% of water. When curcumin in Theracurmin was orally administered to rats at doses of 5 mg/kg and 30 mg/kg, Cmax was 764 ng/ml (Tmax = 1 h) and 1697 ng/ml (Tmax = 2 h), respectively. A 30-mg dose of Theracurmin or conventional curcumin was administered to healthy human volunteers. The area under the blood concentration–time curve (AUC) for Theracurmin was 27-fold higher than that for curcumin for food additive as pigment offered commercially, and Cmax was 30 ng/ml (Tmax = 1 h). Curcumin in Theracurmin at higher doses of 150 mg and 210 mg were also tested, and the Cmax values were 189 ng/ml (Tmax = 4 h) and 275 ng/ml (Tmax = 2 h), respectively. In these studies, plasma curcumin was assayed after hydrolysis with glucuronidase [3]. 2
Recently, many curcumin products with increased bioavailability have been introduced in the market [4, 5]. However, it is difficult to compare the literature in terms of the absorption efficiency because of the different conditions of experiments, dosages, and analytical methods. Table 1 and Figure 1 show the comparison of the products BCM-95, Meriva, and Theracurmin (Curcuminoids 83–88%, Curcumin 79–84%) in a double-blinded, three-way crossover study [6]. Among several attempts that have been made to improve absorption of curcumin, Theracurmin has been shown to be one of the most promising. 2. Effect of curcumin on cancer Resistance to erlotinib in lung cancer may be related to the activation of nuclear factor kappa B (NFkappaB)-related pathways in association with a decrease in ikappaB levels. Therefore, the effects of coadministration of erlotinib and curcumin on lung cancer cells (PC9) were evaluated [7]. Expression of ikappaB was elevated in PC9 cells by curcumin administration, and pretreatment with siRNAs for ikappaB significantly attenuated the decrease in cell viability after coadministration of erlotinib and curcumin (Fig. 2). Coadministration of erlotinib and/or Theracurmin on the growth of PC9 tumors in mice was then investigated. The body weight of the animals did not significantly differ between any of the treatment groups during the experiment (n = 5 in each group). The general behavior of the animals also appeared to be similar in all groups. Coadministration of erlotinib and/or Theracurmin decreased the growth of PC9 tumors in mice, and statistically significant reduction was achieved only by coadministration of erlotinib and Theracurmin (Fig. 3). Histological studies of these tumors showed that the region of necrosis was significantly increased in the coadministered group in comparison with the control group. Based on the results of these findings, safety evaluation of the coadministration of erlotinib and Theracurmin in non-small cell lung cancer patients is now underway (University Hospital Medical Information Network in Japan (UMIN) 000013424). In 2014, Masashi Kanai published a review in the World Journal of Gastroenterology [8] titled “Therapeutic applications of curcumin for patients with pancreatic cancer.” He mentioned that many papers have reported the anticancer effects of curcumin against pancreatic cancer in vitro and in vivo as well as in clinical trials in patients with pancreatic cancer. Several investigators have tested plasma curcumin levels in clinical trials, and 3
most studies have reported that plasma curcumin levels remained at low (ng/mL) levels, despite multi-gram doses of curcumin [9-11]. Kanai highlighted Theracurmin as a curcumin product with improved bioavailability. To verify the improved bioavailability of Theracurmin in human subjects, dose-escalation and pharmacokinetics studies were conducted. Six healthy human volunteers were recruited and given Theracurmin via a single oral dose of curcumin 150 mg. Following an interval of 2 weeks, the same subjects were given Theracurmin via a single oral dose of curcumin 210 mg. The Cmax values for curcumin in Theracurmin for 150 and 210 mg doses were 189 and 275 ng/ml, respectively. No toxicity associated with Theracurmin intake was observed in this study [12]. These results indicate that Theracurmin can lead to higher plasma curcumin levels than those achieved with conventional curcumin (C3 complex, Sabinsa Corporation, Piscataway, NJ, USA). The authors then conducted a phase I study testing the safety of Theracurmin in patients with pancreatic cancer. A total of 16 patients (14 patients with pancreatic cancer and two patients with biliary tract cancer) who had failed standard gemcitabine-based chemotherapy were enrolled in the study. Based on their previous pharmacokinetic study, the authors chose to use Theracurmin containing 200 mg curcumin (Level 1) as the starting dose. Theracurmin was orally administered every day in combination with standard gemcitabine-based chemotherapy. Ten patients were assigned to the level 1 group and six to the level 2 group (Theracurmin containing 400 mg curcumin). Peak plasma curcumin levels (median) following Theracurmin administration were 324 ng/ml (range 47–1029 ng/ml) for level 1 and 440 ng/ml (range 179–1380 ng/ml) for level 2. These values were significantly higher than the median value (85 ng/ml) observed in the authors’ previous study using 8-g doses of conventional curcumin powder [11]. With respect to safety, the toxicity was comparable with that for gemcitabine-based chemotherapy alone, and repetitive exposure to high concentrations of curcumin did not cause any unexpected serious adverse events nor did they increase the incidence of adverse events in patients with pancreatic cancer receiving gemcitabine-based chemotherapy. Fatigue and functioning-associated quality of life (QOL) scores as scaled by EORTC QOL-C30 significantly improved following Theracurmin administration (Table 2). In five patients, the fatigue score improved by >20, which was interpreted as a significant and clinically relevant change [13]. Improved QOL has been demonstrated to contribute 4
to better outcomes in cancer patients; therefore, we speculate that Theracurmin may prolong the overall survival of patients with pancreatic cancer through QOL improvements. A randomized phase II trial using highly bioavailable curcumin (Theracurmin) in patients with unresectable advanced pancreatic cancer (UMIN000010326) is now underway to verify this hypothesis. Prostate cancer is the most common neoplasm in Caucasian men, while its incidence in Asians has been relatively low. Observational studies have suggested that diet is one of the most contributing factors for the lower observed incidence and mortality of prostate cancers in Asia [14]. Among the most often cited dietary factors thought to play a role in protection against prostate cancer are green tea catechins, lycopene, soy isoflavones, pomegranate phenolics, selenium, vitamins E and D, resveratrol, and curcumin [15]. Epidemiological and laboratory data suggest that dietary modifications that enrich one’s intake of these substances may have chemopreventive effects against prostate cancer. Sustained chronic inflammation in the prostate promotes prostate carcinogenesis. Ide et al. [16] reported the combined inhibitory effects of isoflavones and curcumin on prostate-specific antigen (PSA). The authors observed that the production of PSA was markedly decreased by combined treatment of isoflavones and curcumin in the prostate cancer cell line LNCaP. The expression of androgen receptor was also suppressed by this treatment. In clinical trials, 85 participants were randomized to take a supplement containing isoflavones and curcumin or placebo daily in a double-blind study. The results showed that PSA levels decreased in the patient group with PSA ≥10 treated with the supplement containing isoflavone and curcumin (P = 0.01) [16]. The author then starts to investigate a randomized, double-blind, placebo-controlled, preventative study is now underway to postoperatively examine the effects of curcumin on PSA elevation in prostate cancer patients using Theracurmin. 3. Effect of curcumin on cardiovascular disease Curcumin is an inhibitor of p300 histone acetyltransferase activity, which is associated with heart failure [17]. Sunagawa et al. reported that at a dosage of 50-mg/kg native curcumin prevented deterioration of the systolic function in rat models of heart failure [18]. To achieve more efficient oral pharmacological effects against heart failure using curcumin, the authors estimated the dose effects of Theracurmin in the same rat models of heart failure. At a dosage of 0.5 mg/kg curcumin in Theracurmin, but not native curcumin 5
(Wako, Osaka, Japan), restored left ventricular (LV) fractional shortening in postmyocardial infarction rats. A 100× lower dose of Theracurmin was required when compared with native curcumin to restore LV fractional shortening in a postmyocardial infarction model of rats [19]. The authors then hypothesized that highly absorbable curcumin improves LV function in hypertensive patients. Treatment of hypertensive patients using 60 mg/day of Theracurmin (60 mg of curcumin) for 24 weeks significantly improved the ratio of E/E’, which is a parameter of diastolic function, as assessed by Doppler echocardiography. However, systolic and diastolic blood pressures (BP) were unchanged (UMIN000003851). These results suggest that Theracurmin improves left ventricular diastolic function independent of blood pressure in hypertensive patients. Arterial pressure in the central region (e.g., aorta and carotid artery) is mainly composed of the incident wave from the heart and the reflected wave from the periphery. Age-related aortic stiffening and impaired endothelial function may result in the early return (in late systole) of the augmented reflection wave from the periphery, and thereby increase LV afterload [20]. An increase in LV afterload potentiates a corresponding increase in LV mass, which is an independent risk for heart failure and coronary heart disease mortality ; therefore, central arterial hemodynamics has emerged as an important factor underlying the pathophysiology of cardiovascular disease [21-23]. Sugawara et al. aimed to test the hypothesis that regular endurance exercise combined with daily Theracurmin ingestion lowers the age-related increase in LV afterload to a greater extent than either intervention alone in postmenopausal women in a randomized, double-blind, placebo-controlled study [24]. Forty-five women were randomly assigned to four groups: placebo only, Theracurmin only, exercise training with placebo ingestion, and exercise training with Theracurmin ingestion. Theracurmin (curcumin: 150 mg/day) or matching placebo were administered for 8 weeks. Aortic BP and augmentation index (Alx), an index of LV afterload, were evaluated by pulse wave analysis from tonometrically measured radial arterial pressure waveforms. There were no significant differences in baseline hemodynamic variables among the four groups. After these interventions, brachial systolic BP (SBP) significantly decreased in both exercise-training groups, whereas aortic SBP only significantly decreased in the combined-treatment (e.g., Theracurmin and exercise) group. Heart rate (HR)-corrected Alx significantly decreased in the combined-treatment group only (Fig. 4). These findings suggest that regular endurance exercise combined with daily curcumin ingestion 6
may reduce LV afterload to a greater extent than intervention alone in postmenopausal women. 4. Effect of curcumin supplementation and aerobic exercise training on arterial compliance A reduction in arterial compliance due to aging is a risk factor for cardiovascular and cerebrovascular diseases. To overcome these risks, increased physical activity and habitual exercise in daily life may help prevent or inhibit arterial stiffness. Arterial stiffness has been shown to be lower in middle-aged and older people who regularly exercise such as by jogging, walking, or cycling than in those who do not [25]. These findings are not limited to merely fit middle-aged individuals because habitual aerobic exercise-induced decreases in arterial stiffness have also been noted in both the young and elderly as well as in the obese [26-29]. Lifestyle modification, particularly aerobic exercise and dietary modification, has a favorable effect on vascular aging. Curcumin exhibits known anti-inflammatory and antioxidative effects. Therefore, it is plausible to hypothesize that curcumin improves arterial compliance. Maeda et al. investigated the effects of curcumin (Theracurmin) ingestion alone and in combination with aerobic exercise training on arterial compliance in postmenopausal women. A total of 51 postmenopausal women were assigned to four groups: placebo, Theracurmin, exercise and placebo (EX + placebo), and exercise and Theracurmin (EX + Theracurmin). Theracurmin or placebo was orally ingested for 8 weeks. The exercise groups underwent moderate aerobic exercise training for 8 weeks [30]. As shown in Figures 5, carotid arterial compliance significantly increased in the Theracurmin, EX + placebo, and EX + Theracurmin groups, whereas no such changes were observed in the placebo group. The magnitude of the increase in carotid compliance was the greatest in the EX + Theracurmin group. The percent change in carotid arterial compliance was significantly greater in the Ex + Theracurmin group than in the placebo group (Fig. 6). On the other hand, the percent change in the Theracurmin group or the Ex + placebo group statistically did not differ compared with the placebo group. These results suggest that Theracurmin improves carotid arterial compliance like aerobic exercise training. In addition, Theracurmin and exercise training improved vascular endothelial function in postmenopausal women as measured by flow-mediated dilation [31]. 7
5. Effect of curcumin supplementation on exercise-induced oxidative stress, inflammation, and muscle damage Curcumin has beneficial effects on conditions such as injured skeletal muscles. It has been shown that curcumin reduces inflammatory cytokine concentration in skeletal muscles after downhill running [32]. In addition, Kawanishi et al. observed that curcumin attenuates oxidative stress following downhill-running–induced muscle damage. They reported that hydrogen peroxide concentration and NADPH-oxidase mRNA in downhill-running mice were significantly higher than in the resting mice; however, these variables were significantly attenuated by Theracurmin administration in the downhill-running mice. In addition, mRNA expression levels of inflammation cytokines such as MCP-1 and CXCL14 in the downhill-running mice were significantly higher than in the resting mice. However, MCP-1 mRNA expression was not significantly changed by Theracurmin administration in the downhill-running mice [33]. Takahashi et al. [34] investigated the effects of curcumin supplementation on exercise-induced oxidative stress in humans. Their findings indicate that curcumin supplementation can attenuate exercise-induced oxidative stress by increasing blood antioxidant capacity. Recently, Sciberras et al. [35] reported the effect of curcumin supplementation on cytokine and inflammatory marker responses following 2 h of endurance cycling in humans. In addition, Huang et al. [36] reported the effect of curcumin supplementation on physiological fatigue and physical performance in mice, and concluded that curcumin supplementation results in significant benefits for physiological indicators after exercise by increasing muscle glycogen content; exercise performance was improved, including grip strength and endurance. In addition, the results also showed beneficial effects on body composition and biochemistry in terms of lipid profiles and liver and renal parameters. Regarding toxicity, curcumin was determined to be safe in relevant observations. Therefore, curcumin could help ameliorate exercise-induced fatigue and safely contribute to health promotion. 6. Effects of highly bioavailable curcumin on knee osteoarthritis Osteoarthritis, also referred to as degenerative joint disease, is a slow, destructive process in joints that affects millions of people worldwide. Although the exact biochemical cause of osteoarthritis remains unknown, the process usually begins when the joint structures 8
are abnormal or the stress placed on joint surfaces is unusually high. Knee osteoarthritis is a chronic inflammatory condition that is usually treated with analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs); however, these drugs can cause serious adverse GI and cardiovascular events, particularly with long-term use [37, 38]. Thus, there is a need for disease-modifying agents that not only decrease joint pain but also slow the progression of the condition. Nakagawa et al. [39] determined the clinical effects of orally administered Theracurmin in patients with knee osteoarthritis in a randomized, double-blind, placebo-controlled prospective study. Fifty patients with knee osteoarthritis of Kellgren–Lawrence grades II or III and who were >40 years of age were enrolled in this clinical study. Placebo or Theracurmin containing 180 mg/day of curcumin were orally administered every day for 8 weeks. To monitor adverse events, blood biochemistry analyses were performed before and after the 8-week intervention. The patients’ knee symptoms were evaluated at 0, 2, 4, 6, and 8 weeks by the Japanese Knee Osteoarthritis Measure, a knee pain visual analog scale (VAS); the knee scoring system of the Japanese Orthopedic Association; and the need for NSAIDs. At 8 weeks after treatment initiation, knee pain VAS scores were significant lower in the Theracurmin group than in the placebo group (Fig. 7). Theracurmin decreased celecoxib dependence significantly more than placebo after 8 weeks (Fig. 8). No major side effects were observed with Theracurmin treatment. 7. Conclusion Low oral bioavailability is one of the major reasons why curcumin has been unsuccessful in achieving therapeutic outcomes, despite its pleiotropic pharmacological properties. Among these pharmacological properties, inhibition of NF-kB activation is a major benefit against age-related chronic inflammatory conditions such as cancer, cardiovascular disease, Alzheimer’s disease, and bone and cartilage diseases. To increase its absorption through the intestinal membrane, a higher concentration at the membrane surface is essential. Curcumin delivery methods with increased solubility and stability or accessibility to the GI tract have been investigated. The methods that have already been tested in clinical research include microsuspensions [3], phosphatidylcholine complexes [4], and solid lipid nanoparticles [5]. Their bioavailability is much improved compared with that of conventional curcumin powder. In future, with the application of other methods, curcumin with better bioavailability could potentially be developed. Many 9
beneficial effects of Theracurmin on age-related chronic inflammation have been demonstrated, not only in conditions such as cancer, cardiovascular disease, and bone and cartilage diseases but also in vascular function and exercise-related QOL in humans. As reviewed in this article, many studies, ranging from basic studies to clinical studies, have been conducted on curcumin and its clinical applications in treating various diseases. Given its range of effects, curcumin alone may be useful in treating and preventing a number of diseases; however, completely establishing its potential will require further research into its clinical applications. Highly bioavailable curcumin (Theracurmin) is proposed to be a useful tool to elucidate the potential effects of curcumin.
References [1] Yang K-Y, Lin L-C, Tseng T-Y, Wang S-C, Tsai T-H.;1; Oral bioavailability of curcumin in rat and the herbal analysis from Curcuma longa by LC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci 2007;853:183–9. doi:10.1016/j.jchromb.2007.03.010. [2] Kurita T, Makino Y. ;1; Novel Curcumin Oral Delivery Systems. Anticancer Res 2013;33:2807–21. [3] Sasaki H, Sunagawa Y, Takahashi K, Imaizumi A, Fukuda H, Hashimoto T, et al.;1; Innovative preparation of curcumin for improved oral bioavailability. Biol Pharm Bull 2011;34:660–5. [4] Cuomo J, Appendino G, Dern AS, Schneider E, McKinnon TP, Brown MJ, et al.;1; Comparative absorption of a standardized curcuminoid mixture and its lecithin formulation. J Nat Prod 2011;74:664–9. doi:10.1021/np1007262. [5] Gota VS, Maru GB, Soni TG, Gandhi TR, Kochar N, Agarwal MG. ;1; Safety and pharmacokinetics of a solid lipid curcumin particle formulation in osteosarcoma patients and healthy volunteers. J Agric Food Chem 2010;58:2095–9. doi:10.1021/jf9024807.
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[6] Sunagawa Y, Hirano S, Katanasaka Y, Miyazaki Y, Funamoto M, Okamura N, et al.;1; Colloidal submicron-particle curcumin exhibits high absorption efficiency: A double-blind, 3-way crossover study. J Nutr Sci Vitaminol 2015:61:37–44. [7] Yamauchi Y, Izumi Y, Yamamoto J, Nomori H. ;1; Coadministration of erlotinib and curcumin augmentatively reduces cell viability in lung cancer cells. Phytother Res 2014;28:728–35. doi:10.1002/ptr.5056. [8] Kanai M. ;1; Therapeutic applications of curcumin for patients with pancreatic cancer. World J Gastroenterol 2014;20:9384–91. doi:10.3748/wjg.v20.i28.9384. [9] Lao CD, Ruffin MT, Normolle D, Heath DD, Murray SI, Bailey JM, et al.;1; Dose escalation of a curcuminoid formulation. BMC Complement Altern Med 2006;6:9. doi:10.1186/1472-6882-6-10. [10] Sharma RA, Euden SA, Platton SL, Cooke DN, Shafayat A, Hewitt HR, et al. Phase I ;1; Clinical Trial of Oral Curcumin Biomarkers of Systemic Activity and Compliance. Clin Cancer Res 2004;10:6847–54. doi:10.1158/1078-0432.CCR-04-0744. [11] Kanai M, Yoshimura K, Asada M, Imaizumi A, Suzuki C, Matsumoto S, et al.;1; A phase I/II study of gemcitabine-based chemotherapy plus curcumin for patients with gemcitabine-resistant pancreatic cancer. Cancer Chemother Pharmacol 2011;68:157–64. doi:10.1007/s00280-010-1470-2. [12] Kanai M, Imaizumi A, Otsuka Y, Sasaki H, Hashiguchi M, Tsujiko K, et al.;1; Dose-escalation and pharmacokinetic study of nanoparticle curcumin, a potential anticancer agent with improved bioavailability, in healthy human volunteers. Cancer Chemother Pharmacol 2012;69:65–70. doi:10.1007/s00280-011-1673-1. [13] Kanai M, Otsuka Y, Otsuka K, Sato M, Nishimura T, Mori Y, et al.;1; A phase I study investigating the safety and pharmacokinetics of highly bioavailable curcumin (Theracurmin) in cancer patients. Cancer Chemother Pharmacol 2013;71:1521–30. doi:10.1007/s00280-013-2151-8. 11
[14] Hebert JR, Hurley TG, Olendzki BC, Teas J, Ma Y, Hampl JS. ;1; Nutritional and socioeconomic factors in relation to prostate cancer mortality: a cross-national study. J Natl Cancer Inst 1998;90:1637–47. [15] Bemis DL, Katz AE, Buttyan R. ;1; Clinical trials of natural products as chemopreventive agents for prostate cancer. Expert Opin Investig Drugs 2006;15:1191–200. doi:10.1517/13543784.15.10.1191. [16] Ide H, Tokiwa S, Sakamaki K, Nishio K, Isotani S, Muto S, et al.;1; Combined inhibitory effects of soy isoflavones and curcumin on the production of prostate-specific antigen. Prostate 2010;70:1127–33. doi:10.1002/pros.21147. [17] Morimoto T, Sunagawa Y, Kawamura T, Takaya T, Wada H, Nagasawa A, et al.;1; The dietary compound curcumin inhibits p300 histone acetyltransferase activity and prevents heart failure in rats. J Clin Invest 2008;118:868–78. doi:10.1172/JCI33160. [18] Sunagawa Y, Morimoto T, Wada H, Takaya T, Katanasaka Y, Kawamura T, et al.;1; A natural p300-specific histone acetyltransferase inhibitor, curcumin, in addition to angiotensin-converting enzyme inhibitor, exerts beneficial effects on left ventricular systolic function after myocardial infarction in rats. Circ J 2011;75:2151–9. [19] Sunagawa Y, Wada H, Suzuki H, Sasaki H, Imaizumi A, Fukuda H, et al.;1; A novel drug delivery system of oral curcumin markedly improves efficacy of treatment for heart failure after myocardial infarction in rats. Biol Pharm Bull 2012;35:139–44. [20] Brown DW, Giles WH, Croft JB. ;1; Left ventricular hypertrophy as a predictor of coronary heart disease mortality and the effect of hypertension. Am Heart J 2000;140:848–56. doi:10.1067/mhj.2000.111112. [21] Roman MJ, Devereux RB, Kizer JR, Okin PM, Lee ET, Wang W, et al.;1; High central pulse pressure is independently associated with adverse cardiovascular outcome
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the strong heart study. J Am Coll Cardiol 2009;54:1730–4. doi:10.1016/j.jacc.2009.05.070. [22] Safar ME, Blacher J, Pannier B, Guerin AP, Marchais SJ, Guyonvarc’h P-M, et al. ;1; Central pulse pressure and mortality in end-stage renal disease. Hypertension 2002;39:735–8. [23] Safar ME, Levy BI, Struijker-Boudier H. ;1; Current perspectives on arterial stiffness and pulse pressure in hypertension and cardiovascular diseases. Circulation 2003;107:2864–9. doi:10.1161/01.CIR.;1; 0000069826.36125.B4. [24] Sugawara J, Akazawa N, Miyaki A, Choi Y, Tanabe Y, Imai T, et al.;1; Effect of endurance exercise training and curcumin intake on central arterial hemodynamics in postmenopausal women: pilot study. Am J Hypertens 2012;25:651–6. doi:10.1038/ajh.2012.24. [25] Tanaka H, Dinenno FA, Monahan KD, Clevenger CM, DeSouza CA, Seals DR. ;1; Aging, habitual exercise, and dynamic arterial compliance. Circulation 2000;102:1270–5. [26] Kakiyama T, Sugawara J, Murakami H, Maeda S, Kuno S, Matsuda M. ;1; Effects of short-term endurance training on aortic distensibility in young males. Med Sci Sports Exerc 2005;37:267–71. [27] Yoshizawa M, Maeda S, Miyaki A, Misono M, Choi Y, Shimojo N, et al.;1; Additive beneficial effects of lactotripeptides and aerobic exercise on arterial compliance in postmenopausal women. Am J Physiol Heart Circ Physiol 2009;297:H1899–903. doi:10.1152/ajpheart.00433.2009. [28] Maeda S, Tanabe T, Otsuki T, Sugawara J, Ajisaka R, Matsuda M. ;1; Acute exercise increases systemic arterial compliance after 6-month exercise training in older women. Hypertens Res 2008;31:377–81. doi:10.1291/hypres.31.377.
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[29] Miyaki A, Maeda S, Yoshizawa M, Misono M, Saito Y, Sasai H, et al.;1; Effect of habitual aerobic exercise on body weight and arterial function in overweight and obese men. Am J Cardiol 2009;104:823–8. doi:10.1016/j.amjcard.2009.04.057. [30] Akazawa N, Choi Y, Miyaki A, Tanabe Y, Sugawara J, Ajisaka R, et al.;1; Effects of curcumin intake and aerobic exercise training on arterial compliance in postmenopausal women. Artery Research 2013;7:67–72. doi:10.1016/j.artres.2012.09.003. [31] Akazawa N, Choi Y, Miyaki A, Tanabe Y, Sugawara J, Ajisaka R, et al.;1; Curcumin ingestion and exercise training improve vascular endothelial function in postmenopausal women. Nutr Res 2012;32:795–9. doi:10.1016/j.nutres.2012.09.002. [32] Davis JM, Murphy EA, Carmichael MD, Zielinski MR, Groschwitz CM, Brown AS, et al.;1; Curcumin effects on inflammation and performance recovery following eccentric exercise-induced muscle damage. Am J Physiol Regul Integr Comp Physiol 2007;292:R2168–73. doi:10.1152/ajpregu.00858.2006. [33] Kawanishi N, Kato K, Takahashi M, Mizokami T, Otsuka Y, Imaizumi A, et al.;1; Curcumin attenuates oxidative stress following downhill running-induced muscle damage. Biochemical and Biophysical Research Communications 2013;441:573–8. doi:10.1016/j.bbrc.2013.10.119. [34] Takahashi M, Suzuki K, Kim HK, Otsuka Y, Imaizumi A, Miyashita M, et al.;1; Effects of curcumin supplementation on exercise-induced oxidative stress in humans. Int J Sports Med 2014;35:469–75. doi:10.1055/s-0033-1357185. [35] Sciberras JN, Galloway SD, Fenech A, Grech G, Farrugia C, Duca D, et al.;1; The effect of turmeric (Curcumin) supplementation on cytokine and inflammatory marker responses following 2 hours of endurance cycling. J Int Soc Sports Nutr 2015;12:5. doi:10.1186/s12970-014-0066-3.
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[36] Huang W-C, Chiu W-C, Chuang H-L, Tang D-W, Lee Z-M, Wei L, et al.;1; Effect of curcumin supplementation on physiological fatigue and physical performance in mice. Nutrients 2015;7:905–21. doi:10.3390/nu7020905. [37] Smalley WE, Ray WA, Daugherty JR, Griffin MR. ;1; Nonsteroidal anti-inflammatory drugs and the incidence of hospitalizations for peptic ulcer disease in elderly persons. Am J Epidemiol 1995;141:539–45. [38] Felson DT, Lawrence RC, Hochberg MC, McAlindon T, Dieppe PA, Minor MA, et al.;1; Osteoarthritis: new insights. Part 2: treatment approaches. Ann Intern Med 2000;133:726–37. [39] Nakagawa Y, Mukai S, Yamada S, Matsuoka M, Tarumi E, Hashimoto T, et al.;1; Short-term effects of highly-bioavailable curcumin for treating knee osteoarthritis: a randomized, double-blind, placebo-controlled prospective study. J Orthop Sci 2014;19:933–9. doi:10.1007/s00776-014-0633-0.
Figure Captions Fig. 1. Change in plasma concentration of curcumin in healthy volunteers ●, Theracurmin; ♦, BCM-95; ▲, Meriva. Each point and bar represents the mean ± SD (n = 9). * P < 0.05 vs. BCM-95. # P < 0.05 vs. Meriva. Sample preparation and measurement of plasma curcumin levels: Each plasma sample was incubated with beta-glucuronidase to hydrolyze the curcumin conjugates. After extraction with chloroform, the dried extracts were reconstituted in 50% MeOH and injected into a chromatographic system. Plasma concentrations of curcumin were measured using the HPLC-MS/MS system. Adapted from Sunagawa Y, et al. [6]. Colloidal submicron-particle curcumin exhibits high absorption efficiency: A double-blind, 3-way crossover study. J Nutr Sci Vitaminol 2015:61:37–44. Fig. 2. IkappaB expression was elevated in PC9 cells by curcumin administration. 15
(A) Administration of curcumin at 25 µM (cur group, n = 4), or coadministration of erlotinib and curcumin (elt + cur group, n = 4) significantly elevated ikappaB expression in comparison to control (cont group, n = 4) (* P = 0.019, ** P < 0.001 between the indicated groups). (B) Pretreatment with siRNAs for ikappaB (siRNA elt + cur) attenuated the elevation of ikappaB expression by erlotinib and curcumin administration (elt + cur). The figure is representative of three independent experiments. Adapted from Yamauchi Y, et al. [7]. Coadministration of erlotinib and curcumin augmentatively reduces cell viability in lung cancer cells. Phytother Res 2014;28:728–35. Fig. 3. Coadministration of erlotinib and/or curcumin attenuated the growth of PC9 tumors in mice; however, statistically significant attenuation was achieved only by coadministration of erlotinib and curcumin. Macroscopically, no metastases were observed in any of the animals at the time of sacrifice, (* P < 0.01 between the indicated groups). pad: post administration days; cont: DMSO; elt: erlotinib 25 mg/kg; Thera: Theracurmin 100 mg/kg; elt + Thera: erlotinib 25 mg/kg + Theracurmin 100 mg/kg. n = 5 in each group. Adapted from Yamauchi Y, et al. [7]. Coadministration of erlotinib and curcumin augmentatively reduces cell viability in lung cancer cells. Phytother Res 2014;28:728–35. Fig. 4. Changes in aortic augmented pressure (AP75) and augmentation index (AIx75) normalized for a heart rate of 75 bpm. Data are mean ± SEM. bpm: beats per minute; Cur: curcumin; Ex + Cur: exercise training + curcumin; Ex + Pla: exercise training + placebo; Pla: placebo. Adapted from Sugawara J, et al. [24]. Effect of endurance exercise training and curcumin intake on central arterial hemodynamics in postmenopausal women: pilot study. Am J Hypertens 2012;25:651–6. Fig. 5. Carotid arterial compliance before and after intervention. Data are expressed as mean ± SE. * P < 0.05 before vs. after intervention.
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Adapted from Akazawa N, et al. [30]. Effects of curcumin intake and aerobic exercise training on arterial compliance in postmenopausal women. Artery Research 2013;7:67–72. Fig. 6. Percentage changes in arterial compliance in response to intervention. Data are expressed as mean ± SE. * P < 0.05 placebo vs. exercise + curcumin (Ex + curcumin). Adapted from Akazawa N, et al. [30]. Effects of curcumin intake and aerobic exercise training on arterial compliance in postmenopausal women. Artery Research 2013;7:67–72. Fig. 7. The improved VAS scores in the two groups are presented as means ± SD. The two-sample one-sided t test was used to perform the statistical analysis of the VAS, JKOM, and JOA scores. The chi-square test was used to analyze the need for celecoxib. The level of statistical significance was set to a P value of <0.05. Except for the patients with initial VAS scores of 0.15 or less, the VAS scores were significantly improved in the Theracurmin group in comparison to the placebo group at 8 weeks (P = 0.023). VAS: visual analog scale. Adapted from Nakagawa Y, et al. [39]. Short-term effects of highly-bioavailable curcumin for treating knee osteoarthritis: a randomized, double-blind, placebo-controlled prospective study. J Orthop Sci 2014;19:933–9. Fig. 8. NSAID necessity in the two groups. At 8 weeks only, the ratio of patients who needed celecoxib was significantly lower in the Theracurmin group than in the placebo group (P = 0.0252). NSAID: nonsteroidal anti-inflammatory drugs. Adapted from Nakagawa Y, et al. [39]. Short-term effects of highly-bioavailable curcumin for treating knee osteoarthritis: a randomized, double-blind, placebo-controlled prospective study. J Orthop Sci 2014;19:933–9.
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Fig. 1
Fig. 2
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Fig. 3
Fig. 4
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Fig. 5
Fig. 6
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Fig. 7
Fig. 8
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Tables Table 1 Composition of each curcumin capsule Dosage used in Measured Manufacturing Sample
Curcumin this study Ingredients
value
method
content
(number of (mg) capsules)
Theracurmin (Dextrin, Maltose, Curcuma longa extract (Curcuminoids 83–88%, Curcumin dispersed Curcumin 79–84%) , Gum
30 mg/
180 mg
182.4 ±
(6 capsules)
6.0
260 mg/
260 mg
279.3 ±
capsule
(1 capsule)
10.7
75 mg/
150 mg (2
152.5 ±
capsules)
20.3
Theracurmin with colloidal ghatti, Citric acid), Cornstarch, capsule submicron-particles Silicon dioxide, Calcium stearate, Hydroxypropyl methylcellulose (capsule) Curcuma longa extract with Curcumin complex Essential Oils of Turmeric with essential oils of BCM-95
Rhizome, Rice flour, Vegetable the turmeric cellulose (capsule), Vegetable rhizome stearate, Silica Curcuma longa extract (root) / Curcumin complex Phosphatidylcholine complex), with
Hypromellose (capsule),
Meriva phosphatidylcholine Leucine, Calcium citratelaurate, capsule from soy lecithin
Silicon dioxide, Microcrystalline cellulose
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Table 2 Changes in QOL scores after Theracurmin administration Best score during Baseline
Mean change
P valuec
curcumin intake Fatigue score
38.0 ± 13.2
24.8 ± 14.3
–13.2
0.004
Functional scorea,b
82.8 ± 11.9
90.7 ± 8.1
8.0
0.001
Diarrhea
15.0 ± 27.6
5.6 ± 12.4
–9.4
0.006
Financial difficulties
16.7 ± 25.5
2.8 ± 9.2
–13.9
0.027
Appetite loss
38.9 ± 26.6
22.2 ± 28.3
–16.7
0.026
Insomnia
13.9 ± 16.4
8.3 ± 14.4
–5.6
0.083
Pain
22.2 ± 19.6
16.7 ± 18.0
–5.5
0.083
Nausea
6.9 ± 10.7
2.8 ± 4.2
–4.1
0.096
Constipation
19.4 ± 21.3
11.1 ± 20.8
–8.3
0.214
Dyspnea
25.0 ± 27.6
16.7 ± 21.5
–8.3
0.215
Global healthb
56.3 ± 18.7
63.2 ± 20.0
6.9
0.101
Complete EORTC QLQ-C30 scores on day 1 of the first treatment cycle (baseline) and on day 1 of the second or later treatment cycles were available in 12 patients. Three patients could not submit the score sheet after Theracurmin administration because of withdrawal or DLTs, and one failed to complete the score sheet. a. Five functional scores (emotional, role, cognitive, physical, and social functions) were pooled together b. Higher scores indicate better symptoms; otherwise, a lower score indicates a better symptom c. P < 0.005 indicates significance for multiple comparisons
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