New Zealand Green-Lipped Mussel

Scientific Name(s): Perna canaliculus . Family: Mytilidae

Common Name(s): New Zealand green-lipped mussel , Lyprinol (stabilized lipid extract) , Seatone (freeze-dried preparation)

Uses

Limited clinical studies suggest that Perna mussel extracts may have efficacy in the treatment of diseases with inflammatory components, such as arthritis and asthma. However, conflicting trial results have been reported. Claims of efficacy in the treatment of cancer are unsubstantiated by clinical trials.

Dosing

Limited trial data are available to inform therapeutic dosing. In arthritis trials, dosages ranged from 1,150 mg/day in divided doses to 1,500 mg/day of the stabilized lipid extract and 900 to 1,380 mg/day of the freeze-dried preparation.

Contraindications

Hypersensitivity to shellfish. Use with caution in individuals with hepatic impairment.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. Animal studies suggest that components of Perna extracts could be dangerous to a fetus.

Interactions

None well documented.

Adverse Reactions

GI discomfort and transient worsening of arthritic pain have been noted. Hepatic dysfunction has also been recorded, but the incidence appears to be low. Long-term exposure has resulted in occupational asthma in people working in mussel processing plants.

Toxicology

No specific toxicological studies are available.

There are 2 green mussel species: P. canaliculus is found in the temperate waters of New Zealand, whereas Perna viridis occurs widely throughout the Indo-Pacific region, which includes Japan, Malaysia, Indonesia, and the Philippines. Green mussels are farmed commercially in Thailand and the Philippines, although New Zealand is regarded as the major exporter. 1

History

Shellfish supplements have been used as a traditional remedy for arthritis in humans, in particular by the indigenous Maori people of New Zealand. Initial studies were limited by problems in the extraction processes, with activity being lost through heat treatment or freeze drying. 2 , 3

Chemistry

Although composition of the lipid fraction varies, possibly because of differing methods of collection, transport, and storage time, it is usually approximately 8% of the freeze-dried weight. 4 Triglycerides form the largest fraction, followed by free fatty acids, sterols, and phospholipids. Low levels of sterol esters are found in some samples. Fatty acids are predominantly polyunsaturated, mostly in the form of omega-3 (40% of total polyunsaturated fatty acids). Omega-6 fatty acids are present at far lower levels (about 5% of total polyunsaturated fatty acids). The major identified fatty acids are docosahexaenoic, eicosapentaenoic, and palmitic acids. Cholesterol is the major sterol (31% of total sterols) with smaller proportions of desmosterol/brassicasterol, 24-methylenecholesterol, trans-22-dehydrocholesterol, nordehydrocholesterol, and occelastrol. 4 Glycosaminoglycans, a group of unbranched carbohydrates of high molecular weight, are also present; chondroitin sulfate is of particular interest.

Pernin, a nonpigmented, glycosylated protein, has been identified in the Perna mussel, is rich in histine and aspartic acid. Potential functions for this protein may be in binding divalent cations and serine protease inhibition. 5 Freeze-dried Perna mussel powder contains the amino acids glutamine and methionine, vitamins E and C, and minerals zinc, copper, and manganese. 6 The preparation Seatone is a freeze-dried, concentrated powder of Perna lipid extract, while Lyprinol is a stabilized, super-critical fluid extract preparation containing the omega-3 essential fatty acids eicosapentaenoic and docosahexaenoic acids. 2 , 7

Uses and Pharmacology

Anti-inflammatory/Arthritis

In vitro studies demonstrate anti-inflammatory activity via inhibition of the metabolism of arachidonate and reduced formation of leukotrienes and prostaglandins. In vitro modulation of leukotrienes, cytokines, and immunoglobulin has been demonstrated. Such effects, as well as the inhibition of lipoxygenase and cycloxygenase enzymes, are attributed largely to the polyunsaturated fatty acid content. 7 , 8 , 9 , 10 In addition, the content of chondroitin sulfate, a major component of cartilage matrix and synovial fluid, is of interest. 6

Animal data

Studies in rats using an adjuvant-induced arthritis model as well as carrageenan-induced rat footpad swelling have generally demonstrated positive anti-inflammatory effects as measured by cytokine and splenocyte protein expression, radiology, paw-swelling, and pain scores. 11 , 12 , 13 , 14 , 15 , 16 Methodological issues have been noted with route of administration and differing preparations used.

Limited studies in dogs with arthritis have been conducted, with reductions in total arthritic scores observed. 6 , 17 Improvements in long-term pain and radiological assessments suggest efficacy to be less than that seen with traditional nonsteroidal anti-inflammatory medicines but greater than placebo, suggesting a place in therapy when NSAIDs are contraindicated. 17

Clinical data

Two systematic reviews have been published; one reviewing osteoarthritis and rheumatoid arthritis trials through 2005, including a highly publicized 1980 trial that reported benefits in patients with rheumatoid arthritis and osteoarthritis, 18 and the other including only osteoarthritis trials through 2007. 2 Generally, clinical trials investigating the use of Perna mussel extracts in arthritis are small and methodologically weak, due to a lack of consistency in product potency and dosing, an absence of placebo or comparator, or use of active placebo. Despite biological plausibility and limited evidence of efficacy in animal studies, there is little compelling evidence to support a therapeutic role for Perna extracts in the treatment or prevention of arthritis. However, the extract may have a place as adjunctive therapy, because some studies report analgesic effects. 2 , 3 , 18

Asthma

Leukotrienes are mediators of airway inflammation in asthma. They induce bronchoconstriction and increase mucus secretion and microvascular permeability, allowing infiltration of inflammatory cells (eg, eosinophils, neutrophils) into the airway. Perna mussel extract is thought to prevent this cascade by inhibiting leukotriene production. 8

Animal data

In a mouse model of allergic airways disease, Perna extract improved lung function as compared with fish oil, with positive changes in mucus hypersecretion and airway responsiveness. 19

Clinical data

Daytime wheezing was reduced in corticosteroid-naive patients with mild to moderate atopic asthma who received stabilized Perna mussel extract. 5 Morning peak expiratory flow (PEF) was increased in patients receiving mussel extract compared with those receiving placebo. However, mean forced expiratory volume in 1-second and in evening PEF did not differ between the 2 groups. 3 , 8

Other uses
Cancer

In a dose-escalation study, no evidence of tumor response was seen in advanced breast and prostate cancer patients. 20 Claims of efficacy in the treatment of cancer are unsubstantiated by clinical trials. 3 A study in rats found a limited effect of Lyprinol in preventing chemotherapy-induced intestinal mucositis. 21

Dysmenorrhea

In an ex vivo dysmenorrhea model, Perna mussel extract modified the spontaneous and oxytocin-induced contractions of the uterus. Use of Perna mussel as an adjunct to standard therapy with nonsteroidal anti-inflammatory drugs for dysmenorrhoea has been suggested. 22

GI

Mice with induced colitis receiving Perna mussel extract had less weight loss, lower disease activity index scores, smaller crypt area losses in the distal colon, and lower caecum and colon weights than placebo recipients. 23 In rats, oral administration of the mussel lipid fraction concomitantly with aspirin, indomethacin, tolmetin, or diclofenac reduced gastric mucosal damage caused by these drugs up to 100%. 16

Dosage

Limited trial data are available to inform therapeutic dosing.

In arthritis trials, dosages ranged from 1,150 24 to 1,500 mg/day of the stabilized lipid extract Lyprinol , 2 and 900 to 1,380 mg/day of the Seatone preparation. 2 In a dose-escalation study, 1,560 to 4,160 mg/day of Lyprinol was used. 20

Pregnancy/Lactation

An extract of Perna mussel has been shown to modify spontaneous and oxytocin-induced contractions of the uterus. 22 Proprietary preparations of mussel extract fed to pregnant rats retarded fetal development and delayed parturition (the action of giving birth), suggesting that the product contains an orally active prostaglandin inhibitor. 25 Other prostaglandin inhibitors, such as aspirin, indomethacin, and naproxen, are known to interfere with ovulation and prolong gestation periods in rats. The clinical importance of these findings is unclear.

Interactions

None well documented.

Adverse Reactions

Studies with Perna mussel and its extracts have reported a low incidence of adverse effects, generally consisting of GI symptoms (eg, diarrhea, flatulence, nausea), and transient worsening of arthritic pain. 20 , 25 , 26 In a dose-escalation study with Lyprinol , liver function abnormalities were noted in 1 patient who had normal liver function at the start of the study. 20 In an older publication, granulomatous hepatitis, jaundice, colicky epigastric pain, anorexia, and malaise were described in a 64-year-old woman taking Perna mussel. 25

Symptoms suggestive of occupational asthma and lung function abnormalities, possibly an immunoglobulin E-mediated allergic reaction, have been associated with workers in green-lipped mussel processing plants. 27

Toxicology

Information is limited. Neurotoxic food poisoning has been reported from the consumption of fresh Perna shellfish; however, immersion for at least 3 minutes in boiling water has been shown to decrease the risks of viral food-borne infections, such as hepatitis A and norovirus. 28 , 29 Heavy metal exposure from Perna consumption has been estimated to be well below accepted maximum limits. 30 In a study evaluating the efficacy of Perna extracts in rats, no changes in organ weight or histological or biochemical changes were noted. 11

Bibliography

1. Catches and Landings. In: Yearbook of Fishery Statistics . Vol. 62. Rome: Food and Agriculture Organization of the United Nations; 1988.
2. Brien S, Prescott P, Coghlan B, Bashir N, Lewith G. Systematic review of the nutritional supplement Perna canaliculus (green-lipped mussel) in the treatment of osteoarthritis. QJM . 2008;101(3):167-179.
3. Doggrell SA. Lyprinol —is it a useful anti-inflammatory agent? Evid Based Complement Alternat Med . April 21, 2009. [Epub ahead of print]
4. Murphy KJ , Mann NJ , Sinclair AJ . Fatty acid and sterol composition of frozen and freeze-dried New Zealand Green Lipped Mussel ( Perna canaliculus ) from three sites in New Zealand. Asia Pac J Clin Nutr . 2003;12(1):50-60.
5. Scotti PD, Dearing SC, Greenwood DR, Newcomb RD. Pernin: a novel, self-aggregating haemolymph protein from the New Zealand green-lipped mussel, Perna canaliculus (Bivalvia: Mytilidae). Comp Biochem Physiol B Biochem Mol Biol . 2001;128(4):767-779.
6. Bierer TL, Bui LM . Improvement of arthritic signs in dogs fed green-lipped mussel ( Perna canaliculus ). J Nutr . 2002;132(6 suppl 2);S1634-S1636.
7. McPhee S, Hodges LD, Wright PF, et al. Anti-cyclooxygenase effects of lipid extracts from the New Zealand green-lipped mussel, Perna canaliculus . Comp Biochem Physiol B Biochem Mol Biol . 2007;146(3):346-356.
8. Emelyanov A , Fedoseev G , Krasnoschekova O , Abulimity A , Trendeleva T , Barnes PJ . Treatment of asthma with lipid extract of New Zealand green-lipped mussel: a randomised clinical trial. Eur Respir J . 2002;20(3):596-600.
9. Treschow AP, Hodges LD, Wright PF, Wynne PM, Kalafatis N, Macrides TA. Novel anti-inflammatory omega-3 PUFAs from the New Zealand green-lipped mussel, Perna canaliculus . Comp Biochem Physiol B Biochem Mol Biol . 2007;147(4):645-656.
10. Mani S, Lawson JW. In vitro modulation of inflammatory cytokine and IgG levels by extracts of Perna canaliculus . BMC Complement Altern Med . 2006;6:1.
11. Singh M, Hodges LD, Wright PF, et al The CO2-SFE crude lipid extract and the free fatty acid extract from Perna canaliculus have anti-inflammatory effects on adjuvant-induced arthritis in rats. Comp Biochem Physiol B Biochem Mol Biol . 2008;149(2):251-258.
12. Lee CH, Butt YK, Wong MS, Lo SC. Differential protein expression induced by a lipid extract of Perna canaliculus in splenocytes of rats with adjuvant-induced arthritis. Inflammopharmacology . 2008;16(4):188-194.
13. Lee CH, Lum JH, Ng CK, et al. Pain Controlling and Cytokine-regulating Effects of Lyprinol , a Lipid Extract of Perna Canaliculus , in a Rat Adjuvant-induced Arthritis Model. Evid Based Complement Alternat Med . 2009;6(2):239-245.
14. Lawson BR, Belkowski SM, Whitesides JF, Davis P, Lawson JW. Immunomodulation of murine collagen-induced arthritis by N, N-dimethylglycine and a preparation of Perna canaliculus . BMC Complement Altern Med . 2007;7:20.
15. Miller TE , Ormrod D . The anti-inflammatory activity of Perna canaliculus (NZ green lipped mussel). N Z Med J . 1980;92(667):187-193.
16. Rainsford KD , Whitehouse MW. Gastroprotective and anti-inflammatory properties of green lipped mussel ( Perna canaliculus ) preparation. Arzneimittelforschung . 1980;30(12):2128-2132.
17. Hielm-Björkm an A, Tulamo RM, Salonen H, Raekallio M. Evaluating Complementary Therapies for Canine Osteoarthritis Part I: Green-lipped Mussel ( Perna canaliculus ). Evid Based Complement Alternat Med . 2009;6(3):365-373.
18. Cobb CS, Ernst E. Systematic review of a marine nutriceutical supplement in clinical trials for arthritis: the effectiveness of the New Zealand green-lipped mussel Perna canaliculus . Clin Rheumatol . 2006;25(3):275-284.
19. Wood LG, Hazlewood LC, Foster PS, Hansbro PM. Lyprinol reduces inflammation and improves lung function in a mouse model of allergic airways disease. Clin Exp Allergy . 2010;40(12):1785-1793.
20. Sukumaran S, Pittman KB, Patterson WK, et al. A phase I study to determine the safety, tolerability and maximum tolerated dose of green-lipped mussel ( Perna canaliculus ) lipid extract, in patients with advanced prostate and breast cancer. Ann Oncol . 2010;21(5):1089-1093.
21. Torres DM, Tooley KL, Butler RN, Smith CL, Geier MS, Howarth GS. Lyprinol only partially improves indicators of small intestinal integrity in a rat model of 5-fluorouracil-induced mucositis. Cancer Biol Ther . 2008;7(2):295-302.
22. Shiels IA , Whitehouse MW . Lyprinol : anti-inflammatory and uterine-relaxant activities in rats, with special reference to a model for dysmenorrhoea. Allerg Immunol . 2000;32(7):279-283.
23. Tenikoff D , Murphy KJ , Le M , Butler RN , Howarth GS , Howe PR . Lyprinol : a potential preventive treatment for experimental inflammatory bowel disease (IBD). Asia Pac J Clin Nutr . 2004;13(suppl):S94.
24. Gibson RG , Gibson SL , Conway V , Chappell D . Perna canaliculus in the treatment of arthritis. Practitioner . 1980;224(1347):955-960.
25. Green-lipped mussel extract in arthritis. Lancet . 1981;1(8211):85.
26. Cho SH , Jung YB , Seong SC , et al. Clinical efficacy and safety of Lyprinol , a patented extract from New Zealand green-lipped mussel ( Perna canaliculus ) in patients with osteoarthritis of the hip and knee: a multicenter 2-month clinical trial. Allerg Immunol . 2003;35:212-216.
27. Glass WI , Power P , Burt R , Fishwick D , Bradshaw LM , Pearce NE . Work-related respiratory symptoms and lung function in New Zealand mussel openers. Am J Ind Med . 1998;34(6):163-168.
28. Ishida H, Nozawa A, Nukaya H, Tsuji K. Comparative concentrations of brevetoxins PbTx-2, PbTx-3, BTX-B1 and BTX-B5 in cockle, Austrovenus stutchburyi , greenshell mussel, Perna canaliculus , and Pacific oyster, Crassostrea gigas , involved neurotoxic shellfish poisoning in New Zealand. Toxicon . 2004;43(7):779-789.
29. Hewitt J, Greening GE. Effect of heat treatment on hepatitis A virus and norovirus in New Zealand greenshell mussels ( Perna canaliculus ) by quantitative real-time reverse transcription PCR and cell culture. J Food Prot . 2006;69(9):2217-2223.
30. Whyte AL, Hook GR, Greening GE, et al. Human dietary exposure to heavy metals via the consumption of greenshell mussels ( Perna canaliculus Gmelin 1791) from the Bay of Islands, northern New Zealand. Sci Total Environ . 2009;407(14):4348-4355.

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