Ignite Creation Date:
2024-05-06 @ 12:57 PM
Last Modification Date:
2024-10-26 @ 1:07 PM
Study NCT ID:
NCT03897660
Status:
COMPLETED
Last Update Posted:
2020-08-27
First Post:
2019-02-27
Brief Title:
MaxSimil and Vitamin K2 Determining Their Bioavailability
Sponsor:
Université de Sherbrooke
Organization:
Université de Sherbrooke
Study Overview
Official Title:
Pharmacokinetics of Omega-3 Fatty Acids Esterified in Monoglycerides Ethyl Esters or Triglycerides in Humans
Status:
COMPLETED
Status Verified Date:
2020-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The benefits of a diet enriched with omega-3 fatty acids are multiple and confirmed by several clinical studies Supplementation with vitamin K a fat-soluble vitamin can increase or maintain bone density in postmenopausal women and reduce the risk of fracture In addition some studies show that vitamin K may promote the absorption of omega-3 fatty acids Fish oil rich in omega-3 is one of the worlds favorite forms of omega-3 supplements However many people suffer from gastrointestinal discomfort when ingesting fish oil capsules To minimize these discomforts and improve plasmatic omega-3 bioavailability Neptune Wellness Solutions has developed a patented formulation of fish oil called MaxSimil where omega-3s are in the monoglyceride MAG form a predigested omega-3 form This formulation has been tested in humans in a double-blind controlled-randomized pharmacokinetic PK pilot study with crossover design PK is defined as a monitoring of omega-3 levels in the blood by frequent blood sampling over a period of 24 hours following the ingestion of a single dose of omega-3 The results obtained showed that MaxSimil omega-3s are 3 times more absorbed in the blood than the comparison formulation a source of omega-3 in the ethyl ester EE form
Although this first study confirms a greater bioavailability of MaxSimil a complementary PK study is necessary to confirm these results and to correct an important methodological bias In fact the pilot study did not include a comparator group where omega-3s were in the triglyceride TG form the most widely omega-3 form currently consumed but rather use an EE form which have lower bioavailability than TG form This may therefore have biased the study from the point of view of the comparator and thus give the impression that the comparator had been deliberately chosen to be less bioavailable than the MaxSimil
In order to confirm the superiority of MaxSimil omega-3 MAG form both in terms of bioavailability and incidence of side effects the aim of this study is to redo a PK study using this time two comparators the two main forms of omega-3 currently used TG and EE forms as well as a supplementation with vitamin K2 a form of vitamin K Our hypothesis is that MaxSimil will be associated with a better omega-3 bioavailability and a lower incidence of side effects than the other two forms TG and EE and possibly also with a better vitamin K bioavailability
Although this first study confirms a greater bioavailability of MaxSimil a complementary PK study is necessary to confirm these results and to correct an important methodological bias In fact the pilot study did not include a comparator group where omega-3s were in the triglyceride TG form the most widely omega-3 form currently consumed but rather use an EE form which have lower bioavailability than TG form This may therefore have biased the study from the point of view of the comparator and thus give the impression that the comparator had been deliberately chosen to be less bioavailable than the MaxSimil
In order to confirm the superiority of MaxSimil omega-3 MAG form both in terms of bioavailability and incidence of side effects the aim of this study is to redo a PK study using this time two comparators the two main forms of omega-3 currently used TG and EE forms as well as a supplementation with vitamin K2 a form of vitamin K Our hypothesis is that MaxSimil will be associated with a better omega-3 bioavailability and a lower incidence of side effects than the other two forms TG and EE and possibly also with a better vitamin K bioavailability
Detailed Description:
Long Chain-Polyunsaturated fatty acids LC-PUFA are needed to support normal physiological functions Unlike saturated and monounsaturated fatty acids synthesis of eicosapentaenoic acid EPA 205 omega-3 and docosahexaenoic acid DHA 226 omega-3 from its omega-3 PUFA precursor alpha-linolenic acid 183 omega-3 is extremely limited in humans Thus it is recommended that DHA be obtained from dietary sources such as fish and seafood Intake of EPA and DHA from fish normally correlates positively with the concentrations of EPA and DHA in plasma However recent data suggest that EPA levels are approximately twice higher in plasma lipids of the elderly as compared to young individuals suggesting that potential alterations in EPA incorporation and utilization occur during aging Similar results were obtained with a DHA-enriched supplement where the increase of DHA in plasma total lipids was 42 higher in the elderly compared to the young At sufficient levels of cellular content the LC-PUFA influence the physical nature of cell membranes and membrane protein-mediated responses lipid-mediator generation cell signalling and gene expression in many different cell types Through these mechanisms ARA arachidonic acid 204 omega-6 and DHA influence both cell and tissue responses to external signals and thereby their physiology Therefore imbalances in LC-PUFA homeostasis potentially induce dysfunctions in the physiology of organs
Aging of the Canadians and their nutrition Canadas population is expected to age more rapidly in the coming years Senior citizens have become more numerous than children in 2015 A major concern about old age both the individual and society is a decline in health especially if this means a loss of self-sufficiency and independence Increasing research for promoting healthy aging is ongoing but there are physiological modifications occurring during aging that might change bioavailability of LC-PUFA For instance intake of EPA and DHA concentrated in fish normally correlates positively with the concentrations of EPA and DHA in plasma However recent data from our laboratories suggest that EPA levels are approximately twice higher in plasma lipids of the elderly as compared to young individuals suggesting that potential alterations in EPA incorporation and utilization occur during aging DHA response to a DHA-rich supplement was significantly higher in the elderly as compared to the young While on DHA-rich supplement ARA was not decreased in the young and the elderly but similarly to EPA ARA remained significantly higher in the elderly compared to the young The investigators also have publish data suggesting that 40 years old is the age where the EPA and DHA levels in the plasma are higher than expected and this was independent to their dietary omega-3 fatty acid intake Hence these results are important indications that the metabolism of LC-PUFA is modified by age and this observation lead to the idea that their uptake and usage by organs and tissue can be compromised
13C-DHA in humans Tracing metabolism of carbon 13 13C-labelled fatty acids may provide some insight into possible aging-related changes in fatty acid metabolism in humans The investigators recently used 13C-DHA to trace its metabolism in six young and six elderly participants The investigators found that in the elderly 13C-DHA was 4 times higher in plasma triglycerides and free fatty acids at 4 h post-dose beta-oxidation was 19 times higher whereas apparent retro-conversion of 13C-DHA to other 13C-omega-3 fatty acids was 21 times higher 24 h and 7 d after tracer intake compared to the young Hence because DHA seems to remain transiently for longer periods of time in the blood of the elderly compared to the young it may thus indicate that efficiency to remove DHA from the blood is lower in the elderly than in the young resulting in lower incorporation of DHA in the membrane of cells that serve to initiate signalization This observation is potentially at the root of altered signalization in the elderly compared to the young
Bioavailability of EPA and DHA esterified in TG PL or as an ethyl ester EE Most of fish oil supplements on the market are EPA and DHA esterified in TG and to a lower level in EE and PL There has been a lot of study evaluating whether one form of esterification enhances bioavailability of EPA and DHA In pharmacology Bioavailability is defined as a subcategory of absorption and it is the portion of the administered dose of a drug or in this case EPADHA that reaches the systemic circulation By definition an intravenous drug is 100 bioavailable but when a drug is administered orally its bioavailability is usually decreased due to incomplete absorption or first-pass metabolism Hence in the review paper of Ghasemifard et al they reviewed 21 papers that evaluated whether omega-3 fatty acid were more bioavailable when given in the form of EE TG non-esterified form or as a PL Four studies were rejected because there were no control group eight studies were evaluating pharmacokinetics PK defined as a follow up between 8 h up to 72 h of a single oral dose of the omega-3 fatty acid product whereas nine studies evaluated the long term intake pharmacodynamic PD of a repeated daily dose of omega-3 fatty acids over a period of 2 weeks and up to 6 months Although the methodologies of the studies differ some conclusion about the PK was that bioavailability of EPA DHA was higher when given in the forms of non-esterified fatty acid TG EE Lower absorption of the EE form might be because pancreatic hydrolysis of EPA and DHA of the EE form compared to the TG form is 10-50 times lower Hence the esterification form of omega-3 fatty acids might change their short-term bioavailability and this information is particularly relevant in the context of metabolic diseases that can either affect fat absorption or to an aging population where there are dyslipidemias that might change omega-3 fatty acid bioavailability
Is MAG-Omega-3 form a better bioavailable source of EPADHA One study in rats reported bioavailability of DHA esterified in TG PL or MAG 2-mono-acylglycerol in plasma erythrocytes retina and brain tissue They reported that after giving DHA in the different forms to rats for 35 days DHA given in the MAG and PL form were 23-50 more concentrated in plasma total lipids and erythrocytes compared to TG-DHA In the retina and the brain DHA increase to the same levels whatsoever esterification form it was provided
In conditions of lipid malabsorption MAG enriched with EPA DHA enhance their delivery to circulatory system in humans In humans with cystic fibrosis a disease recognized as having fat malabsorption especially the long chain fatty acids such as DHA it was reported that providing a MAG-DHA supplementation for one month was efficient to increase levels of DHA in the erythrocytes This pilot study indicates that MAG-DHA supplementation corrects erythrocyte ARADHA imbalance and may exert anti-inflammatory properties However whether MAG-DHA is more efficient in participants without malabsorption problems remains to be established
Side effects associated to fish oil intake In a meta-analysis evaluating the safety and tolerability of prescribed omega-3 fatty acid supplements it was reported that only three minor side effects were associated to fish oil intake fishy taste fishy burp and nausea Although these sides effects seem limited to gastro-intestinal discomforts it can largely compromise short- and long-term adherence to fish oil intake One protective microorganism to gastroesophageal reflux is the presence of Helicobacter Pylori H Pylori Moreover it was recently suggested that omega-3 fatty acid supplementation inhibit H Pylori by inhibiting the synthesis of vitamin K that is required by this microorganism for its own survival A pre-digested form of omega-3 fatty acid such as a MAG form with added vitamin K might limit these gastro-intestinal discomforts and this is something the investigators want to investigate in this research project
What is Vitamin K2 Vitamins are essential for different physiological functions of the body Vitamin K is a fat-soluble vitamin Its discovery was mainly driven by its role on blood coagulation but other roles of this vitamin include regulation of calcium metabolism in tissues cell growth and proliferation There are three main forms for vitamin K K1 K2 and K3 Vitamin K2 is referred as menaquinone since it shares a naphthoquinone ring and a side chain with variable length Most of menaquinones are synthesized by bacteria Since omega-3 fatty acid intake seems to inhibit vitamin K2 synthesis by bacteria such as H Pylori the investigators decided to add vitamin K2 in the MAG-omega-3 formulation to evaluate whether this formulation could decrease side effects of fish oil supplement consumption
Rationale of this study Over the 20th century consumption of linoleic acid 182 n-6 increased from 279 to 721 of energy and this is largely due to our dependence on new food production methodologies including soybean oil This has created over decades a diet that is deficient in long chain omega-3 fatty acids Recently and because of the enthusiasm around consumption of fish oil there is increasing concerns about fish sustainability These critical issues leads us to have a sustainable source of omega-3 fatty acids that is the most bioavailable and to recommend lower doses of EPADHA to be consumed by the population to have similar health effects At the same time having a source of omega-3 fatty acid with limited side effects would also contribute to a better adherence of the population to their consumption and perhaps decrease capsule waste The plasma DHA pool is critical to bring DHA to the brain and other organs and it is dynamic constantly exchanging FA with organs and tissues Numerous studies have assessed the absorption bioavailability and accretion of DHA in the plasma with the conclusion that non-esterified DHA TG EE Recently there has been enthusiasm for MAG-Omega-3 formulations since it was shown to improve EPA and DHA bioavailability in humans with lower intestinal lipid absorption However whether EPA and DHA are better absorbed and bioavailable in humans without any issues with intestinal lipid absorption remain to be established Therefore this project will test a MAG-Omega-3 formulation enriched with vitamin K2 since the investigators hypothesized that this formulation will be the most absorbed and bioavailable with the lowest side effects in men and women without any disease such as intestinal lipid absorption issues
Aging of the Canadians and their nutrition Canadas population is expected to age more rapidly in the coming years Senior citizens have become more numerous than children in 2015 A major concern about old age both the individual and society is a decline in health especially if this means a loss of self-sufficiency and independence Increasing research for promoting healthy aging is ongoing but there are physiological modifications occurring during aging that might change bioavailability of LC-PUFA For instance intake of EPA and DHA concentrated in fish normally correlates positively with the concentrations of EPA and DHA in plasma However recent data from our laboratories suggest that EPA levels are approximately twice higher in plasma lipids of the elderly as compared to young individuals suggesting that potential alterations in EPA incorporation and utilization occur during aging DHA response to a DHA-rich supplement was significantly higher in the elderly as compared to the young While on DHA-rich supplement ARA was not decreased in the young and the elderly but similarly to EPA ARA remained significantly higher in the elderly compared to the young The investigators also have publish data suggesting that 40 years old is the age where the EPA and DHA levels in the plasma are higher than expected and this was independent to their dietary omega-3 fatty acid intake Hence these results are important indications that the metabolism of LC-PUFA is modified by age and this observation lead to the idea that their uptake and usage by organs and tissue can be compromised
13C-DHA in humans Tracing metabolism of carbon 13 13C-labelled fatty acids may provide some insight into possible aging-related changes in fatty acid metabolism in humans The investigators recently used 13C-DHA to trace its metabolism in six young and six elderly participants The investigators found that in the elderly 13C-DHA was 4 times higher in plasma triglycerides and free fatty acids at 4 h post-dose beta-oxidation was 19 times higher whereas apparent retro-conversion of 13C-DHA to other 13C-omega-3 fatty acids was 21 times higher 24 h and 7 d after tracer intake compared to the young Hence because DHA seems to remain transiently for longer periods of time in the blood of the elderly compared to the young it may thus indicate that efficiency to remove DHA from the blood is lower in the elderly than in the young resulting in lower incorporation of DHA in the membrane of cells that serve to initiate signalization This observation is potentially at the root of altered signalization in the elderly compared to the young
Bioavailability of EPA and DHA esterified in TG PL or as an ethyl ester EE Most of fish oil supplements on the market are EPA and DHA esterified in TG and to a lower level in EE and PL There has been a lot of study evaluating whether one form of esterification enhances bioavailability of EPA and DHA In pharmacology Bioavailability is defined as a subcategory of absorption and it is the portion of the administered dose of a drug or in this case EPADHA that reaches the systemic circulation By definition an intravenous drug is 100 bioavailable but when a drug is administered orally its bioavailability is usually decreased due to incomplete absorption or first-pass metabolism Hence in the review paper of Ghasemifard et al they reviewed 21 papers that evaluated whether omega-3 fatty acid were more bioavailable when given in the form of EE TG non-esterified form or as a PL Four studies were rejected because there were no control group eight studies were evaluating pharmacokinetics PK defined as a follow up between 8 h up to 72 h of a single oral dose of the omega-3 fatty acid product whereas nine studies evaluated the long term intake pharmacodynamic PD of a repeated daily dose of omega-3 fatty acids over a period of 2 weeks and up to 6 months Although the methodologies of the studies differ some conclusion about the PK was that bioavailability of EPA DHA was higher when given in the forms of non-esterified fatty acid TG EE Lower absorption of the EE form might be because pancreatic hydrolysis of EPA and DHA of the EE form compared to the TG form is 10-50 times lower Hence the esterification form of omega-3 fatty acids might change their short-term bioavailability and this information is particularly relevant in the context of metabolic diseases that can either affect fat absorption or to an aging population where there are dyslipidemias that might change omega-3 fatty acid bioavailability
Is MAG-Omega-3 form a better bioavailable source of EPADHA One study in rats reported bioavailability of DHA esterified in TG PL or MAG 2-mono-acylglycerol in plasma erythrocytes retina and brain tissue They reported that after giving DHA in the different forms to rats for 35 days DHA given in the MAG and PL form were 23-50 more concentrated in plasma total lipids and erythrocytes compared to TG-DHA In the retina and the brain DHA increase to the same levels whatsoever esterification form it was provided
In conditions of lipid malabsorption MAG enriched with EPA DHA enhance their delivery to circulatory system in humans In humans with cystic fibrosis a disease recognized as having fat malabsorption especially the long chain fatty acids such as DHA it was reported that providing a MAG-DHA supplementation for one month was efficient to increase levels of DHA in the erythrocytes This pilot study indicates that MAG-DHA supplementation corrects erythrocyte ARADHA imbalance and may exert anti-inflammatory properties However whether MAG-DHA is more efficient in participants without malabsorption problems remains to be established
Side effects associated to fish oil intake In a meta-analysis evaluating the safety and tolerability of prescribed omega-3 fatty acid supplements it was reported that only three minor side effects were associated to fish oil intake fishy taste fishy burp and nausea Although these sides effects seem limited to gastro-intestinal discomforts it can largely compromise short- and long-term adherence to fish oil intake One protective microorganism to gastroesophageal reflux is the presence of Helicobacter Pylori H Pylori Moreover it was recently suggested that omega-3 fatty acid supplementation inhibit H Pylori by inhibiting the synthesis of vitamin K that is required by this microorganism for its own survival A pre-digested form of omega-3 fatty acid such as a MAG form with added vitamin K might limit these gastro-intestinal discomforts and this is something the investigators want to investigate in this research project
What is Vitamin K2 Vitamins are essential for different physiological functions of the body Vitamin K is a fat-soluble vitamin Its discovery was mainly driven by its role on blood coagulation but other roles of this vitamin include regulation of calcium metabolism in tissues cell growth and proliferation There are three main forms for vitamin K K1 K2 and K3 Vitamin K2 is referred as menaquinone since it shares a naphthoquinone ring and a side chain with variable length Most of menaquinones are synthesized by bacteria Since omega-3 fatty acid intake seems to inhibit vitamin K2 synthesis by bacteria such as H Pylori the investigators decided to add vitamin K2 in the MAG-omega-3 formulation to evaluate whether this formulation could decrease side effects of fish oil supplement consumption
Rationale of this study Over the 20th century consumption of linoleic acid 182 n-6 increased from 279 to 721 of energy and this is largely due to our dependence on new food production methodologies including soybean oil This has created over decades a diet that is deficient in long chain omega-3 fatty acids Recently and because of the enthusiasm around consumption of fish oil there is increasing concerns about fish sustainability These critical issues leads us to have a sustainable source of omega-3 fatty acids that is the most bioavailable and to recommend lower doses of EPADHA to be consumed by the population to have similar health effects At the same time having a source of omega-3 fatty acid with limited side effects would also contribute to a better adherence of the population to their consumption and perhaps decrease capsule waste The plasma DHA pool is critical to bring DHA to the brain and other organs and it is dynamic constantly exchanging FA with organs and tissues Numerous studies have assessed the absorption bioavailability and accretion of DHA in the plasma with the conclusion that non-esterified DHA TG EE Recently there has been enthusiasm for MAG-Omega-3 formulations since it was shown to improve EPA and DHA bioavailability in humans with lower intestinal lipid absorption However whether EPA and DHA are better absorbed and bioavailable in humans without any issues with intestinal lipid absorption remain to be established Therefore this project will test a MAG-Omega-3 formulation enriched with vitamin K2 since the investigators hypothesized that this formulation will be the most absorbed and bioavailable with the lowest side effects in men and women without any disease such as intestinal lipid absorption issues
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None