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High Nutrition Business API

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Semantic technology company Edamam launched today two new APIs, providing data-driven, cloud-based nutrition solutions for businesses in the food, health and wellness sectors.

The Nutrition Analysis and Recipe Search APIs are business ready. They provide “real-time analysis of any recipe or ingredient list with detailed information for over 30 nutrients and nutrition claims for more than 20 major diets, such as vegan, paleo and gluten-free.”

Drawing from over 500 of the top food sites in the English web, Edamam’s Recipe Search API builds on their semantically organized database of 1.5 million nutritionally tagged and analyzed recipes and provides results for high quality recipes that fit a particular diet need or calorie requirement.

Among the current users of Edamam’s API solutions are Epicurious, Random House and Gannett.

“The Nutrition Analysis and Recipe Search APIs will open our unmatched, ground-breaking technology to a wide range of businesses at very affordable prices,” added Victor Penev, Edamam’s Founder and CEO.

Read more: http://www.digitaljournal.com/pr/2465731#ixzz3RTR67fBI

Pick Me Up

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Pick Me Up

NOW® B12 Instant Energy is back and features natural ingredients including 2000 mcg of multisource B12 and energizing co-factors that promote lasting energy. Convenient single–serve packets help meet the physical demands of busy, health-conscious consumers. Free of refined sugar, caffeine or other stimulants, and the “jolt-and-crash” effect seen with many energy products.

This is the ideal mix of energy and mood supporting nutrients.to help you stay well fuelled. Perfect for busy professionals, parents, students, physically active folks, athletes, vegetarians or anyone in need of an instant boost. Or take one package daily as a dietary supplement.

NOW B-12 Instant Energy combines three forms of B-12 for maximum utilization by the body. This perfectly balanced formula takes the guesswork out of staying well fueled by providing a mix of the most beneficial compounds in one easy-to-use formula. With additional nutrients such as Chromium, Creatine and six other B-Vitamins, NOW B-12 Instant Energy can give you the spark you need, no matter where life takes you.

Ethical Nutrition Explained

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Ethical Nutrition Explained

In the preamble to their newly released “Report on Ethical Nutrition,” BCC Research defines “Ethical Nutrition” as “the practice of providing the proper nutrients to a wide range of individuals, including infants, children, adults, and individuals with illnesses and injuries.”

They go on to say: The global ethical nutrition market is divided into three very distinct categories:

  • infant formula market
  • enteral formula market
  • parenteral formula market

Aha! Since the term “ethical nutrition” is neither a widely known nor often used bit of health category jargon, you may well wonder where the term comes from and what it actually means. The inclusion of parenteral formulas – which can encompass both intravenous and force feeding brings the “ethical” aspect into the equation because it raises the whole question of how long you keep (or when you stop) feeding unresponsive patients – especially in cases of terminal illness. How that applies to infants and regular adult formulas is anybody’s guess, but it is enough to know that in this particular study, “Ethical Nutrition” refers to the full range of infant and adult clinical nutrition supplements.

As a retailer, it’s good to know that the field is expected to boom. BCC Research says, “In 2014, the market reached $37.1 billion at manufacturers’ sales levels. The developing number of elderly and critically ill, along with a shift toward home care and increasing inroads into developing countries has continued to fuel growth. By 2019, it is anticipated that revenues will likely reach $58.2 billion, expanding at a compound annual growth rate (CAGR) of 9.4%. The infant formula segment will account for approximately 54.5% of total revenues by 2019.

Says BCC Research analyst Mary Anne Crandall. “The impact of managed care and demand for cost-effective healthcare dramatically has changed the structure of this market and has altered significantly the strategies that companies use to survive and succeed.”

A 2005 article in Practical Gastroenterology said there were well over 100 enteral formulas available at that time and the market has blossomed and grown dramatically since then. Specialized formulas are designed for a variety of clinical conditions or disease states. There are over thirty-five specialized formulas currently on the market. But having said that, there is only a handful of major manufacturers, led by Abbott Nutrition’s Ross Product Division (makers of Similac, Ensure and Glucerna), Nestlé Health Science (makers of Nutren Junior Infant Formula, Boost High Calorie Supplements and Vivonex) along with Mead Johnson and Norvartis.

Wake Me Up

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Wake Me Up

Since opening its original location in 2002 on Dupont Street in Toronto, Live Organic Food Bar has continued growing and innovating ever since.

In the past few years it’s been enjoying an out-and-out growth spurt that began when they started wholesaling their plant-based, organic, gluten and refined sugar-free products under the brand name Live Organic Raw. Those products are now available at over 50 locations in southern Ontario and one in Nova Scotia. In 2012, they began marketing the products directly to consumers from their online store. In 2013, they opened their Liberty Village location.

And this week, they’ve announced the launch of two new products: Live Organic Raw Matcha Glow and Coffee Glow Cashew Mylks in 12 ounce bottles: Matcha green tea with chlorophyll, hemp seeds, cashews and dates is great to wake up to, have breakfast with or sip throughout the day and Coffee Glow cold brewed coffee with hemp seeds, cashews, and dates – less acidic and easier on sensitive stomachs – a great pick me up during the day or skip the morning coffee lineups.

Supplement Line Revitalized

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Vitality shows net loss

One of the longest lived and most respected natural health products lines in Canada is being revitalized by the children of the company’s long time owner. Bill Grant bought Vitality in 1979 and grew the line of supplements to 92 licenced products before he died in 2011.

But rather than going toe to toe with the industry giants like their dad did in the 1980s, Doug and Cheryl Grant are setting out with a more strategic approach.

They narrowed their focus to just four products: Digest +, Relax +, B Complete +C and Super Multi + and targeted small independent retailers rather than the big chains. Unlike the sun, they’re rising in the west – and now have Vitality products back into more than 140 stores. On the strength of a respected brand name, some first rate products, some business savvy and a bit of recent media attention, they are well on their way to a full out resurgence.

Products to Fill your Heart and Spark Your Memory

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Products to Fill your Heart and Spark Your Memory

Ascenta, makers of NutraSea and NutraVege – two of Canada’s favourite Omega 3 supplements, is preparing for their biggest product launch of the year. After making its American debut last October at the Ultimate Women’s Expos in Phoenix and Los Angeles, Ascenta Spark has made it through Canada’s more stringent regulatory process and will be celebrating it’s Canadian launch this April at CHFE West in Vancouver!

Ascenta Marketing Director Geoff Wills told IhR, “there’s really nothing else like Ascenta Spark on the market right now. This is a complete brain health formula. One teaspoon a day will help ensure that you have the healthy brain to live that vital life you want your retirement to be. We know there are a lot of consumers coming into stores now asking what products they should take as they age – so we’re pretty excited about it.”

 

 

Chemotherapy and Radiation- Induced Oral Mucositis: Integrative management

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Abstract

Oral mucositis is characterized by erythema, inflammation, and ulcerations of the mucous membranes in the oral cavity. This common side effect from radiation and chemotherapy can have significant impacts on quality of life, including alterations in immunity, malnutrition, and weight loss. At present, treatment options for this condition are limited. This review highlights the current state of evidence regarding oral mucositis and treatments that may help prevent or reduce its occurrence.

 

Introduction

Mucositis is a common complication among patients receiving chemotherapy or radiation therapy, occuring in approximately 40% of this population (Raeessi 2014 A). It can be especially problematic during treatment of head and neck malignancies, as well as during treatment with concurrent chemotherapies, which include alkylating agents such as cyclophosphamide and various platinums, anti-tumour antibiotics such as bleomycin, adriamycin (doxorubicin) and epirubicin, and antimetabolites such as 5-fluorouracil (5-FU).

Uncontrolled mucositis can profoundly impact quality of life and treatment effectiveness for patients with cancer, as it may lead to dose limitations for cancer therapy. It can cause immense pain, increases the risk of infection and dysphagia, cause difficulty with food and fluid ingestion, affect nutrition and hydration status and lead to weight loss (Keefe 2007, Stubbe 2013, Worthington 2011).

 

Treatments

In addition to good oral hygiene, avoidance of spicy, acidic, hard, and hot foods and beverages, the use of mild-flavoured toothpastes, and repeated mouthwashes with suggested rinses from the patient’s local cancer clinic, the following have been shown to be effective in reducing oral mucositis induced by conventional cancer treatment.

 

CHAMOMILE

In a recent randomized phase II clinical trial, 40 patients undergoing hematopoietic stem cell transplantation (HSCT) received routine care plus a mouthwash containing a liquid extract of the botanical Chamomilla recutita at 0.5%, 1%, or 2% or standard care alone (control group). Use of the mouthwash ended when the oral mucosa was reestablished or the granulocyte count exceeded 500 mm3 for 3 consecutive days in patients who did not develop mucositis. Control patients received standard care without use of a herbal mouthwash. Patients were evaluated daily using the measurement scale for oral toxicity defined by the World Health Organization.

Of the three concentrations, the experimental group at the 1% dosage demonstrated the greatest reduction in incidence, intensity and duration of oral mucositis compared to the control group. Patients tolerated the herbal extract well and it was found to be safe with no moderate or severe adverse effects (Braga 2014).

 

DGL

Deglycyrrhizinated licorice (DGL) is an extract of licorice that has had the glycyrrhetinic acid component removed. This avoids the potential hypertensive properties of glycyrrhetinic acid. DGL is well-known to possess demulcent properties that promote the healing of mucus membranes (Dehpour 1994, Morgan 1982). DGL is available in multiple forms, easily dissolved and is cost-effective. While it does require frequent dosing for effectiveness it has been shown to be clinically beneficial in healing mucus membranes. A number of studies dating from the 1970s to present have demonstrated its usefulness in treating peptic ulcer, aphthous ulcers, as well as radiotherapy induced mucositis.

One of the earlier studies reported on the 2-week use of mouthwash containing DGL in the treatment of aphthous ulcers. In this study, DGL provided pain relief and accelerated the healing time of the ulcers (Das 1989). In a more recent study, a randomized, double-blinded clinical trial, subjects with recurrent aphthous ulcers were assigned to receive either a patch with glycyrrhiza root extract, a placebo patch, or no treatment at the onset of a lesion. Treatment with topical glycyrrhiza resulted in improvements in ulcer size (p <0.05) and pain (p <0.01), compared to both the placebo and no-treatment groups (Martin 2008).

Other, older clinical trials have compared DGL to carbenoxolone, cimetidine, and ranitidine (Mills 2000, Morgan 1982) and found it to be equally effective in healing gastric and duodenal ulcers.

With respect to cancer related mucositis, a couple recent studies demonstrated significant benefit. One clinical trial pertaining to mucositis induced by cancer treatment involved a total of 75 patients who received radiotherapy to the head and neck and were divided into 4 groups: Group A applied licorice powder and honey locally and consumed 10mL of a licorice preparation twice daily; Group B applied licorice powder and honey locally; Group C applied only honey locally; and Group D was the control group which received standard medical treatment for mucositis (Das 2011). Each group received treatment for 7 weeks. Of the four groups, Group A had the greatest reduction in radiation-induced mucositis (p< 0.001) compared to the control group.   While this study had many inherent flaws in that the treatment agents were not standardized, and blinding of assessors for the evaluation of mucositis was not used, it is one of only two studies to date published in the literature showing promise of DGL’s efficacy in treating radiation-induced mucositis.

The second study was a randomized, double blind trial examining the topical use of mucoadhesive patch containing licorice extract (Ghalayani 2014). A total of 60 patients with radiotherapy-induced mucositis were randomized to treatment with a patch containing triamcinolone acetonide or a patch containing licorice. Over consecutive weeks, both groups experienced significant improvements (p<0.05) in the symptoms listed as part of the WHO Mucositis Score (Table 1). There was little change seen in pain ratings however.

DGL is contraindicated in hormone-sensitive breast, uterine, and ovarian cancer due to its phytoestrogenic effects and may interfere with medications and chemotherapy that rely on cytochrome P450 2B6, 2C9, and 3A4 metabolism (Stolpman 1999).

 

GLUTAMINE

Glutamine is the most abundant free amino acid in the human blood stream and is conditionally essential to cells (Chen 2012). It plays a regulatory role in metabolism (oxidative fuel, gluconeogenic precursor, lipogenic precursor), cell integrity (apoptosis and cell proliferation), protein synthesis, and degradation, among other processes (Curi 2005).

While many practitioners find great benefit using glutamine as a treatment for mucositis induced by chemotherapy and radiation, existing research shows mixed findings. A 2011 Cochrane review by Worthington et al. evaluated the prevention of oral mucositis and showed no statistically significant benefit of using oral glutamine. The review did find weak but statistically significant evidence for intravenous glutamine in preventing severe mucositis however (Worthington 2011).

Smaller trials suggest a benefit for using glutamine during radiation (Savarese 2003) and recommend contact with mucous membranes via a swish and swallow method of administration (Noe 2009, Savarese 2003). A small trial reviewed by Worthington et al. found similar protective effects with intravenous glutamine, 0.4 g/kg weight/day given on chemotherapy days, among patients undergoing chemo-radiotherapy for head and neck cancer (Cerchietti 2006). Phase I and II pilot studies on dosage guidelines found that 20 to 30 g daily of glutamine in divided doses was more effective than lower doses (Noe 2009). It is most effective when administered from the start of radiation until 2 weeks after completion.

A systematic review by Gibson et al performed in 2013 analyzed the available literature and defined evidence-based clinical practice guidelines for the use of agents used to treat and prevent mucositis. One of the most important findings in this review was the change in guideline in regards to the use of systemic glutamine. Newer literature demonstrates that glutamine may be effective and without severe toxicity. However, due to conflicting evidence at this time, the guidelines were merely changed from “not recommended” to “no guideline possible.” (Stubbe 2013)

Due to the fact that cancer produces a state of glutamine deficiency (Guarav 2012) that can be further aggravated by the toxic effects of chemotherapy, common recommendations made by naturopathic physicians with special interests in oncology include 15g swish and swallow twice daily for approximately 5 days after chemotherapy agents such as Taxol for example, and 8-10 days post 5-Fluorouracil (5-FU).

Preparation of the following recipe has been shown to help clinically in the prevention and treatment of oral mucositis. Directions are to prepare one glass per day; take frequent sips and swish and spit throughout the day.

  • ½ tsp salt
  • ½ tsp baking soda
  • 1 tablespoon glutamine
  • 250mL room temperature water

 

Currently, there is controversy regarding whether glutamine may serve as a possible fuel for cancer cells, when orally ingested. As a result, it is generally advised that as a precaution, glutamine should be administered as a swish and swallow formula rather than being swallowed. Limitations of the idea that glutamine may fuel cancer cell growth is that it is based predominantly on in vitro studies, whose generalizability to the complex human body is uncertain (Son 2013). Some have argued that since it is the most abundant amino acid in the body, and is synthesized in vivo when not supplied externally, supplemental glutamine is unlikely to have harmful effects on cancer progression, especially when weighed against the benefits of correcting the state of malnutrition produced by cancer, supporting immune function, and preventing mucositis and neuropathy. Data from higher level evidence appears to support this counter-argument: a retrospective study of patients with stage IIIB non-small cell lung cancer (NSCLC) found that glutamine supplementation (10g 3 times daily) given for the prevention of radiation induced esophagitis was not associated with worse survival metrics or tumor control (Topkan 2012). On the other hand there was significant benefits for preventing radiation esophagitis, weight loss, and associated treatment delays. Nonetheless, it may be prudent that when possible, glutamine supplementation be limited to periods of active chemo- and/ or radiation therapy for the time being.

 

HONEY

Honey is an agent that has long been used to soothe mucus membranes. Impressively, a recent systematic review and meta-analysis showed an 80% relative risk reduction in radiation-induced oral mucositis among honey-treated patients when compared with control group (Song 2012). The meta-analysis included three studies in which 120 patients with head and neck cancers receiving radiation therapy were evaluated for radiation-induced mucositis using the WHO (Table 1) and Radiation Therapy Oncology Group (RTOG) criteria (Table 2).

In these three studies, honey was applied before, directly after, and several hours after radiation therapy, to the inside of the mouth. The control group did not actively receive treatment for mucositis. The risk of developing mucositis in the honey-treatment group was 80% lower than in the control group (relative risk [RR] 0.19, 95% confidence interval [CI] 0.098-0.371) (Song 2012).

The topical application of natural honey is a simple and cost-effective treatment for radiation mucositis that warrants further investigation in large multicentre randomized trials.

 

Honey Plus Coffee

In addition to use of honey alone, research has investigated the effect of honey when used in conjunction with coffee, a surprising addition. A recent double-blinded randomized controlled trial evaluated a total of 75 eligible adult patients who were assigned to one of three treatment groups. Each patient was given a syrup-like solution. The first group was given 20 ampoules of betamethasone, each containing 8mg betamethasone. The second group was given 300g of honey only. The third group was given 300g of honey plus 20g of instant coffee. The participants were told to sip 10mL (three teaspoons) of the prescribed product and then swallow it every three hours for one week. The severity of the lesions was clinically evaluated before the treatment as well as one week after the intervention. Results showed that all three treatment regimens reduced the severity of the mucositis lesions, however the greatest reduction in lesion severity was achieved in the honey plus coffee group, followed by the honey only group.

The idea to combine coffee plus honey was extrapolated from previous studies performed by the same research team in which they assessed the effect of honey plus coffee on the treatment of persistent post-infectious cough (Raeessi 2014 B, 2013, 2011). In these studies, researchers noted the rapid healing effect of this treatment modality on the lesions in the hypopharynx mucosal membranes, and decided to design a new trial to evaluate the effect of this regimen on oral mucositis induced by cancer chemotherapy (Raeessi 2014 B). The biological basis for this additive effect is unclear, but may be due to possible antioxidant and anti-inflammatory effects (Raeessi 2014 B).

 

LOW LEVEL LASER

Finally, a systematic review and meta-analysis by Oberoi et al. found that prophylactic Low Level Laser Therapy (LLLT) was able to reduce severe mucositis and pain in patients with cancer undergoing hematopoietic stem cell transplantation and associated chemo/ radiation. The review included 18 RCTs with 1144 subjects. Results showed that LLLT reduced the overall risk of severe mucositis (RR 0.37, 95%CI 0.20-0.67, p =0.001). When compared to placebo (no therapy), LLLT also reduced severe mucositis at the time of anticipated maximal mucositis (RR 0.34, 95% CI 0.20-0.59), overall mean grade of mucositis (standardized mean difference -1.49, 95% CI -2.02 to -0.95), duration of severe mucositis (weighted mean difference -5.32, 95% CI -9.45 to -1.19), and incidence of severe pain (RR 0.26, 95% CI 0.18 to 0.37) (Oberoi 2014).

Increasing supportive evidence for low-level laser therapy has allowed for new guidelines in the prevention of oral mucositis in adult patients receiving hematopoietic stem cell transplantation with high-dose chemotherapy and with or without total body irradiation. Treatment recommendations included using a wavelength of 650nm, power of 40mW, and each square centimetre treated with the required time to a tissue energy dose of 2 J/cm(2) (2s/point)) (Migliorati 2013).

 

HPV Status

An important clinical management consideration when aiding patients in preparation for radiotherapy is HPV (Human Papillomavirus) status. A new study evaluated HPV positive patients with oropharyngeal cancer and found that consideration of additional specific risk factors is required to optimize care (Vatca 2014). This retrospective analysis of 72 patients found that there was a 6.86-fold increase in the risk of having severe, grade 3-4 mucositis in HPV-positive patients. This effect was observed after adjusting for patient smoking status, nodal stage, radiotherapy technique, and radiotherapy maximum dose. Additionally, HPV status had significant effects on the objective weight loss during treatment and at three months following treatment. Non-smokers had a significant 2.70-fold increase in the risk of developing severe mucositis (Vatca 2014). This study highlights the need to take extra precaution and employ aggressive prophylactic measures in these patient populations.

 

Conclusion

Naturopathic doctors are well equipped with a variety of natural interventions to help prevent and manage mucositis in patients with cancer undergoing chemo and/ or radiation therapy. These include the use of chamomile, licorice, DGL, glutamine, honey, and low level laser therapy. As is often the case, it is unlikely there will be one therapy that is suitable for treating all patients with oral mucositis. Using a multi-agent and sequenced approach tailored to each individual patient, while taking into consideration specific risk factors such as local radiation to the head or neck, chemotherapy agents known to cause high grades of mucositis, HPV-status, may be the most effective treatment approach at this time. Patients in these high risk categories should be treated more aggressively. Controversy around use of glutamine currently dictates that its use should be limited to patients undergoing active treatment. Further investigation of these safe, simple measures is needed.

 

 

REFERENCES

 

Braga, F., Santos, A., Bueno, P., et al. Use of Chamomilla recutita in the prevention and treatment of oral mucositis in patients undergoing hematopoietic stem cell transplantation: A Randomized Controlled, Phase II Clinical Trial. Cancer Nursing 2014 Sep 17.

 

Cerchietti LC, Navigante AH, Lutteral MA, Castro MA, Kirchuk R, Bonomi M, Cabalar ME, Roth B, Negretti G, Sheinker B, Uchima P. Double-blinded,

placebo-controlled trial on intravenous L-alanyl-L-glutamine in the incidence of oral mucositis following chemoradiotherapy in patients with head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2006 Aug 1;65(5):1330-7.

 

Chen, J., Herrup, K. Glutamine acts as a neuroprotectant against DNA damage, beta-amayloid and H2O2-induced stress. PLoS one. 2012 7(3).

 

Curi, R., Lagranha, C., Doi, S., et al. Molecular Mechanisms of Glutamine Action. Journal of Cellular Physiology. 2005. 204:392-401.

 

Das, S., Agarwal, S., and Chandola, H. Protective effect of Yashtimadhu (Glycyrrhiza glabra) against side effects of radiation/chemotherapy in head and neck malignancies. Ayu. 2011. 32(2):196-199.

 

Das, S., Das, V., Guati, A., et al. Deglycyrrhizinated liquorice in aphthous ulcers. Journal of the Association of Physicians of India. 1989. 47(10):647.

 

Dehpour AR, Zolfaghari ME, Samadian T, Vahedi Y. The protective effect of liquorice components and their derivatives against gastric ulcer induced by aspirin in rats. J Pharm Pharmacol. 1994 Feb;46(2):148-9.

 

Ghalayani P, Emami H, Pakravan F, Nasr Isfahani M. Comparison of triamcinolone acetonide mucoadhesive film with licorice mucoadhesive film on radiotherapy-induced oral mucositis: A randomized double-blinded clinical trial. Asia Pac J Clin Oncol. 2014 Oct 28. doi: 10.1111/ajco.12295. [Epub ahead of print]

 

Gibson, R., Keefe, D., Lalla, R., et al. Systematic review of agents for the management of gastrointestinal mucositis in cancer patients. Supportive Care in Cancer. 2013. 21(1), 313-326.

Keefe, D. M., Schubert, M. M., Elting, L.S., et al. Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer. 2007 109(5):820-831.

 

Guarav, K., Goel, R., Shukla, M., et al. Glutamine: A novel approach to chemotherapy-induced toxicity. Indian J Med PAediatr Oncol. 2012 Jan 33(1):13-20.

 

Martin, M., Sherman, J., van der Ven, P., et al. A controlled trial of a dissolving patch concerning glycyrrhiza (licorice) herbal extract for the treatment of aphthous ulcers. General Dentistry. 2008. 56(2):206-210.

 

Migliorati, C., Hewson, I., Lalla, R., et al. Systematic review of laser and other light therapy for the management of oral mucositis in cancer patients. Support Care Cancer 2013 Jan; 21 (1): 333-41.

 

Mills, S., Bone, K. Principles and Practice of Phytotherapy. Edinburgh: Churchill Livingstone. 2000. 472.

 

Morgan AG, McAdam WA, Pacsoo C, Darnborough A. Comparison between cimetidine and Caved-S in the treatment of gastric ulceration, and subsequent maintenance therapy. Gut. 1982 Jun;23(6):545-51.

 

Noe, J.E. L-glutamine use in the treatment and prevention of mucositis and cachexia: a naturopathic perspective. Integrative Cancer Therapies. 2009. 8(4):409-415.

 

Oberoi, S et al. Effect of prophylactic low level laser therapy on oral mucositis: a systematic review and meta-analysis. PLoS one. 2014 Sep 8;9(9):e107418

 

Radiation Therapy Oncology Group. Acute radiation morbidity scoring criteria. 2014 Retrieved from http://www.rtog.org/ResearchAssociates/AdverseEventReporting/AcuteRadiationMorbidityScoringCriteria.aspx

 

Raeessi, M., Raeessi, N., Panahi, Y., et al. “Coffee plus Honey” versus “topical steroid” in the treatment of Chemotherapy-induced Oral Mucositis: a randomized controlled trial. BMC Complementary and Alternative Medicine. 2014. 14:2293. A

 

Raeessi, M., Aslani, J., Raeessi, N., et al. Persistent post-infectious cough is better treated by which one? Prednisone, Honey, Coffee or Honey plus Coffee: a meta-analysis. Indian J Traditional Knowledge. 2014, 13(3):453-460. B

 

Raeessi, M., Aslani, J., Raeessi, N., et al. Honey plus Coffee versus systemic steroid in the treatment of persistent post-infectious cough: a randomized controlled trial. Prim Care Respir J 2013. 22(3):325-330.

 

Raeessi, M. Aslani, J., Gharaie, H., et al. Honey with Coffee: a new finding in the treatment of Persistent Postinfectious Cough. Iran J Otorhinolaryngol. 2011 23(2):1-8.

 

Savarese, D. M., Savy, G., Vahdat, L. Prevention of chemotherapy and radiation toxicity with glutamine. Cancer Treatment Reviews. 2003. 29(6):501-513.

 

Son J, Lyssiotis CA, Ying H, Wang X, Hua S, Ligorio M, Perera RM, Ferrone CR, Mullarky E, Shyh-Chang N, Kang Y, Fleming JB, Bardeesy N, Asara JM, Haigis MC, DePinho RA, Cantley LC, Kimmelman AC. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature. 2013 Apr 4;496(7443):101-5.

 

Song, J., Twusmasi-Ankrah, P., & Salcido, R. Systematic review and meta-analysis on the use of honey to protect from the effects of radiation-induced oral mucositis. Advances in Skin and Wound Care. 2012. 25(1):23-28.

 

Sonis, S., et al. Mucositis as a biological process: a new hypothesis for the development of chemotherapy-induced stomatotoxicity. Oral Oncol. 1998. 34:39-43.

 

Stolpman, D., Benner, K., & Flora, K. A cautionary note regarding glycyrrhiza (licorice root). Am J Gastroenterol. 1999 Feb 94(2):540-541.

 

Stubbe, C., Valero, M. Complementary Strategies for the Management of Radiation Therapy Side Effects. Journal of the Advanced Practitioner in Oncology. 2013;4:219-231.

 

Vatca, M., Lucas, J., Laudadio J., et al. Retrospective analysis of the impact of HPV status and smoking on mucositis in patients with oropharyngeal squamous cell carcinoma treated with concurrent chemotherapy and radiotherapy. Oral Oncology 2014 Sep; 50(9):869-76.

 

World Health Organization. WHO Handbook for reporting results of cancer treatment. Geneva: World Health Organization 1979.

 

Worthington HV, Clarkson JE, Bryan G, Furness S, Glenny AM, Littlewood A, McCabe MG, Meyer S, Khalid T. Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev. 2011 Apr 13;(4):CD000978.

 

Meditation: Impact on gene expression

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Abstract

There is growing evidence to demonstrate that mind-body practices, such as yoga and meditation, can influence our gene expression and in fact counteract cellular damage that may be induced by states of chronic stress. The changes in genetic expression, as a result of doing these mind-body exercises to elicit the “relaxation response,” a physiological and psychological state that is opposite to the fight-or-flight response, play a significant role in reducing the body’s inflammation and states of anxiety. Clinically, this applies to a variety of treatment approaches including heart disease, mental health, autoimmune disease and cancer. These findings highlight the importance of a mind-body “prescription” in medicine and provide tangible data to reaffirm the benefits of what has been practiced for centuries in various parts of the globe.

Background

There is increasing awareness as well as research to show the negative impacts of chronic stress on health. On the other hand, we are just starting to discover what is occurring on a molecular level in a relaxed state. The “relaxation response” (RR) is defined as a physiological and psychological state that is opposite to the stress or fight-or-flight response (Bhasin 2013). The RR can be elicited through multiple mind-body approaches such as yoga, mediation, tai chi, qi gong, progressive muscle relaxation, biofeedback, and breathing exercises (Bhasin 2013). The common thread between these techniques is two-fold: (1) the focus on a word, sound, phrase, repetitive prayer, or movement and (2) the disregard of everyday thought. These two steps are critical in breaking the train of everyday thinking and influencing physiological changes including decreased oxygen consumption and carbon dioxide elimination, changes in blood pressure, heart and respiratory rate, norepinephrine responsiveness, increased heart rate variability, and alterations in cortical and subcortical brain regions (Bhasin 2013).

Practices such as yoga and meditation have been in use for over 5000 years in India (Qu 2013), but there still remain questions around their biological effects on our health as well as how yoga compares to other types of exercise. Recent evidence shows that meditation practices influence our biology through epigenetic changes. Epigenetic changes involve modifications of gene expression and transcription, with the potential to affect virtually any cell in the body through alterations in cell membrane receptor expression and/ or various signaling factors. Due to these pervasive and far-reaching effects, meditation practices have the potential to modify chronic disease risk and progression, including heart disease, mood disorders, and autoimmune disorders, and cancer. Current studies are looking at how short and long-term meditation practitioners may regulate immunity, metabolic rate, and response to oxidative stress (Ravnik-Glavac 2012). Such new knowledge helps us understand the best therapeutic applications of meditation, and helps reinforce its importance as an intervention for practitioners and patients alike. This paper will examine the current evidence seeking to elucidate the biological effects of meditation practices.

 

Clinical Trials

Dusek et al. (2008) provide evidence that a RR practice results in genomic expression alterations in healthy subjects. Sustained genetic expression alterations were found in both short-term (N2 group) and long-term meditators (M group) when compared to novices (N1). These types of changes are significantly linked to oxidative phosphorylation, antigen processing and presentation, and apoptosis (Dusek 2008). The authors conclude that regular daily practice is recommended for sustained beneficial effects.

Ravnik et al. (2012) further show that a higher state of consciousness is associated with significant changes in gene expression and brain waves. Table 1 shows a summary of results from their study that followed two long-term meditators (20+ years experience) for one year. Their results showed that a higher state of consciousness is characterized by both down-regulation and up-regulation of various genes, including down-regulation of the stress response, up-regulation of genes involved in hemoglobin synthesis, transport of oxygen and nitric oxide, and enrichment in glutamate transport, glutamate receptor activity, and NADH dehydrogenase activity. Brain EEG showed that there was an increase in theta and alpha brain frequencies during a meditative state. This study does have a small sample size and may not apply to novice meditators, but the results are statistically significant and it is at present the only study that has evaluated brain waves. Long-term meditation practitioners were chosen in this case, according to the authors, in order to isolate the expression changes of a higher state of consciousness, however this does not mean that benefits would be absent among novice practitioners.

Bhasin et al. (2013) studied the acute changes in gene expression that took place within a single session of a RR-eliciting practice. Over an 8-week period, healthy novice subjects were exposed to 20 minutes of any of the following mind-body interventions: yoga/ meditation/ qi gong/ tai chi/ progressive /biofeedback/ breathing exercises. Fractional exhaled nitric oxide (FeNO) samples were collected at three time points during each session to explain the physiological effects of RR including reduction in blood pressure. FeNO is known to play a prominent role in vascular dilatation (Bashin 2013). This study showed that a relaxed state influences various pathways via mitochondrial signaling. Subjects experienced down-regulation of the NF-kB pathway, mitigating oxidative stress, inflammation, and chronic disease vulnerability. Qu (2013) also looked at the immediate changes that occur within two hours of yoga for four consecutive days. This study showed that yogic practices have rapid effects at the molecular level in circulating immune cells.

All the studies described thus far have been prospective or cross-sectional. However, a randomized control trial (RCT) conducted in 2013 investigated a unique population group experiencing chronic stress: caregivers of elderly family members with dementia. This was defined as caring for the family member for at least three days per week. Caregivers often report lower levels of satisfaction with life than healthy controls, showing higher markers of inflammation such as C-reactive protein and IL-1 receptor antagonist, and reduced levels of cellular immunity such as interferon (IFN) (Black 2013). This RCT tested whether a daily yogic meditation intervention could reverse a pattern of pro-inflammatory and anti-antiviral leukocyte transcriptional alterations induced by stress. Results showed a reduction in the activity of pro-inflammatory NF-kB and increased interferon response factors (IRF) (Black 2013). The authors concluded that eight weeks of structured daily yogic meditation reversed the pattern of increased NF-κB-associated pro-inflammatory gene expression and decreased expression of IRF1-associated genes.

 

Future Directions

In summary, there is a growing body of evidence to show that mind-body practices such as yoga and meditation indeed influence our gene expression and counteract cellular damage induced by chronic stress. More questions still remain: are there certain populations or individuals this kind of practice can make a bigger impact? How do we measure one’s progress in clinical practice based on this information (how much, how often, what type of activity and technique, alone or in a group, how advanced)? Could individual genetic backgrounds influence the ability to achieve higher state of consciousness?

Nonetheless, we now know that the changes in genetic expression as a result of doing mind-body exercises to elicit the relaxation response, both over short and long-term, can play a role in general health but also in specific diseases by reducing inflammation, hypertension (via FeNO vasodilation), and influence states of anxiety. The potential to alter gene expression profiles of circulating immune cells toward a less pro-inflammatory profile is impressive. Clinically this could also have significant implications in treatment approaches of autoimmune disease, cancer and chronic infections. These findings highlight the importance of not underestimating a mind-body prescription: the importance of taking time to de-stress and bring one’s awareness to the present moment.

 

References

 

Bhasin MK, Dusek JA, Chang BH, Joseph MG, Denninger JW, Fricchione GL, Benson H, Libermann TA. Relaxation response induces temporal transcriptome changes in energy metabolism, insulin secretion and inflammatory pathways. PLoS One. 2013 May 1;8(5):e62817.

 

Black DS, Cole SW, Irwin MR, Breen E, St Cyr NM, Nazarian N, Khalsa DS, Lavretsky H. Yogic meditation reverses NF-κB and IRF-related transcriptome dynamics in leukocytes of family dementia caregivers in a randomized controlled trial. Psychoneuroendocrinology. 2013 Mar;38(3):348-55.

 

Dusek JA, Otu HH, Wohlhueter AL, Bhasin M, Zerbini LF, Joseph MG, Benson H, Libermann TA. Genomic counter-stress changes induced by the relaxation response. PLoS One. 2008 Jul 2;3(7):e2576.

 

Qu S, Olafsrud SM, Meza-Zepeda LA, Saatcioglu F. Rapid gene expression changes in peripheral blood lymphocytes upon practice of a comprehensive yoga program. PLoS One. 2013 Apr 17;8(4):e61910.

 

Ravnik-Glavač M, Hrašovec S, Bon J, Dreo J, Glavač D. Genome-wide expression changes in a higher state of consciousness. Conscious Cogn. 2012 Sep;21(3):1322-44.

Mechanism of melatonin in oncology the great multi-tasker

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Background

Melatonin (chemically named N-acetyl-5-methoxytryptamine) is indeed a great multi-tasker. Whereas it is well known for its role in regulating circadian rhythm, much interest has been generated for its possible role in the pathogenesis and treatment of other disorders, namely cancer. The deviation from its primary role in the control of circadian rhythms including sleep came about from the observation that not only is it synthesized in the pineal gland, but also in the retina, GI tract, bone marrow and leukocytes (Hardeland 2011). Furthermore, in humans, melatonin receptors have been identified in enterocytes, gallbladder epithelium, exocrine and endocrine pancreatic cells, breast epithelium, ovarian granulosa cells, cardiac ventricular cells, and platelets, just to name a few (Fernando 2014, Hardeland 2011).

Melatonin is secreted from the pineal gland in a diurnal rhythm, being higher at night in darkness than during the daylight hours. Another significant source of melatonin in the body is the gastrointestinal system, where gastrointestinal tract (GIT) cells synthesize melatonin to regulate digestive function (Bubenik 2008). Much research has been devoted to the oncological risk that night shift workers may experience due to the disruption of their circadian clock, and therefore disruption of melatonin secretion (Bracci 2013). It was proposed that this risk may be mediated by the loss of antioxidant and hormone modulating properties of melatonin.

In addition to its antioxidant properties, melatonin also acts as an immune modulator, anti-inflammatory, and possesses cytostatic as well as cytotoxic properties in vitro as well as in vivo. A PubMed search of “melatonin and cancer” reveals thousands of articles on the subject, and many excellent reviews have been published. This article will outline some of the mechanisms behind the powerful pleiotropic effects of melatonin, and how this translates clinically with respect to naturopathic oncology. The focus of this article will be elucidating melatonin’s mechanism of action, while clinical data can be found summarized elsewhere (Fritz 2009, Seely 2012, Wang 2012).

 

Mechanisms

Melatonin as antioxidant

Several simultaneous processes act harmoniously to grant melatonin its impressive antioxidant abilities. First, it directly scavenges free radicals, both reactive oxygen species (ROS) and reactive nitrogen species (RNS). Hydrogen peroxide, while not a free radical but still an oxidizing agent, is also neutralized by melatonin. Interestingly, several melatonin metabolites produced during the scavenging reactions, such as N1-acetyl-N2-formyl-5-

methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK) also have free radical scavenging abilities (Hardeland 2011). Melatonin indirectly acts an antioxidant by way of stimulating the production of glutathione, the most abundant intracellular antioxidant our cells possess. In one study, melatonin outperformed the hepatoprotective effects of the antioxidant N-acetylcysteine in rat models of methanol intoxication (Koksal 2012). In another study, a more dilute solution of melatonin was able to mimic the antioxidant effect of a much more concentrated vitamin C solution (Montilla-López 2002). In addition, melatonin up regulates the production of detoxifying enzymes such as glutathione peroxidase (GPx), glutathione reductase (GR) and superoxide dismutase (SOD) (Reiter 2003). Oxidation leading to cell and DNA damage is a major contributor to oncogenesis, and melatonin may therefore be beneficial as a chemopreventive agent.

 

Melatonin as immune modulator

Melatonin has immune enhancing effects on both the innate and adaptive immune system. Melatonin has been shown to increase the production of natural killer cells (NK), monocytes and leukocytes (Srinivasan 2008). NK cells are the primary innate immune cell responsible for killing cancer cells by releasing cytotoxic proteins such as perforin and granzyme (Lui 2012). Melatonin also enhances the production of IL-1, IL-6, TNF-α and IL-12 from monocytes, and enhances the production of IL-2, IFN-ψ and IL-6 from peripheral blood mononuclear cells (Srinivasan 2008). Together these cytokines activate and regulate the cytotoxic T cell response, which kill tumour cells. The immunosurveillance that the innate and adaptive immune system help provide may have more of a role in the prevention of tumours.

 

Melatonin as anti-inflammatory

It is well accepted that over expression of COX-2 in tissues is important in mediating cancer growth and metastasis (Generali 2014, Khan 2011). Further, cancer cells themselves over express COX-2, leading to a self perpetuating system. Several studies have shown that melatonin possesses COX-2 suppressing actions at a pharmacological dose of 1mM (Wu 2014). Additionally, the previously mentioned metabolites of melatonin, AMFK and AMK, in addition to having antioxidant potential, also inhibit COX-2 expression (Wu 2014). Other immune cells involved in the inflammatory process, such as macrophages, have been shown to secrete melatonin, suggesting that melatonin is a key endogenous molecule released in response to inflammation (Wu 2014). Melatonin has also been shown to inhibit pro-inflammatory cytokines IL-8 and TNF-α in neutrophils, suggesting it may help to reduce the effects of acute and chronic inflammation (Silva 2004).

 

Melatonin as cytostatic

Cytostasis refers to the inhibition of cellular growth and replication. There are numerous studies on the anti-proliferative effects of melatonin on various types of cancer cells both in vitro and in vivo, and a comprehensive review of these is beyond the scope of this article. However, one of the mechanisms suggested as responsible for such inhibition is activation of p21 and p53 tumour suppressor genes, which act by halting the cell cycle (Mediavilla 1999). A second cytostatic mechanism may be via melatonin’s antiangiogenic effects. Melatonin appears to inhibit hypoxia inducible factor (HIF-1) and vascular endothelial growth factor (VEGF), both of which drive the growth of new blood vessels in the tumour environment (Lissoni 2001). Thirdly, melatonin may have anti-metastatic effects via inhibition of matrix metalloproteinase-9 (MMP-9) activity, an enzyme associated with extracellular matrix remodelling and cancer metastasis (Rudra 2013). Melatonin also appears to increase expression of cell surface adhesion proteins, E-cadherin and beta1-integrin, which may decrease cancer cell migration and metastasis (Ortiz-Lopez 2009).

 

Melatonin as cytotoxic

Cytotoxicity refers to the ability of an agent to be toxic to cells, in other words, to klll them. Conventional therapies, such as chemotherapy, aim at being cytotoxic to cells. One such way an agent can be cytotoxic is by promoting apoptosis.

The studies on the apoptotic potential and mechanisms of melatonin are quite exciting, as studies are showing it has this ability in both hematological and solid tumour cell lines, such as breast cancer, colon cancer, hepatocarcinoma, glioma and neuroblastoma, lymphoma and leukemia (Bizzarri 2013). Studies have shown that Burkitt lymphoma cells, and both acute and myeloid leukaemia undergo apoptosis via activation of caspase-3, an increase in cytochrome c levels, and down regulation of the anti-apoptotic protein Bcl-2 (Trubiani 2005). Whereas not all studies in these cells lines confirm this exact mechanism, studies generally support the apoptotic effects of melatonin.

In solid tumours, many interesting findings have been published. One study published evidence with respect to the apoptotic effect in breast cancer cell lines, showing that not only was p53 upregulated, but also its transcriptional agents, Bax, p21 and p27 (el-Aziz 2005). This effect was evident in both hormone dependent and hormone independent cancers. Studies in highly aggressive pancreatic cell lines show that melatonin had apoptotic effects via stimulation of caspase proteins (Gonzalez 2011, Leja-Szpak 2010). Melatonin exerted apoptotic effects in hormone sensitive and insensitive prostate cancer cells via inhibition of Sirt1, a gene over expressed in many cancers that when inhibited is associated with increased levels of apoptosis (Jung Hynes 2011). The same inhibition of Sirt1 was found in osteosarcoma cell lines (Cheng 2013). Sirt1 activity in cancer cells is associated with silenced tumour suppressor genes and cancer resistance to chemotherapy and ionizing radiation (Gonzalez 2011), and therefore inhibition of same may prove to be a target for gene therapy regimens.

 

Melatonin and Radiochemotherapy

The basic tenet for the use of radiochemotherapy is that the ionizing radiation or drug will cause sufficient damage to kill cancer cells. However, this damage is extended to non-cancerous cells as well, resulting in often severe side effects. Recent studies have investigated the role of melatonin alongside radiochemotherapeutic regimens. Specifically, studies demonstrate that melatonin reproducibly decreases the toxic side effects of these treatments (Kucuktulu 2012, Mand 2009, Ortiz 2014, Seely 2012).

Radioprotective agents are those that are given prior to radiotherapy to reduce injuries. Rat studies have shown that melatonin given after irradiation provides no radioprotective benefit (Shirazi 2007). It appears that melatonin may need to be administered beforehand to be present inside the cell prior to irradiation (Manda 2009).

An ideal radioprotector should fulfill several criteria: 1) must provide significant protection against the effects of radiation; 2) must have a general protective effect on the majority of organs; 3) must have an acceptable route of administration, preferable orally or intramuscularly; 4) must have an acceptable toxicity profile; 5) must have an acceptable stability profile; and 6) must have compatibility with the wide range of other drugs that will be available to patients (Hosseinimehr 2007).

Vijayalaxmi et al. conducted the first in vivo/in vitro studies showing that melatonin could be used as a cytoprotective agent for human cells exposed to ionizing radiation. In a study of healthy human volunteers, blood was taken before, one hour and two hours after a single dose of 300 mg of melatonin was given orally. Immediately after the blood was taken, it was exposed to 150 cGy of radiation and was cultured. The exposure of the cells to the radiation caused chromosomal aberrations, and lymphocytes collected after melatonin administration exhibited 60-65% reduced incidence of damage, with the best protective effect after two hours (Vijayalaxmi 2002). As the typical dose of melatonin is 20 mg per day, 300 mg seems at first to be quite high. However, the author showed that in humans, a dose of 1 gram daily for 30 days resulted in no observable negative side effects (Vijayalaxmi 2004).

A recent meta-analysis looked at the efficacy of adjuvant melatonin on response rates, survival and reduction of side effects related to radiochemotherapy (Wang 2012). The pooled data showed remission rates of 32.6% for the melatonin group versus 16.5% for the groups without melatonin. Similarly, survival rates were 52.2% for the melatonin group and 28.4% for the groups without melatonin. Studies that reported side effects showed overall rates markedly reduced when melatonin was used as an adjuvant with radiochemotherapy, including thrombocytopenia (2.2% versus 19.7%), neurotoxicity (2.5% versus 15.2%), and fatigue (17.2% versus 49.1%).

Another recent meta-analysis of 19 studies compared the cancer response rates to melatonin plus a chemotherapeutic drug to chemotherapy without melatonin (Seely 2012). The overall result showed a significant benefit on complete response, partial response, and stable disease with the addition of melatonin. Pooled results from trials evaluating mortality showed that the addition of melatonin reduced mortality rates at one year, compared to patients who did not receive melatonin, relative risk (RR) 0.63, 95% confidence interval (CI) 0.53-0.74; p< .001 (Seely 2012). Regarding the results for the effect of adjuvant melatonin on toxicities associated with chemotherapy, positive outcomes were found for the reduction of asthenia, leucopenia, nausea and vomiting, hypotension and thrombocytopenia. Side effects not improved with the addition of melatonin included diarrhea, anemia and alopecia (Seely 2012). Dosages from the trials included in this meta analysis ranged from 10-40mg, with 20mg being most common, given at bedtime (Seely 2012).

 

Conclusion

As briefly reviewed above, melatonin truly is a great multi-tasker. Its many actions include immune modulator, antioxidant, anti-inflammatory, anti-angiogenic, anti-metastatic, anti-proliferative, and pro-apoptotic. In addition, it has the ability to modify gene expression, reduce side effects of radio chemotherapy, and improve response rates to radio chemotherapy. Whereas the molecular mechanisms reviewed in this article are by no means exhaustive, this article is meant to ignite a level of excitement about an impressive supplement for anyone interested in naturopathic oncology.

 

References

Bizzarri M, Proietti S, Cucina A, Reiter RJ. Molecular mechanisms of the pro-apoptotic actions of melatonin in cancer: a review. Expert Opin Ther Targets. 2013 Dec;17(12):1483-96.

 

Bracci M, Copertaro A, Manzella N, Staffolani S, Strafella E, Nocchi L, Barbaresi M, Copertaro B, Rapisarda V, Valentino M, Santarelli L. Influence of night-shift and napping at work on urinary melatonin, 17-β-estradiol and clock gene expression in pre-menopausal nurses. J Biol Regul Homeost Agents. 2013 Jan-Mar;27(1):267-74.

Bubenik GA. Thirty four years since the discovery of gastrointestinal melatonin. J Physiol Pharmacol. 2008 Aug;59 Suppl 2:33-51.

 

Cheng Y, Cai L, Jiang P, Wang J, Gao C, Feng H, Wang C, Pan H, Yang Y. SIRT1 inhibition by melatonin exerts antitumor activity in human osteosarcoma cells. Eur J Pharmacol. 2013 Sep 5;715(1-3):219-29.

 

el-Aziz MA, Hassan HA, Mohamed MH, Meki AR, Abdel-Ghaffar SK, Hussein MR. The biochemical and morphological alterations following administration of melatonin, retinoic acid and Nigella sativa in mammary carcinoma: an animal model. Int J Exp Pathol. 2005 Dec;86(6):383-96.

Fernando S, Rombauts L. Melatonin: shedding light on infertility? – a review of the recent literature. J Ovarian Res. 2014 Oct 21;7(1):98.

 

Fritz H. Melatonin: clinical applications. IHP Magazine. 2009 Jun/ Jul: 73-80.

Generali D, Buffa FM, Deb S, Cummings M, Reid LE, Taylor M, Andreis D, Allevi G, Ferrero G, Byrne D, Martinotti M, Bottini A, Harris AL, Lakhani SR, Fox SB. COX-2 expression is predictive for early relapse and aromatase inhibitor resistance in patients with ductal carcinoma in situ of the breast, and is a target for treatment. Br J Cancer. 2014 Jul 8;111(1):46-54.

 

Gonzalez A, del Castillo-Vaquero A, Miro-Moran A, Tapia JA, Salido GM. Melatonin reduces pancreatic tumor cell viability by altering mitochondrial physiology. J Pineal Res. 2011 Apr;50(3):250-60.

 

Hardeland R, Cardinali DP, Srinivasan V, Spence DW, Brown GM, Pandi-Perumal SR. Melatonin–a pleiotropic, orchestrating regulator molecule. Prog Neurobiol. 2011 Mar;93(3):350-84.

 

Hosseinimehr SJ. Foundation review: trends in the development of radioprotective agents. Drug Discovery Today, 2007; 12(19/20).

 

Jung-Hynes B, Schmit TL, Reagan-Shaw SR, Siddiqui IA, Mukhtar H, Ahmad N. Melatonin, a novel Sirt1 inhibitor, imparts antiproliferative effects against prostate cancer in vitro in culture and in vivo in TRAMP model. J Pineal Res. 2011 Mar;50(2):140-9.

 

Kucuktulu E. Protective effect of melatonin against radiation induced nephrotoxicity in rats. Asian Pac J Cancer Prev. 2012;13(8):4101-5.

 

Khan Z, Khan N, Tiwari RP, Sah NK, Prasad GB, Bisen PS. Biology of Cox-2: an application in cancer therapeutics. Curr Drug Targets. 2011 Jun;12(7):1082-93.

 

Koksal M, Kurcer Z, Erdogan D, Iraz M, Tas M, Eren MA, Aydogan T, Ulas T. Effect of melatonin and n-acetylcysteine on hepatic injury in rat induced by methanol intoxication: a comparative study. Eur Rev Med Pharmacol Sci. 2012 Apr;16(4):437-44.

 

Leja-Szpak A, Jaworek J, Pierzchalski P, Reiter RJ. Melatonin induces pro-apoptotic signaling pathway in human pancreatic carcinoma cells (PANC-1). J Pineal Res. 2010 Oct;49(3):248-55.

 

Lissoni P, Rovelli F, Malugani F, Bucovec R, Conti A, Maestroni GJ. Anti-angiogenic activity of melatonin in advanced cancer patients. Neuro Endocrinol Lett. 2001;22(1):45-7.

 

Liu Y, Zeng G. Cancer and innate immune system interactions: translational potentials for cancer immunotherapy. J Immunother. 2012 May;35(4):299-308.

 

Manda K, Ueno M, Anzai K. Cranial irradiation-induced inhibition of neurogenesis in hippocampal dentate gyrus of adult mice: attenuation by melatonin pretreatment. J Pineal Res. 2009 Jan;46(1):71-8.

Mediavilla MD, Cos S, Sánchez-Barceló EJ. Melatonin increases p53 and p21WAF1 expression in MCF-7 human breast cancer cells in vitro. Life Sci. 1999;65(4):415-20.

 

Montilla-López P, Muñoz-Agueda MC, Feijóo López M, Muñoz-Castañeda JR, Bujalance-Arenas I, Túnez-Fiñana I. Comparison of melatonin versus vitamin C on oxidative stress and antioxidant enzyme activity in Alzheimer’s disease induced by okadaic acid in neuroblastoma cells. Eur J Pharmacol. 2002 Sep 20;451(3):237-43.

 

Ortíz-López L, Morales-Mulia S, Ramírez-Rodríguez G, Benítez-King G. ROCK-regulated cytoskeletal dynamics participate in the inhibitory effect of melatonin on cancer cell migration. J Pineal Res. 2009 Jan;46(1):15-21.

 

Ortiz F, Acuña-Castroviejo D, Doerrier C, Dayoub JC, López LC, Venegas C, García JA, López A, Volt H, Luna-Sánchez M, Escames G. Melatonin blunts the mitochondrial/NLRP3 connection and protects against radiation-induced oral mucositis. J Pineal Res. 2014 Nov 11.

 

Reiter RJ, Tan DX, Mayo JC, Sainz RM, Leon J, Czarnocki Z. Melatonin as an antioxidant: biochemical mechanisms and pathophysiological implications in humans. Acta Biochim Pol. 2003;50(4):1129-46.

 

Rudra DS, Pal U, Maiti NC, Reiter RJ, Swarnakar S. Melatonin inhibits matrix metalloproteinase-9 activity by binding to its active site. J Pineal Res. 2013 May;54(4):398-405

 

Seely D, Wu P, Fritz H, Kennedy DA, Tsui T, Seely AJ, Mills E. Melatonin as adjuvant cancer care with and without chemotherapy: a systematic review and meta-analysis of randomized trials. Integr Cancer Ther. 2012 Dec;11(4):293-303.

 

Shirazi A, Ghobadi G, Ghazi-Khansari M. A radiobiological review on melatonin: a novel radioprotector. J Radiat Res. 2007 Jul;48(4):263-72.

 

Silva SO, Rodrigues MR, Ximenes VF, Bueno-da-Silva AE, Amarante-Mendes GP, Campa A. Neutrophils as a specific target for melatonin and kynuramines: effects on cytokine release. J Neuroimmunol. 2004 Nov;156(1-2):146-52.

 

Srinivasan V, Spence DW, Pandi-Perumal SR, Trakht I, Cardinali DP. Therapeutic actions of melatonin in cancer: possible mechanisms. Integr Cancer Ther. 2008 Sep;7(3):189-203.

 

Trubiani O, Recchioni R, Moroni F, Pizzicannella J, Caputi S, Di Primio R. Melatonin provokes cell death in human B-lymphoma cells by mitochondrial-dependent apoptotic pathway activation. J Pineal Res. 2005 Nov;39(4):425-31.

 

Vijayalaxmi, Reiter RJ, Tan DX, Herman TS, Thomas CR Jr. Melatonin as a radioprotective agent: a review. Int J Radiat Oncol Biol Phys. 2004 Jul 1;59(3):639-53.

 

Vijayalaxmi, Thomas CR Jr, Reiter RJ, Herman TS. Melatonin: from basic research to cancer treatment clinics. J Clin Oncol. 2002 May 15;20(10):2575-601.

 

Wang YM, Jin BZ, Ai F, Duan CH, Lu YZ, Dong TF, Fu QL. The efficacy and safety of melatonin in concurrent chemotherapy or radiotherapy for solid tumors: a meta-analysis of randomized controlled trials. Cancer Chemother Pharmacol. 2012 May;69(5):1213-20.

 

Wu KK, Cheng HH, Chang TC. 5-methoxyindole metabolites of L-tryptophan: control of COX-2 expression, inflammation and tumorigenesis. J Biomed Sci. 2014 Mar 3;21:17.

Canadian Consumers Should Rest Assured

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IHR Magazine
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The next big market: natural antioxidants

What should you do if you find yourself facing a sudden maelstrom of consumer concern following the testing and recall of a range of health food supplements from the shelves of major retailers including Wal-Mart, Walgreens, Target and GNC in New York State?

Canadian Health Food Association (CHFA) President Helen Long advises sharing some details about the pre-market approval process that has positioned Canada as a global leader in the regulation of natural health products (NHPs).

The American tests used a new and relatively untested process called DNA bar-coding. After the results made headlines, Harvard Medical School assistant professor Pieter Cohen told the New York Times that the test results were so extreme he found them hard to accept, suggested that “the manufacturing process may have destroyed some of the ingredients’ DNA, rendering the DNA barcode test ineffective.”

Echinacea, gingko biloba, ginseng, garlic, saw palmetto, valerian root and St. John’s wort samples were tested. One product claiming to be gingko biloba was found to contain no gingko biloba at all. Other products contained unlisted ingredients including wheat and beans that have been known to cause allergic reactions – and could be potentially dangerous to consumers.

CHFA points out that Natural Health Products in Canada follow a strict licencing protocol to prevent this sort of thing from happening here. From the moment Product Licence Applications (PLAs) are filed with Health Canada, product safety, effectiveness and quality are monitored. Applications must provide information about the medicinal and non-medicinal ingredients used, scientific research supporting any health claims, product labeling, and information about the manufacturing site. The licencing process includes standardized laboratory tests demonstrating that the product contains the advertised medicinal and non-medicinal ingredients.

“Once approved,” says Long, “Health Canada issues an 8-digit Natural Product Number (NPN), which can be found on the product label and the Licensed Natural Health Product Database.”

The CHFA statement concluded by saying, “While CHFA in principle supports the evolution of new and proven testing techniques to ensure consistent and high-quality products are available to Canadians, the DNA bar-coding technique for the review of NHPs has not been validated by Health Canada or other regulatory authorities, nor is it widely available to manufacturers at this time.”

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