Update on Enzymes and Probiotics in Canada

by Manushvi Chadha, BPharm, RA Cert
Regulatory Affairs Associate, dicentra

The past year had the NHPD re-evaluate their strategy for enzyme and probiotic-containing products, which had been on hold for years. With the exception of compendial applications, the assessment of all other submissions containing enzymes and probiotics were suspended by the directorate, though they continued to receive submission numbers.

However, in mid September, mass Information Request Notices (IRNs) and Section 16 Notices were received by industry. Essentially, the notices asked to either reformulate or revise the presentation of the product to match the new standards for enzymes and probiotics, or provide evidence for doing otherwise.

“New standards” included a revised monograph for Probiotics, revised abbreviated labelling standard (AbLS) for Live Microorganisms and new AbLSs for the following enzymes:

Alpha – Amylase
Bromelain, Fruit
Bromelain, Stem
Cellulase
Chymotrypsin
alpha-Galactosidase
Lipase
Pancreatic Enzymes
Papain
Protease, Fungal
Trypsin

After months of waiting for NHPD’s revised standards, these changes did catch the industry off guard because some of the changes that came about were unexpected.

Major issues that left the industry grappling were 1) the fact that the term ‘probiotic’ was applicable to only a few select strains, 2) claims for many products were cut down, and 3) that previously issued NPNs were called into question, essentially tainting the standard of all licenced products.

Industry felt that after considerable time and effort spent on educating consumers on the benefits of probiotics, they were now being barred from using this term on their products and instead must label and advertise as “Live Microorganisms”. The claims available for a majority of products previously identified as “Probiotics” (now “Live microorganisms”) were substantially cut down, while many enzyme AbLS’ do not list set uses, but require submission of evidence to get any type of claim. All products attesting to an AbLS now required submission of an FPS.

After considerable backlash from stakeholders, the NHPD substantially extended the due date for the responses to give companies some time to reformulate / comply. However, the deadline for these notices is almost up now, and all enzyme products will soon officially be off-hold.

For consumers though, this may be considered a good thing. Many deficient submissions and products will have been identified in this exercise, and weeded out, or updated to current standards, which means better products.

As the time frame for the expiry of UPLAR is fast approaching (February 2013), it appears that the NHPD is trying to clear their backlog as fast as they can. The enzymes represent a significant portion of the backlog, and these notices may have helped clear the NHPD’s files and also provided a standard for all future enzyme products.

dicentra provides regulatory and scientific solutions for accelerated business growth. We specialize in the areas of natural health products, dietary supplements, foods, beverages, cosmetics and OTCs. We can be reached at 1-866-647-3279 or at dicentra.com

Dicentra Newsletter Issue 2 for 2011

Welcome Spring and Summer 2011

After a long cold winter it’s with extreme excitement that we welcome the spring and the coming summer. Spring always brings with it a feeling of renewal and enthusiasm for new developments and progress forward. In light of this statement, there is an issue that needs to be brought up for discussion that, despite its consequences, receives little attention and is surely due for review and renewal.

As a regulatory consultant, Dicentra often assists its clients in meeting the regulatory requirements to ship Canadian made products to the United States and U.S. made products to Canada. I’m sure that those of you familiar with the processes involved would agree with me when I say that the paper work requirements are a nightmare, seemingly unnecessary and that they impede the ability for companies on both sides of the border to do business. In fact, it’s probably safe to say that the main impediment to greater trade and investment between Canada and the U.S. is not the presence of tariffs and quotas but rather the unnecessary differences in product regulations.

Nowhere is this more apparent than with the trade of dietary supplements between both countries. As an example, a Canadian made supplement with a gelatin capsule (or any product containing animal-derived components) bound for export to the U.S. market must be accompanied by special permits from the United States Department of Agriculture and also from the Canadian Food Inspection Agency. It’s understandable that these requirements are put in place to protect the safety of a U.S. consumer. No one wants to consume a gelatin capsule, for example, derived from BSE cattle. The issue is the time it takes to acquire some of these permits. It may take 3 to 4 months before both permits are obtained. The same goes for U.S. made dietary supplements. You may be looking at a 3 to 5 month bottleneck before the appropriate authorities at Health Canada finally review and approve a foreign manufacturer and issue the necessary licenses to export the product to Canada.

In light of these types of problems U.S. President Barack Obama and Canadian Prime Minister Stephen Harper met last February to announce a collaborative effort on reducing barriers to open trade and established the Regulatory Cooperation Council. As a follow up to this, the U.S. Department of Commerce announced in March that it was seeking public input to help identify regulatory divergences between Canada, the U.S. and Mexico in an effort to reduce or eliminate differences that hinder trade and reduce competitiveness. It was announced at the G8 meeting last week in France that following the review of these public consultations an ambitious action plan will be announced this summer. Let’s keep our fingers crossed that our industry’s frustrations were well heard and that changes are in store for us.

We would love to hear your comments and your experiences in dealing with these issues. You can visit our LinkedIn Group where this article is also posted and open for comments. And as always, don’t forget to sign up for our free regulatory update webinars. Our previous update had nearly 200 companies tune in and the next one is on June 22.

Science and Research Updates

Marchbank T, Davison G, Oakes JR, Ghatei MA, Patterson M, Moyer MP, Playford RJ. The nutriceutical bovine colostrum truncates the increase in gut permeability caused by heavy exercise in athletes. Am J Physiol Gastrointest Liver Physiol.2011 Mar;300(3):G477-84.

Prolonged strenuous exercise can affect the integrity of the intestinal barrier and may result in loss of function and inflammation of the intestine. Long distance runners have been reported to commonly experience gastrointestinal complaints such as cramps, diarrhea, nausea, and bleeding which is likely due to a combination of physiological factors, one of which is increased gut permeability. In this double-blind crossover trial, 12 healthy males were supplemented with 20 g of bovine colostrum daily for 14 days. Following a 14 day lead-in period, the subjects participated in exercise trials. The results of the study suggest that supplementation with 20 g bovine colostum daily was associated with truncated exercised-induced gut permeability when compared to placebo control.

Nova E, Viadel B, Wärnberg J, Carreres JE, Marcos A. Beneficial effects of a synbiotic supplement on self-perceived gastrointestinal well-being and immunoinflammatory status of healthy adults. J Med Food. 2011 Jan-Feb;14(1-2):79-85.

Synbiotic preparations containing a combination of probiotics and fermentable fibre are considered beneficial for the restoration and maintenance of colonic flora. The suggested health promoting effect of probiotics is the enhancement of mucosal immune defenses. The main objective of this study was to evaluate the effects of a synbiotic product containing five lactic acid bacterial strains and fructo-oligosaccharides on self-perceived gastrointestinal well-being and immunoinflammatory status of healthy adults. In a randomized, double-blind, placebo-controlled clinical trial, 42 healthy adults were given a supplement containing equal quantities ofLactobacillus acidophilus La5, Bifidobacterium animalis ssp. lactis B12, L. delbrueckii ssp. Bulgaricus, Streptococcus thermophilus, L. paracasei ssp. paracasei and fructo-oligosaccharides or a placebo supplement. The subjects were asked to subjectively evaluate any alleviation in previously reported gastrointestinal symptoms and report any improvement in bowel habits over the 6 week intervention period. Following supplementation, improvements in self-perceived bowel habits and gastrointestinal symptoms were observed more often in the symbiotic group when compared to placebo control.

Rahbar AR, Nabipour I. The hypolipidemic effect of Citrullus colocynthis on patients with hyperlipidemia. Pak J Biol Sci. 2010 Dec 15;13(24):1202-7.

Elevated levels of low density lipoprotein (LDL) and triglycerides and reduced high-density lipoprotein (HDL) levels are often associated with an increase in coronary heart disease. Various traditional herbal remedies have been suggested as beneficial for the treatment of elevated serum cholesterol and triglyceride levels. Citrullus colocynthis has been traditionally used as an anti-diabetic remedy in tropical and subtropical countries. While this herb has minimal effects on cholesterol and triglyceride levels in diabetic patients, this study aimed to evaluate the effects of C. colosynthis seed on the lipid profile in non-diabetic individuals. In this randomized, double-blind, placebo-controlled clinical trial, 100 non-diabetic patients with hyperlipidemia were given 300 mg C. colosynthis seed or placebo daily for 6 weeks. During the trial, serum triglyceride and cholesterol levels were measured following an overnight fast. The results of the study suggest that supplementation with C. colosynthis seed has a beneficial effect on fasting triglyceride and total cholesterol levels in hyperlipidemic patients when compared to placebo control.

Rowe CA, Nantz MP, Nieves C Jr, West RL, Percival SS. Regular consumption of concord grape juice benefits human immunity. J Med Food. 2011 Jan-Feb;14(1-2):69-78.

Immune cells, such as γδ T cells, predominate as major surveillance cells in the epithelial linings of the intestine, lung, and genitourinary tract where they recognize non-protein compounds. It has been suggested that these cells respond to pathogen-associated stimuli similar to those of innate immune cells. This study aimed to assess the effects of grapes as immunomodulators by investigating their role on γδ T-cell function. In a 9-week double-blind, randomized, placebo-controlled parallel intervention, 85 healthy men and women (ages 50-75years) were provided with 100% Concord grape juice or placebo and asked to consume 360 ml of the beverage daily. The overall results of this study suggest that Concord grape juice enhanced preservation of serum antioxidant activity and improved proliferation of γδ T cells when compared to placebo control.

Thank you for reading. We can be reached at 1-866-647-3279 or at dicentra.com

Your Dicentra Team

 

Nutra-ingredients – Regulatory Updates: Omega-3 Scientists oppose EFSA ALA Claim – May 19, 2011

 

http://www.nutraingredients.com/

May 16, 2011

Omega-3 scientists oppose EFSA ALA claim

An omega-3 researcher has written to the European Commission demanding a recent European Food Safety Authority (EFSA)-approved claim for omega-3 form ALA be revoked.

In his letter to the EC, Professor Jack Winkler from the UK Nutrition Policy Unit, challenges EFSA’s article 14 children’s development verdict that an ALA (Alpha-linolenic acid)-fortified infant food can benefit brain and nerve tissue development.

Professor Winkler, one of a group of about 20 omega-3 scientists that have long opposed ALA and EPA (eicosapentaenoic acid)/DHA (docosahexaenoic acid) being treated with parity in product labelling due to bioavailability differentials, said the claim should be blocked because infant requirements for ALA are relatively low.

http://www.nutraingredients.com/Regulation/Omega-3-scientists-oppose-EFSA-ALA-claim

May 6, 2011

To benefit industry, consumers must understand health claims

Ensuring EFSA-approved health claims are understood and trusted by consumers is just as important as providing the scientific evidence to back them up, according to Dr Fiona Lalor.

A recent study, led by Lalor and her colleagues at the University College Dublin, found that an informed food choice regarding nutrition content from ‘health claim’ labels is only one aspect when consumers choose foods, noting that taste, price and trust in brands have high levels of influence in consumers’ purchase behaviours.

Lalor told NutraIngredients that one of the major issues in consumer perceptions is trust, and who to trust: Do they trust a large multinational company whose claims will be known globally, or are they more likely to trust a smaller local manufacturer who has maybe conducted a couple of product tests?

http://www.nutraingredients.com/Regulation/To-benefit-industry-consumers-must-understand-health-claims

May 12, 2011

Beta glucan; Touchi win novel foods approval

A yeast beta glucan ingredient called Wellmune WGP and a fermented black bean extract have won novel foods approval for use in foods, drinks and food supplements from the European Food Safety Authority (EFSA).

EFSA’s Panel on Dietetic Products, Nutrition and Allergies (NDA) this week issued a positive scientific opinion for the yeast-derived immunity ingredient.

“We are pleased with the finding of EFSA’s review of our clinical and safety data supporting Wellmune WGP,” said Richard Mueller, chief executive officer of the ingredient’s manufacturer, Biothera.

http://www.nutraingredients.com/Regulation/Beta-glucan-Touchi-win-novel-foods-approval

May 3, 2011

Class actions mount up as Bayer gets slapped with complaint over probiotic claims

The surge class action complaints against health claims on food, beverage and dietary supplements shows no sign of calming, as Bayer is targeted in a new class action lawsuit in California against claims made on some of its probiotic products.

On April 22, a consumer filed a class action lawsuit in California against Bayer HealthCare LLC accusing the company of false and deceptive advertising regarding benefits of its Phillips Probiotics Colon Health supplementpurchased on April 7 for $15.99.

The complaint, which can be read here , states: “Bayer manufactures, markets and sells health products known as Phillips Probiotics Colon Health, Probiotics + Fiber and Probiotics Caps. Through an extensive and comprehensive nationwide marketing campaign, Bayer claims that the products help ‘support’ consumers’ health benefits that other products cannot.

http://www.nutraingredients-usa.com/Regulation/Class-actions-

mount-up-as-Bayer-gets-slapped-with-complaint-over-probiotic-claims/?c=Alyh9M%252BhDb48XONESbUxuw%253D%253D&utm

_source=Newsletter_Subject&utm_medium=email&utm_campaign=Newsletter%252BSubject

Dicentra Newsletter Issue 1 for 2011

 

This is Dicentra’s first newsletter for 2011. We will be releasing these newsletters every three months and the purpose of the newsletter is to keep our readers up to date on important issues related to our industry and to keep you informed on developments within Dicentra.

In addition to our newsletter we will also release Special Alerts on an ongoing basis outlining issues that we feel you should be immediately informed about. Feel free to forward this newsletter onto your colleagues and encourage them to sign up for our Newsletter and Special Alerts to ensure that they stay informed as well.

We would like to begin the year by welcoming Scott Sawler as the new Director General of the Natural Health Products

Directorate (NHPD). Mr. Sawler comes with a wealth of experience and a strong understanding of the industry’s needs and we are excited to see his enthusiasm for the industry’s development at work.

Last year was our first year in providing the industry with free regulatory updates delivered via webinar every quarter. The response was very exciting and our last update had over 100 companies from across Canada and the world sign in. We will continue to deliver these updates as a sign of our commitment to keep our industry educated and informed. Please see the dates announced for this year in the article below and make sure to sign up.

2011 is expected to bring new developments, and new challenges are bound to follow. We will remain at the forefront of these developments and will continue to be here to help with any particular challenges you may face. We will also be attending many more industry events this year. You can have a look at these to the column to the left. Feel free to contact us if you would like to arrange a meeting with one of us at any of these functions.

Wishing you great success for the year,

Peter Wojewnik and the Dicentra Team

 

The Natural Health Products Directorate is requesting information from product license holders and applicants in light of the proposed amendments to the Food & Drug Regulations regarding enhanced labelling for priority food allergens. The following foods or protein derived from one of the following foods are considered priority food allergens: almonds, Brazil nuts, cashews, hazelnuts, macadamia nuts, pecans, pine nuts, pistachios, walnuts, peanuts, sesame seeds, wheat, kamut, spelt or triticale, eggs, milk, soybeans, crustaceans, shellfish, and fish.

Currently those natural health products containing probiotics are the subject of Section 16 Notices because of the concern that the probiotic was derived or grown on a dairy or soy based medium.

As a product license holder and/or applicant who has received one of these Section 16 Notices you will need to confirm whether your product has come into contact with any priority allergens during the manufacturing process. If the product has not come into contact with any priority allergens during the manufacturing process, you must supply a certificate from the manufacturer confirming this. If the product has come into contact with a priority allergen during the manufacturing process you must commit to add the following statement under Cautions & Warnings, within the sooner of 6 months or the next label run: “This product has come into contact with [name of priority allergen]. Do not use this product if you have a [name of priority allergen] allergy.”

All suppliers are encouraged to review their labels to ensure that all priority allergens are clearly identified as medicinal or non medicinal ingredients and that claims that a product is “free of [a priority allergen]” are factual.

We can be reached at 1-866-647-3279 or at dicentra.com

In order to fulfill Dicentra’s mission to serve the natural health products industry as a source for education and trusted scientific and regulatory information, we offer free quarterly regulatory updates (every 3 months) through an online webinar.

These webinars are meant to keep you and all of your coworkers up-to-date on the latest issues pertaining to scientific and regulatory affairs. The main focus of each webinar will be for anything important pertaining to natural health products and their regulations in Canada. Examples include a summary of the Natural Health Products Directorate’s status of submissions reports, the latest regulatory status of ingredients, new published monographs, and all other important issues. We will also cover major issues related to other product categories that may have an effect on natural health products.

All webinars are presented by a qualified member of our team and will last approximately 30 minutes. Sit back and enjoy our interpretation and navigation to help propel your business forward at no cost.

The 2011 dates are March 23, June 22, September 21 and December 7. Click here to sign up.

Oral intake of purple passion fruit peel extract reduces pain and stiffness and improves physical function in adult patients with knee osteoarthritis. Nutr Res. 2010 Sep;30(9):601-6.

Osteoarthritis (OA) is considered a degenerative disorder involving cartilage degradation, accompanied by local inflammation that accelerates joint destruction and represents the most common joint disorder among adults. This randomized, parallel-group, double-blind, placebo-controlled trial aimed to assess the role of the Passion Fruit Peel (PFP) extract containing bioflavonoids with antioxidant and anti-inflammatory activity in alleviating symptoms of knee OA. Thirty-three OA patients were given 150 mg concentrated PFP extract or matched placebo daily for 60 days. The results of this study suggest that PFP may be an alternative treatment to help reduce the symptoms associated with OA.

Pigmented potato consumption alters oxidative stress and inflammatory damage in men.

J Nutr. 2011 Jan;141(1):108-11.

Purple Potato (PP) cultivars have been found to contain 186% more antioxidants than their White Potatoes (WP) counterparts. The purpose of this randomized, placebo-controlled study was to evaluate the effects of consumption of pigmented potatoes on oxidative stress and inflammation biomarkers in healthy adult males. Twelve healthy males were supplemented with 150 g of cooked yellow potato (YP), WP or PP daily for 6 weeks. Levels of oxidative stress and plasma Interleukin-6 (IL-6) levels were observed to be lower in the PP group following 6 weeks of potato supplementation suggesting that pigmented potatoes may be beneficial for use as an alternative anti-inflammatory.

Consumption of wheat aleurone-rich foods increases fasting plasma betaine and modestly decreases fasting homocysteine and LDL-cholesterol in adults.

J Nutr. 2010 Dec;140(12):2153-7.

Betaine is a component found at relatively high concentrations in wheat grain, particularly in the bran and aleurone fractions. This parallel, single-blinded, placebo-controlled intervention trial aimed to investigate the effects of cereal products enriched with wheat aleurone on plasma betaine and related biomarkers in apparently healthy, older, overweight men and women at risk for metabolic syndrome. Eight participants were provided with aleurone-enriched bread (in the form of rolls) and ready-to-eat cereal products, containing 9 g aleurone each. The participants were asked to consume 3 of the aleurone-containing products daily for 4 weeks. The results of this study suggest that aleurone may be a good source of betaine to help decrease plasma tHcy, a risk factor for cardiovascular disease.

Prebiotic evaluation of cocoa-derived flavanols in healthy humans by using a randomized, controlled, double-blind, crossover intervention study.

Am J Clin Nutr. 2011 Jan;93(1):62-72.

Effective probiotics have low digestibility and bioavailability, are selective for the growth and metabolism of commensal bacteria, and alter the microbiota to a healthy composition. The aim of this randomized, double-blind, controlled, crossover human clinical trial was to validate the prebiotic potential of flavanol-containing supplements for 4 weeks. Study participants were instructed to consume either a high-cocoa flavanol (HCF) or low-cocoa flavanol (LCF) beverage containing 494 mg and 29 mg cocoa flavanols, respectively. The results of this study suggest that supplementation with a high dose of cocoa flavanols may have significant effects on the growth of select gut microbiota in vivo.

Thank you for reading. We can be reached at 1-866-647-3279 or at dicentra.com

Your Dicentra Team

NHPD Continues to Issue Section 16 Notices

 

The Natural Health Products Directorate is requesting information from product license holders and applicants in light of the proposed amendments to the Food & Drug Regulations regarding enhanced labelling for priority food allergens. The following foods or protein derived from one of the following foods are considered priority food allergens: almonds, Brazil nuts, cashews, hazelnuts, macadamia nuts, pecans, pine nuts, pistachios, walnuts, peanuts, sesame seeds, wheat, kamut, spelt or triticale, eggs, milk, soybeans, crustaceans, shellfish, and fish.

Currently those natural health products containing probiotics are the subject of Section 16 Notices because of the concern that the probiotic was derived or grown on a dairy or soy based medium.

As a product license holder and/or applicant who has received one of these Section 16 Notices you will need to confirm whether your product has come into contact with any priority allergens during the manufacturing process. If the product has not come into contact with any priority allergens during the manufacturing process, you must supply a certificate from the manufacturer confirming this. If the product has come into contact with a priority allergen during the manufacturing process you must commit to add the following statement under Cautions & Warnings, within the sooner of 6 months or the next label run: “This product has come into contact with [name of priority allergen]. Do not use this product if you have a [name of priority allergen] allergy.”

All suppliers are encouraged to review their labels to ensure that all priority allergens are clearly identified as medicinal or non medicinal ingredients and that claims that a product is “free of [a priority allergen]” are factual.

Please contact us should you require assistance in responding to a Section 16 Notice.

Dicentra Newsletter – Issue #10

 

Executive Summary

UPLAR

  • Products in queue for over 180 days awaiting product licenses will now be issued ENs (exemption number) allowing the product to be legal for saleProducts must now have an EN, Natural Product Number (NPN) or homeopathic-Drug Identification Number (HM-DIN) to be legal for sale
  • A full assessment will be completed after the issue of the EN – safe and efficacious products of high quality will the receive NPNs following full assessment
  • Products which are classified as higher risk for safety will not be issued an EN
  • NHPD (Natural Health Product Directorate) performance targets will hopefully be met such that a product will get a license before an EN is issued – if the NHPD cannot meet their internal performance target and the product is in queue for 180 days, then an EN will be issued allowing the product to be sold legally, provided there are no significant safety concerns associated with the product
  • UPLAR will remain in effect for the next 30 months

New Application Management Policy

  • Total proposed time to license a product referencing pre-cleared information (PCI): 60 days following the submission of the application
  • Total proposed time to license a non-traditional, traditional, homeopathic or amendment requiring the assessment of safety, efficacy and/or quality (with 1 information request notice (IRN) issued): 210 calendar days following the submission of the PLA
  • All ingredients, medicinal and non-medicinal, must be present in the NHPD ingredients database prior to submission of a Product License Application (PLA)
  • In the future, the only accepted form of PLA will be the e-PLA, but all applicants are encouraged to begin using the e-PLA now
  • The new Compliance and Enforcement Policy will come into full effect in February 2011, and until then enforcement will be in the form of education on how to comply with the new policy

We will also be hosting a free webinar this Thursday, August 12, at 1:00 PM Eastern Time. The webinar should not last longer than 30 minutes. The webinar will cover everything important pertaining to the new regulations and will outline all necessary steps to obtain your ENs. We strongly encourage you to attend this session.To join the webinar please click on the following link several minutes prior to the starting time.

Topic: UPLAR Update Webinar
Date: Thursday, August 12, 2010
Time: 1:00 pm, Eastern Daylight Time (New York, GMT-04:00)

Meeting Number: 572 802 082

Meeting Password: Nhpd2010

To join the online meeting:
1. Go to https://dicentra.webex.com/dicentra/j.php?ED=153124192&UID=0&PW=NNzIxODBhZDIw&RT=NCMxMQ%3D%3D
2. If requested, enter your name and email address.
3. If a password is required, enter the meeting password: Nhpd2010

4. Click “Join”.

As of August 4, 2010, the new Unprocessed Product License Application Regulations (UPLAR) have passed and will be published in Canada Gazette Part II (http://www.gazette.gc.ca/rp-pr/p2/index-eng.html).

The regulations provide a temporary solution for:

natural health products that have submitted a complete product license application, been issued a submission number, and after 180 days are still awaiting a licensing decision,

new product license applications eligible for the exemption after 180 days if no licensing decision is made.
Upon receiving ENs, companies will be allowed to legally sell their products in Canada.

For products which have been in queue for 180 calendar days or more as of August 4, 2010:
These products are eligible for ENs, provided they do meet any of the risk criteria. In order to receive your ENs, you will need to fill out and submit an Exemption Number Fax-Back Form to the NHPD within 60 days of August 4, 2010. Applicants who do not return the fax back form within the 60 days will not receive ENs for these products.

For products which have been in queue for less than calendar 180 days as of August 4, 2010:
These products are not currently eligible for ENs. Once they have been in queue for 180 days, then they will be eligible to receive ENs. The beginning of the 180 day waiting period starts when the applicant receives a submission number for the application. The NHPD has provided a Fax-Back Form which will allow your product to automatically receive an EN once it reaches the 180 day mark. If the Fax-Back Form is not filed pre-emptively, the applicant will have 60 calendar days to return the completed fax back form to receive the EN once the product has been in queue for 180 days. If the completed fax back form is not returned to the NHPD by the 60 day deadline, then the NHPD will assume that the applicant does not want their product to be exempted.

For products which have been submitted, but have not received a submission number as of August 4, 2010:
Products which have not received a submission number as of yet will be eligible for pre-emptive opt-in and will receive a Fax-Back Form along with their application acknowledgement letter. The completion and return of the pre-emptive Fax-Back Form will allow the product to automatically receive an EN after 180 days in queue, provided that the product is eligible for an EN. Please note that submission numbers will now be used for administration purposes only as a method to track the application and determine when the 180 day count begins. The new application acceptance letter will replace the submission number and will include:

if the product is eligible for an exemption;

what the exemption number would be for that product;

the date on which the product would be eligible for an exemption;

what is needed to apply for an exemption; and

the fact that a complete Fax-Back Form must be submitted within 60 calendar days of the eligibility date
For all products, the EN becomes valid only when the EN number appears in the Natural Health Products Exempted Products Database (http://webprod3.hc-sc.gc.ca/product-produit/search-rechercheReq.do?lang=eng). Applicants are responsible for checking the database for the presence of their product and EN. Included in the database entry are the EN, Company Name, Brand Name, Dosage Form, Status (valid, not valid or licensed) and Status Date. The information should appear in the database 5 calendar days after submitting the Fax-Back Form.

The following types of products will not be eligible to receive an EN:

  • A sterile product for opthalamic use
  • A product which is recommended for use as a treatment, preventative or cure a disease, disorder or physical state which is set out in Schedule A of the Food and Drug Regulations
  • A product containing a substance present in sections C.01.036, C.01.036.1, C.01.040, C.01.040.1 or C.01.038 of the Food and Drug Regulations
  • A product which is recommended for children under the age of 12 – this includes products which are recommended for all ages
  • A product whose target population is pregnant or breastfeeding women
  • Products which have previously been withdrawn or refused
  • Products which have been subject to a stop sale or recall in the past, even if the stop sale/recall was lifted

 

Products in queue which have been deemed ineligible to receive ENs can be revised in order to obtain ENs. Changes made to the PLA and label may include the removal of a subpopulation or ingredient and revised PLA and label should be submitted to your Submission Coordinator. Then when the Fax-Back Form is filed with the NHPD, the revised product will receive its EN after 180 days in queue.

Once a product has received its EN, a notification may be filed outlining changes to the application which do not to impact the safety, efficacy and/or quality of the product, including:

  • The company information
  • The site information as required by section 22 of the Natural Health Products Regulations (NHPR)
  • The addition or substitution of a non-medicinal ingredient that does not affect the safety or efficacy of the product
  • The brand name of the product
  • The common or proper name of any of the medicinal ingredients
  • The addition of risk information

If any of the above changes are made to an exempt NHP, exemption number holders should consult NHPD’s Post-Licensing Guidance Document – http://www.hc-sc.gc.ca/dhp-mps/prodnatur/legislation/docs/plgd_psdldr_2-eng.php- for information on how to submit a notification to NHPD.

Please note that an EN may remain valid for up to 30 months from August 4, 2010, provided that a license is not granted prior to the 30 month end point. Furthermore, the EN must appear on the label within a reasonable amount of time, i.e. the lesser of the next label run or 12 months.

Under these regulations, products with ENs are subject to the NHPR, including key on-market safety oversight provisions. Some examples of these provisions include: adverse reaction reporting, good manufacturing practices, site licensing, the ability for the Minister to order a stop sale, and recall reporting requirements. Please note that site information must be provided to Health Canada before the sale of an NHP begins.

A new Compliance and Enforcement Policy for NHPs has come into effect along with the new UPLAR with a 6 month educational period. The full legislature comes into effect February 2011 meaning that at this point a product which is being sold without an EN, NPN or DIN-HM will be subject to enforcement procedures, such as a stop sale or recall. Prior to February 2011, products being sold without ENs, NPNs or DIN-HMs will not be subject to stop sales or product recalls, instead the government will provide education on how to come into compliance with the NHPR.

 

As of August 4, 2010, the new Unprocessed Product License Application Regulations (UPLAR) have passed and will be published in Canada Gazette Part II (http://www.gazette.gc.ca/rp-pr/p2/index-eng.html).

The regulations provide a temporary solution for:

natural health products that have submitted a complete product license application, been issued a submission number, and after 180 days are still awaiting a licensing decision,

new product license applications eligible for the exemption after 180 days if no licensing decision is made.
Upon receiving ENs, companies will be allowed to legally sell their products in Canada.

For products which have been in queue for 180 calendar days or more as of August 4, 2010:
These products are eligible for ENs, provided they do meet any of the risk criteria. In order to receive your ENs, you will need to fill out and submit an Exemption Number Fax-Back Form to the NHPD within 60 days of August 4, 2010. Applicants who do not return the fax back form within the 60 days will not receive ENs for these products.

For products which have been in queue for less than calendar 180 days as of August 4, 2010:
These products are not currently eligible for ENs. Once they have been in queue for 180 days, then they will be eligible to receive ENs. The beginning of the 180 day waiting period starts when the applicant receives a submission number for the application. The NHPD has provided a Fax-Back Form which will allow your product to automatically receive an EN once it reaches the 180 day mark. If the Fax-Back Form is not filed pre-emptively, the applicant will have 60 calendar days to return the completed fax back form to receive the EN once the product has been in queue for 180 days. If the completed fax back form is not returned to the NHPD by the 60 day deadline, then the NHPD will assume that the applicant does not want their product to be exempted.

For products which have been submitted, but have not received a submission number as of August 4, 2010:
Products which have not received a submission number as of yet will be eligible for pre-emptive opt-in and will receive a Fax-Back Form along with their application acknowledgement letter. The completion and return of the pre-emptive Fax-Back Form will allow the product to automatically receive an EN after 180 days in queue, provided that the product is eligible for an EN. Please note that submission numbers will now be used for administration purposes only as a method to track the application and determine when the 180 day count begins. The new application acceptance letter will replace the submission number and will include:

if the product is eligible for an exemption;

what the exemption number would be for that product;

the date on which the product would be eligible for an exemption;

what is needed to apply for an exemption; and

the fact that a complete Fax-Back Form must be submitted within 60 calendar days of the eligibility date
For all products, the EN becomes valid only when the EN number appears in the Natural Health Products Exempted Products Database (http://webprod3.hc-sc.gc.ca/product-produit/search-rechercheReq.do?lang=eng). Applicants are responsible for checking the database for the presence of their product and EN. Included in the database entry are the EN, Company Name, Brand Name, Dosage Form, Status (valid, not valid or licensed) and Status Date. The information should appear in the database 5 calendar days after submitting the Fax-Back Form.

The following types of products will not be eligible to receive an EN:

  • A sterile product for opthalamic use
  • A product which is recommended for use as a treatment, preventative or cure a disease, disorder or physical state which is set out in Schedule A of the Food and Drug Regulations
  • A product containing a substance present in sections C.01.036, C.01.036.1, C.01.040, C.01.040.1 or C.01.038 of the Food and Drug Regulations
  • A product which is recommended for children under the age of 12 – this includes products which are recommended for all ages
  • A product whose target population is pregnant or breastfeeding women
  • Products which have previously been withdrawn or refused
  • Products which have been subject to a stop sale or recall in the past, even if the stop sale/recall was lifted

 

Products in queue which have been deemed ineligible to receive ENs can be revised in order to obtain ENs. Changes made to the PLA and label may include the removal of a subpopulation or ingredient and revised PLA and label should be submitted to your Submission Coordinator. Then when the Fax-Back Form is filed with the NHPD, the revised product will receive its EN after 180 days in queue.

Once a product has received its EN, a notification may be filed outlining changes to the application which do not to impact the safety, efficacy and/or quality of the product, including:

  • The company information
  • The site information as required by section 22 of the Natural Health Products Regulations (NHPR)
  • The addition or substitution of a non-medicinal ingredient that does not affect the safety or efficacy of the product
  • The brand name of the product
  • The common or proper name of any of the medicinal ingredients
  • The addition of risk information

If any of the above changes are made to an exempt NHP, exemption number holders should consult NHPD’s Post-Licensing Guidance Document – http://www.hc-sc.gc.ca/dhp-mps/prodnatur/legislation/docs/plgd_psdldr_2-eng.php- for information on how to submit a notification to NHPD.

Please note that an EN may remain valid for up to 30 months from August 4, 2010, provided that a license is not granted prior to the 30 month end point. Furthermore, the EN must appear on the label within a reasonable amount of time, i.e. the lesser of the next label run or 12 months.

Under these regulations, products with ENs are subject to the NHPR, including key on-market safety oversight provisions. Some examples of these provisions include: adverse reaction reporting, good manufacturing practices, site licensing, the ability for the Minister to order a stop sale, and recall reporting requirements. Please note that site information must be provided to Health Canada before the sale of an NHP begins.

A new Compliance and Enforcement Policy for NHPs has come into effect along with the new UPLAR with a 6 month educational period. The full legislature comes into effect February 2011 meaning that at this point a product which is being sold without an EN, NPN or DIN-HM will be subject to enforcement procedures, such as a stop sale or recall. Prior to February 2011, products being sold without ENs, NPNs or DIN-HMs will not be subject to stop sales or product recalls, instead the government will provide education on how to come into compliance with the NHPR.

 

What Health Canada’s Post-Market Surveillance Program Means to You as a Market Authorization Holder (MAH)

Canada Vigilance is Health Canada’s post-market surveillance program operated by the Marketed Health Products Directorate (MHPD). Canada Vigilance collects and assesses adverse reaction (ARs) to marketed health products including natural health products (NHPs). The collection of ARs and the monitoring thereof remain a viable means of identifying previously unrecognized, rare or serious ARs. This may result in changing product safety information, facilitating decisions on regulatory actions such as withdrawal of a product from the Canadian market, contributing to international data regarding risks and effectiveness of health products, and imparting health product safety knowledge that benefits all Canadians.

There are many stakeholders involved in the reporting of ARs, including the manufacturers of health products, known as Market Authorization Holders (MAHs). MAHs are required to submit serious adverse reaction reports to the Canada Vigilance Program when they become aware of a serious adverse reaction to a product as outlined in the Canada Food and Drugs Act and the Natural Health Products Regulations. The MAH must also, on an annual basis, prepare and maintain a Summary Report that contains a concise and critical analysis of all domestic ARs to an NHP, and all foreign serious unexpected ARs to an NHP taken at the recommended dose reported during the previous 12 months.

The Summary Report is maintained by the MAH, and when requested by Health Canada, must be submitted to the MHPD within 30 calendar days. In addition to complying with regulatory requirements to report safety and efficacy information, Health Canada expects that MAHs inform MHPD if the MAH concludes from the annual Summary Report that there is a significant change in the risk-benefit profile of a product relating to its safe use.

For more information, please read the “Frequently Asked Questions” that follow, and if you are unclear on your responsibilities or would like to enlist our expert aide, please contact us! dicentra will be hosting a brand new webinar on Adverse Reaction Reporting this coming fall, details will be on our website soon!

How does Health Canada (HC) collect post-market surveillance data?

HC collects post-market surveillance data through Canada Vigilance, a program of MedEffect™ Canada. HC’s post-market surveillance program collects and assesses AR reports for the following marketed health products:
· pharmaceuticals,
· biologics,
· natural health products, and
· radiopharmaceuticals.

Central to the Canada Vigilance Program is its AR database. The Canada Vigilance database consists of a core application for collecting, coding, assessing and reporting both domestic and foreign AR data. It is a signal-detection and data-mining tool, and one of its modules automatically routes AR cases to specialists and assessors. The database is fully compliant with the International Conference on Harmonisation’s (ICH’s) technical requirements and is bilingual.

What post-market data must be reported to Health Canada regarding NHPs?

-Serious adverse reactions inside Canada: mandatory case report within 15 days
-Serious unexpected adverse reactions outside Canada: mandatory case report within 15 days

-All adverse reactions: recorded and critically analyzed in a Summary Report, prepared annually

Note: It is not mandatory to submit the Summary Report to HC – however, if requested by HC, the report is required to be submitted within 30 business days

For natural health products, MAHs must submit domestic and foreign AR reports to the MHPD as set out in Section 24 of the Natural Health Products Regulations once their health product is licensed to be marketed in Canada.

When Health Canada requests the annual summary report, it is preferred that it be submitted in the Periodic Safety Update Report (PSUR) format in accordance with the standards defined in the ICH E2C(R1)10 guideline.

MAHs may also use an annual summary report format. This annual summary report format does not contain information regarding the worldwide market authorization status and completed and planned studies, both of which are included in the PSUR format.

Must the Annual report describe ARs by product or by ingredient?

Guidance documents are administrative instruments not having force of law and, as such, allow for flexibility in approach. Alternate approaches to the principles and practices described in this document may be acceptable provided they are supported by adequate justification. Alternate approaches should be discussed in advance with the relevant program area to avoid the possible
finding that applicable statutory or regulatory requirements have not been met.

For natural health products, it is important to include the Latin binomial, author reference, family, type of extract (e.g., aqueous versus alcoholic, including percent of solvent), part of the plant used (in the case of an herbal product), ingredients and quantity of each (for combination products – the suspected ingredient), and potency (for homeopathic products).

Depending on the health product or circumstances, it may be useful or practical to have more than one line listing, such as for different dosage forms or indications, if such differentiation facilitates presentation and interpretation of the data.
What are the responsibilities of the Market Authorization Holders (companies authorized to market health products) for monitoring the safety and therapeutic effectiveness of their products (which extends to post-market as well)?
They must advise stakeholders, including consumers, health professionals and regulators, of changes in the benefit/risk balance of their products. They must have continued monitoring of ARs in the post-market phase – or adverse incidents in the case of medical devices. Continued monitoring is essential for maintaining a comprehensive safety and effectiveness profile of health products available to Canadians. Mandatory reporting by Market Authorization Holders provides both domestic and foreign AR information to Health Canada.

How does Health Canada monitor regulated product safety internationally?

Health Canada monitors regulated product safety through an International Collaboration. MHPD staff collaborates with leading foreign regulatory partners through Memoranda of Understanding (MOUs), especially regarding the effective sharing of confidential and personal information on regulated product safety. A regular video/teleconference with federal regulatory partners in the United States, New Zealand and Australia enables the sharing of ongoing federal regulatory post-market surveillance / vigilance issues. Where possible, MHPD and its MOU partners collaborate on risk communications requiring simultaneous action to reduce public confusion.

Date MOU Signed

Country/Region

Name of the Organization

December 2007 European Union European Commission’s Directorate-General Enterprise and Industry & European Agency for the Evaluation of Medicinal Products
October 2006 Switzerland Swissmedic
September 2006 Singapore Health Science Authority
November 2003 Australia Therapeutic Goods Administration
November 2003 United States Food and Drug Administration
September 1999 China State Food and Drug Administration of China

 

How frequently does Health Canada provide safety updates to health professionals?
The Canadian Adverse Reaction Newsletter (CARN), a quarterly publication since 1991, alerts health professionals to potential signals detected through the review of case reports submitted to Health Canada. CARN provides subscribers with early information on suspected ARs to health products before comprehensive risk/benefit evaluations and regulatory decisions are undertaken. CARN is available on the MedEffect™ Canada Web site by subscribing to the MedEffect™ e-Notice.

How frequently is the Canada Vigilance Online Database updated?

On a quarterly basis, the MedEffect™ Canada Web site is updated with the latest adverse reaction reports, so that the public has access to ARs that have been reported to Health Canada. The information on the MedEffect™ Canada Web site is a subset of the actual data contained within the Canada Vigilance AR database.

Is there a worldwide governing body that collects worldwide ARs?

MHPD continues the work of those who were among the founding members of the WHO International Drug Monitoring program in 1968. Canada is one of 180 member countries and is ranked fourth in the rate of submission of domestic AR reports to the WHO vigilance database, which is located at the Uppsala Monitoring Centre in Sweden.

MHPD is engaged in developing better collaboration and work-sharing opportunities with other regulators internationally. This approach is consistent with that of the HPFB of Health Canada.
To date, MHPD has been an observer in the ICH of Technical Requirements for Registration of Pharmaceuticals for Human Use and applied their post-market surveillance standards in the development of the Canada Vigilance database; has participated in the Council for International Organizations of Medical Science VIII working group report on signal detection development and in the International Society on Pharmacogivilance; has held regular four-way video-conference meetings with the U.S.
Food and Drug Administration (FDA), Australian Therapeutic Goods Administration (TGA)

How is the AR information processed?

AR reports are analyzed to discover potential health product safety signals. A signal is considered to be the preliminary indication of a product-related issue. The identification of a signal is not by itself the proof of the association of an AR to a health product, but it triggers the need to further investigate a potential association. Signals must be carefully evaluated in order to confirm or to disprove the potential association between the product and the AR.

Need more info? More information on natural health products, the new NHP Regulations, and guidance on interpreting and using this information can be found on Health Canada’s website at http://www.hc-sc.gc.ca/index-eng.php.

In order to fulfill dicentra’s mission to serve the natural health products industry as a source for education and trusted scientific and regulatory information, we now offer free quarterly regulatory updates (every 3 months) through an online webinar.

These webinars are meant to keep you and all of your fellow coworkers up-to-date on the latest issues pertaining to scientific and regulatory affairs. The main focus of each webinar will be for anything important pertaining to natural health products and their regulations in Canada. Examples include a summary of the Natural Health Products Directorate’s status of submissions reports, the latest regulatory status of ingredients, new published monographs, and all other important issues. We will also cover major issues related to other product categories that may have an effect on natural health products.

All webinars are presented by a qualified member of our team and will last approximately 30 minutes. Sit back and enjoy our interpretation and navigation to help propel your business forward at no cost. Remaining dates for 2010 are as follows:

Wednesday, September 29, 2010, 1:00 PM Eastern Time
Wednesday, December 8, 2010, 1:00 PM Eastern Time

Visit www.dicentra.ca/updates to register now!

Our most recent webinar in this series occured on June 23rd, 2010. To view the video of this presentation please visit our website at http://www.dicentra.ca/NHP_Regulatory_Update_Q2_2010.html.

Kadooka Y, Sato M, Imaizumi K, Ogawa A, Ikuyama K, Akai Y, Okano M, Kagoshima M, Tsuchida T. Regulation of abdominal adiposity by probiotics (Lactobacillus gasseri SBT2055) in adults with obese tendencies in a randomized controlled trial. Eur J Clin Nutr. 2010 Jun;64(6):636-43.

Probiotics are live microorganisms that when administered in adequate amounts confer a health benefit to the host. Recently, probiotics have been administered in fermented milk products. Lactobacillus gasseri SBT2005 (LG2055) is a probiotic that originates from human intestine and has been selected for its ability to improve the intestinal environment. The organism demonstrates bile tolerance, bile acid conjugation as well as cholesterol binding to produce a cholesterol lowering effect in humans suffering from mild hypercholesterolemia. A multicentred, randomized placebo-controlled study was conducted to assess the anti-obesity effects of LG2055 in healthy adults. Clinical outcome measures include abdominal fat area, body weight and serum adiponectin, a hormone involved in fatty acid catabolism. Following a 4 week lead-in period, fermented milk containing 5 x 1010 cfu/100g of LG2055 was administered to participants twice daily for 12 weeks. When compared to the control group, significant decreases in the treatment group were observed at weeks 8 and 12 for body weight, BMI, hip, waist-to-hip ratio and fat mass. At week 12, probiotic administration was associated with a significant decrease in visceral, subcutaneous and total fat area when compared to baseline levels. Moreover, significant decreases in body weight, BMI, waist circumference were observed at weeks 8 and 12 when compared to baseline levels. Probiotic supplementation was also associated with no changes in adiponectin levels, whereas the control group experienced increases in adiponectin levels. Overall, this study suggests that probiotic LG2055 is beneficial effect on abdominal adiposity and body weight measures.

Schütz K, Saß M, de With A, Graubaum HJ, Grünwald J. Immune-modulating efficacy of a polyphenol-rich beverage on symptoms associated with the common cold: a double-blind, randomised, placebo-controlled, multi-centric clinical study. Br J Nutr. 2010 May 21:1-9.

The common cold is the most frequent infectious disease in humans. The majority of adults are affected by the disease 2-3 times per year. Symptoms often start with headache, sneezing, chills, sore throat and then progress to nasal discharge, nasal obstruction, cough and a general feeling of sickness. The health promoting potentials of polyphenols and polysaccharides are mainly attributed to the immunostimulative, antiviral, anti-inflammatory and antioxidative activity. A randomized, double-blind, multicentred clinical trial was conducted to evaluate a polyphenol-rich beverage containing green tea, grape seed, grape skin, and shiitake mushroom extract on the reduction of cold symptoms. Ninety-eight volunteers suffering from the common cold were recruited for the study. Inclusion criteria were that the subject must achieve a score of 5 for their severity of cold symptoms including headache, joint pains, sore throat/difficulty swallowing, hoarseness/cough, nasal congestion in addition to 1 cold-related throat condition. The primary efficacy endpoint was defined as a decrease in the total 5 point score. The secondary efficacy measure was the subject becoming “complaint-free” by the end of the study period. No significant adverse reactions were observed during the study. When compared to the placebo-controlled group, significant differences in the severity of cold symptoms were observed following 3-4 days of treatment. At the final examination, 19 out of 49 subjects in the treatment group claimed to be complaint free, whereas only 4 out of 47 in the placebo-controlled group reported to be symptom-free. No significant differences were observed in the use of additional cold therapy between the two test groups. Overall, the subjects receiving the investigational beverage experienced a faster decline in cold-associated symptoms when compared to the placebo-controlled group.

Skarupski KA, Tangney C, Li H, Ouyang B, Evans DA, Morris MC. Longitudinal association of vitamin B-6, folate, and vitamin B-12 with depressive symptoms among older adults over time. Am J Clin Nutr. 2010 Jun 2. [Epub ahead of print].

Depression is the most prevalent mental disorder affecting the US population and is also a key risk factor for numerous other health outcomes. Biochemically, vitamin B6, folate and vitamin B12 are implicated in the metabolism of homocysteine. It is hypothesized that vitamin B6, vitamin B12 and folate deficiencies may lead to elevated homocysteine levels, which is thought to be associated with depression. Skarupski et al. conducted this longitudinal study to investigate the daily consumption of vitamin B12, vitamin B6 and folate in 3503 participants over an average time course of 7.2 years. Depressive symptoms were evaluated based on the 10 item analysis of the Centre for Apidemiologic Studies Depression scale (CES-D) and cognitive function was assessed based on 4 tests: the Symbol Digital Modalities Test and the Mini-Mental State Examination and two separate tests for memory. Higher intakes of the vitamins were associated with higher cognitive processes, particularly in participants with higher levels of education and income. Vitamins B6 and B12 were inversely correlated with depressive symptoms. However, no correlation between folate intake and severity of depressive symptoms was observed. Overall, the results of the study suggest that higher intakes of both vitamin B6 and vitamin B12 may help to prevent the development of depression over an average time period of 7.2 years.

 

Terushkin V, Bender A, Psaty EL, Engelsen O, Wang SQ, Halpern AC. Estimated equivalency of vitamin D production from natural sun exposure versus oral vitamin D supplementation across seasons at two US latitudes. J Am Acad Dermatol. 2010 Jun;62(6):929.e1-9.
It has been proposed that vitamin D deficiencies may be associated with musculoskeletal disease. Recommendations to achieve adequate serum vitamin D levels include daily supplementation with 1000 IU vitamin D, or exposure of the face, arms and hands to sunlight for adequate lengths of time. This study aimed to assess the length of time a person might need to spend in the sun with 25.5% of their skin exposed to achieve a blood serum levels equivalent to those achieved following oral administration of either 400 IU or 1000 IU of vitamin D. The researchers chose to assess theoretical sunlight parameters in 2 locations: Boston, MA and Miami, FL using a computerized simulation tool. The results of the analysis suggest that in the summer, the amount of sunlight needed to generate the set levels of vitamin D were equivalent between the two cities. However, in the winter, the analysis suggests that there is an insufficient amount of UVB to produce levels upwards of 400 IU in Boston, MA. Which is substantially low compared the 15 min of sun exposure needed in Miami, Fl to generate blood vitamin D levels equivalent to oral administration of 1000 IU. The researchers do address that limitations are associated with results generated by theoretical simulation experiments. However, they conclude that oral supplements of vitamin D are most likely the safest route to achieving adequate vitamin D levels since prolonged sun exposure is associated with various health risks.

Kapil V, Milsom AB, Okorie M, Maleki-Toyserkani S, Akram F, Rehman F, Arghandawi S, Pearl V, Benjamin N, Loukogeorgakis S, Macallister R, Hobbs AJ, Webb AJ, Ahluwalia A. Inorganic Nitrate Supplementation Lowers Blood Pressure in Humans. Role for Nitrite-Derived NO. Hypertension. 2010 Jun 30. [Epub ahead ofprint].

Hypertension is associated with cardiovascular disease which is the leading cause of deaths in North America. Clinical evidence suggests the use of nitrates may be used to control high blood pressure. Furthermore, clinical evidence has suggested that beetroot, a vegetable containing high levels of nitrate, has been implicated in promoting healthy blood pressure levels. This study aimed to assess the effects of inorganic nitrate, from both beetroot juice and potassium nitrate, on blood nitrate/nitrite levels, blood pressure (BP) and endothelial function following ischemia/reperfusion injury. The dose of potassium nitrate administered was equivalent to the nitrite present in 250 ml of beetroot juice (24 mmol nitrate). Three separate studies were conducted to test the effects of each of the test substances against a control. Two randomized open-labelled crossover studies were conducted to assess the effects of either beetroot juice or potassium nitrate (a nitrate-positive control). As a nitrate-negative control, a double-blind crossover study was conducted to assess the effects of potassium chloride in comparison to beetroot juice and potassium nitrate. The results of the trials indicated that a dose-dependent increase in circulating nitrate and nitrite levels were associated with both potassium nitrate and beetroot juice administration. Cyclic GMP (cGMP), the ultimate indicator of NO bioactivity and vasodilation, was increased in both the potassium nitrate- and beetroot juice- supplemented groups. Ischaemia/reperfusion-induced endothelial dysfunction was prevented in both the potassium nitrate and beetroot juice groups when compared to control. However, beetroot juice administration was associated with no changes in diastolic BP and heart rate when compared to placebo-control. No significant changes in any of the measured parameters were observed for potassium chloride when compared to low nitrate-containing water. Overall, this study suggests that beetroot juice was as effective as potassium nitrate in preventing ischaemia/reperfusion-induced endothelial dysfunction and increasing the levels of circulating nitrate/nitrite and cellular levels of cGMP.

Thank you for reading, if you have any comments or questions, we can be reached at 1-866-647-3279 or at dicentra.com

Sincerely,