Oral curcumin in elective abdominal aortic aneurysm repair: a multicentre randomized controlled trial
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- RE: Oral Curcumin in elective abdominal aortic aneurysm repairLora L. AllerPosted on: 02 January 2019
- Posted on: (20 January 2019)Page navigation anchor for RE: why use the medianRE: why use the median
- shan lu, family doctor/COE resident, University of Alberta
Hi There,
Interesting article. I would like to use it for a journal club article, and I'm wondering why did you choose to use the median for all the outcome measures instead of using the mean?
Thanks.Competing Interests: None declared. - Posted on: (7 January 2019)Page navigation anchor for Bioavailability of oral curcuminBioavailability of oral curcumin
- Amit X. Garg, Professor, Departments of Medicine and of Epidemiology and Biostatistics, Western University
Jan 5, 2019
We conclude the regimen of curcumin we tested exerted no beneficial pharmacodynamic effect on the outcomes we assessed in the elective abdominal aortic aneurysm repair setting. These findings advance knowledge.
Dr. Aller seems to suggest the lack of observed effect is entirely due to poor pharmacokinetic properties of the regimen we selected. It is true a concern with curcumin is that it is poorly absorbed from the gastrointestinal tract and is rapidly metabolized resulting in low free blood and tissue concentrations. We acknowledged this in our report, and in the Discussion write: "Curcumin is notorious for being poorly absorbed from the gastrointestinal tract … ". However, animal studies of the plasma and tissue distribution of curcumin do prove there are detectable levels of radiolabeled curcumin in the blood and kidney after its oral administration. (1) We also share with Dr. Aller and others the following details.
i. Everything Dr. Aller mentions was fully discussed in planning this trial and was addressed in our successful grant application funded by the Nutrition, Food and Health peer-review panel at the Canadian Institutes of Health Research.
ii. We tested a regimen of oral curcumin that we hypothesized would have beneficial effects. Seven reasons to justify the curcumin regimen we tested are fully described in section 4 of Appendix 1 of the report. Patients were instructed to take the capsules with food to impro...
Show MoreJan 5, 2019
We conclude the regimen of curcumin we tested exerted no beneficial pharmacodynamic effect on the outcomes we assessed in the elective abdominal aortic aneurysm repair setting. These findings advance knowledge.
Dr. Aller seems to suggest the lack of observed effect is entirely due to poor pharmacokinetic properties of the regimen we selected. It is true a concern with curcumin is that it is poorly absorbed from the gastrointestinal tract and is rapidly metabolized resulting in low free blood and tissue concentrations. We acknowledged this in our report, and in the Discussion write: "Curcumin is notorious for being poorly absorbed from the gastrointestinal tract … ". However, animal studies of the plasma and tissue distribution of curcumin do prove there are detectable levels of radiolabeled curcumin in the blood and kidney after its oral administration. (1) We also share with Dr. Aller and others the following details.
i. Everything Dr. Aller mentions was fully discussed in planning this trial and was addressed in our successful grant application funded by the Nutrition, Food and Health peer-review panel at the Canadian Institutes of Health Research.
ii. We tested a regimen of oral curcumin that we hypothesized would have beneficial effects. Seven reasons to justify the curcumin regimen we tested are fully described in section 4 of Appendix 1 of the report. Patients were instructed to take the capsules with food to improve curcumin absorption (which occurred for all doses in over 85% of patients based on their self-report).
iii. The fact that free curcumin is difficult to measure in the blood does not equate to an assertion that the agent is not biologically active. In our report we cite a smaller randomized controlled trial of 121 consecutive patients undergoing coronary artery bypass graft surgery at a single centre in Thailand, where oral curcumin relative to placebo reduced the risk of postoperative myocardial infarction and lowered concentrations of plasma biomarkers for inflammation, oxidation and injury. This justified further testing oral curcumin in the peri-operative setting as done in our report. Our curcumin regimen of 4000 mg a day is a common dose used in many published small single-centre trials that reported biological effects. (2)
iv. Unlike free curcumin, major curcumin metabolites (glucuronide and sulfate conjugates) are readily detected after an oral dose, and these metabolites exert biological activity. In the Results section of our paper we share: "In the curcumin group, curcumin metabolites were detected in the urine using high-performance liquid chromatography and mass spectrometry, as described in section 9 of Appendix 1, at a concentration significantly higher than detected in the placebo group."
v. We considered co-administering oral curcumin with another agent such as piperine (from black pepper), turmeric oil or quercetin to increase its bioavailability. However, the addition of these adjuvants had regulatory implications for trial conduct and could have resulted in a highly selected participant population. For example, possible pleiotropic effects of piperine, the most well-studied adjuvant, raised concerns about safety. Piperine is a non-specific inhibitor of drug metabolism and enhances the bioavailability of several standard drugs including β-lactam antibiotics, phenytoin, and several beta-blockers.
vi. We remain open-minded about the possible health benefits of novel formulations of curcumin, including nanoparticle-based delivery systems, liposomal curcumin, and micelle and phospholipids complexes. Funded by the Canadian Institutes of Health Research we are now conducting a multi-centre controlled trial of a micro-particle curcumin in patients at risk of progressive chronic kidney disease. (3) We encourage others to do the same with preparations of turmeric / curcumin and in settings where they believe there may be health benefits. Our position is that it is responsible to rigorously test what we think might be beneficial according to best standards in medicine before espousing health benefits, as often occurs in the popular media when it comes to curcumin and other natural health products.
Drs. Amit Garg, Louise Moist, Neesh Pannu, Sheldon Tobe, Michael Walsh and Matthew Weir for the Curcumin AAA AKI Investigators
References
1. Ravindranath V, Chandrasekhara N. Metabolism of curcumin--studies with [3H]curcumin. Toxicology 1981;22(4):337-44
2. Gupta SC, Patchva S, Aggarwal BB. Therapeutic roles of curcumin: lessons learned from clinical trials. AAPS J. 2013 Jan;15(1):195-218.
3. Weir MA, Walsh M, Cuerden MS, Sontrop JM, Chambers LC, Garg AX. Micro-Particle Curcumin for the Treatment of Chronic Kidney Disease-1: Study Protocol for a Multicenter Clinical Trial. Can J Kidney Health Dis. Dec 5, 2018
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https://journals.sagepub.com/doi/full/10.1177/2054358118813088Competing Interests: None declared. - Posted on: (2 January 2019)Page navigation anchor for RE: Oral Curcumin in elective abdominal aortic aneurysm repairRE: Oral Curcumin in elective abdominal aortic aneurysm repair
- Lora L. Aller, Physician - retired, FP/GP Number of previous hospital affiliations.
There seems to be a fundamental error in this research. Both turmeric and curcumin have extremely poor oral bioavailability. If one googles 'oral availability of curcumin' an immediate 62 articles and citations are populated from PubMed and NCBI from journals as diverse as Biomaterials 2014, J Drug Target 2016, etc. etc. This has been a topic of scholarly research for some years. Efforts to develop SNEDDS (self nano emulsifying drug delivery systems) and complexing the molecule with lipid carriers to improve bioavailability of curcumin are not obscure topics. On the cultural level historically, Aryuvedic practionners and Indian households have utilized turmeric (curcumin) in combination with fat i.e. coconut oil (homestyle lipid complexes!) and black pepper (vasodilates the gastric mucosa, enhancing absorption) with ginger, cinnamon and cardamon (similar effects). A quick check on the ingredients in Blume Tumeric lattes as well as the '‘immune enhancer‘ tea at my local Iranian pharmacy reveals all these ingredients to be present in combination. Possibly there is something the authors didn’t investigate which cultural wisdoms advocate for.
One expects rigorous earnest scientific methods to be applied to a study of this size. A review of the methods showed NO mention nor discussion of oral bioavailability that I could find yet their curcumin ‘drug’ was administered orally. To illustrate: one would not expect neomycin orally to treat any conditio...
Show MoreThere seems to be a fundamental error in this research. Both turmeric and curcumin have extremely poor oral bioavailability. If one googles 'oral availability of curcumin' an immediate 62 articles and citations are populated from PubMed and NCBI from journals as diverse as Biomaterials 2014, J Drug Target 2016, etc. etc. This has been a topic of scholarly research for some years. Efforts to develop SNEDDS (self nano emulsifying drug delivery systems) and complexing the molecule with lipid carriers to improve bioavailability of curcumin are not obscure topics. On the cultural level historically, Aryuvedic practionners and Indian households have utilized turmeric (curcumin) in combination with fat i.e. coconut oil (homestyle lipid complexes!) and black pepper (vasodilates the gastric mucosa, enhancing absorption) with ginger, cinnamon and cardamon (similar effects). A quick check on the ingredients in Blume Tumeric lattes as well as the '‘immune enhancer‘ tea at my local Iranian pharmacy reveals all these ingredients to be present in combination. Possibly there is something the authors didn’t investigate which cultural wisdoms advocate for.
One expects rigorous earnest scientific methods to be applied to a study of this size. A review of the methods showed NO mention nor discussion of oral bioavailability that I could find yet their curcumin ‘drug’ was administered orally. To illustrate: one would not expect neomycin orally to treat any condition systemically as it is not orally absorbed. Much time, energy and funding was spent on this study. How could such a basic background question not be addressed? It may be unfamiliarity with turmeric and curcumin but in that case wouldn’t one do a literature search to learn all one could? Would not one be curious as to the topic of oral bioavailability since the study participants were administering curcumin orally?
One root cause for this apparent oversight may be unfamiliarity with the entity curcumin. Another may be bias - towards "natural health products" as well as the inherent structural application of a single variable (curcumin) as opposed to a multivariable study (i.e. tumeric with all its friends). If curcumin been a drug its pharmacology would have been addressed.
The harm this type of neglect does is much clearer in the editorial for this issue. I see it as subtly shaming both a basic cultural practice which uses turmeric (+ buds) daily as well as the earnest reaching for health of many of our patients and communities who are exposed to these cultural practices in their yoga studios, with friends and cross cultural pollination, trips to India, etc. Could anyone reading the editorial now order their turmeric latte (in which the active ingredients are undoubtedly better absorbed and active) without feeling a bit ridiculous or subtly shamed? Could any researcher now seriously ask for funding for studies regarding the potential of turmeric to help prevent Alzheimer’s disease which we are increasingly learning has roots in inflammation?
We owe it to our profession and community to practice rigorous scientific methods and to respect our subject or we stand the risk of losing the respect of alienating them. We also lose out on opening valuable new doors (prevention of familial colon cancer, mitigating the tolerance to morphine in burn patients and potential treatments for ‘fatty liver”- Let us work to mitigate unconscious bias in our BI work.
1.Liu W, Zhai Y, Heng X, Che FY, Chen W, Sun D, Zhai G. Oral bioavailability of curcumin: problems and advancements. J Drug Target. 2016 Sep;24(8):694-702. doi: 10.3109/1061186X.2016.1157883. Epub 2016 Mar 17.
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2.Shukla M, Jaiswal S, Sharma A, Srivastava PK, Arya A, Dwivedi AK, Lal J. A combination of complexation and self-nanoemulsifying drug delivery system for enhancing oral bioavailability and anticancer efficacy of curcumin. Drug Dev Ind Pharm. 2017 May;43(5):847-861.
3.Shen H, Hu X, Szymusiak M, Wang ZJ, Liu Y. Orally administered nanocurcumin to attenuate morphine tolerance: comparison between negatively charged PLGA and partially and fully PEGylated nanoparticles. Mol Pharm. 2013 Dec 2;10(12):4546-51.
4.Cheppudira B, Fowler M, McGhee L, Greer A, Mares A, Petz L, Devore D, Loyd DR, Clifford JL. Curcumin: a novel therapeutic for burn pain and wound healing. Expert Opin Investig Drugs. 2013 Oct;22(10):1295-303.
5.Shen H, Hu X, Szymusiak M, Wang ZJ, Liu Y. Orally administered nanocurcumin to attenuate morphine tolerance: comparison between negatively charged PLGA and partially and fully PEGylated nanoparticles. Mol Pharm. 2013 Dec 2;10(12):4546-51Competing Interests: I'm off to drink a turmeric latte then to dinner at a Sikh friend's home Turmeric will be on the menu.
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