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An Evidence-Based Systematic Review of Green-Lipped Mussel (Perna canaliculus) by the Natural Standard Research Collaboration Catherine Ulbricht, PharmD Wendy Chao, PhD Dawn Costa, BA, BS Yen Nguyen, PharmD Erica Seamon, PharmD Wendy Weissner, BA
ABSTRACT. This paper is an evidence-based systematic review including written and statistical analysis of scientific literature, expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing. Search strategy. To prepare each Natural Standard review, electronic searches are conducted in nine databases, including AMED, CANCERLIT, CINAHL, CISCOM, the Cochrane Library, EMBASE, HerbMed, International Pharmaceutical Abstracts, Medline, and NAPRALERT. Search terms include the common name(s), scientific name(s), and all listed synonyms for each topic. Hand searches are conducted of 20 additional journals (not Catherine Ulbricht is affiliated with the Massachusetts General Hospital and the Natural Standard Research Collaboration Wendy Chao, Dawn Costa, and Wendy Weissner are affiliated with the Natural Standard Research Collaboration Yen Nguyen is affiliated with the Massachusetts College of Pharmacy and the Natural Standard Research Collaboration Erica Seamon is affiliated with the Nova Southeastern University and the Natural Standard Research Collaboration Address correspondence to: Catherine Ulbricht (
[email protected])
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Journal of Dietary Supplements, Vol. 6(1), 2009 Available online at www.informaworld.com/WJDS C 2009 by Informa Healthcare USA, Inc. All rights reserved. doi: 10.1080/19390210802690191
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indexed in common databases), and of bibliographies from 50 selected secondary references. No restrictions are placed on language or quality of publications. Researchers in the field of complementary and alternative medicine (CAM) are consulted for access to additional references or ongoing research. Selection Criteria. All literature is collected pertaining to efficacy in humans (regardless of study design, quality, or language), dosing, precautions, adverse effects, use in pregnancy/lactation, interactions, alteration of laboratory assays, and mechanism of action (in vitro, animal research, human data). Standardized inclusion/exclusion criteria are utilized for selection. Data Analysis. Data extraction and analysis are performed by healthcare professionals conducting clinical work and/or research at academic centers, using standardized instruments that pertain to each review section (defining inclusion/exclusion criteria and analytic techniques, including validated measures of study quality). Data are verified by a second reviewer. Review Process. A blinded review is conducted by multidisciplinary research-clinical faculty at major academic centers with expertise in epidemiology and biostatistics, pharmacology, toxicology, CAM research, and clinical practice. In cases of editorial disagreement, a three-member panel of the Editorial Board addresses conflicts, and consults experts when applicable. Authors of studies are contacted when clarification is required. KEYWORDS. Adverse effects, green-lipped mussel (Perna canaliculus), dosing, evidence-based, interactions, pharmacodynamics, pharmacology, pharmacokinetics, systematic review
Synonyms/Common Names/Related Substances: Betain, brevetoxin B analog B4 (BTXB4), chondroitin sulfate, eicosatetraenoic acids, freeze-dried mussel powder, glycosaminoglycans, green lipped mussel, R R R R Green Lips , green shell mussel, Greenback , Greenshell , Greenshell R Mussel, heparin, Lyprinol , marine oils, mollusk, Mytilidae (family), New Zealand green-lipped mussel, okadaic acid, pectenotoxins, Perna canaliculus, pernin, shellfish lipid extract, Seatone, sterol esters, yessotoxins. R Combination product examples: Sanhelios Mussel Lyprinol Lipid Complex (green-lipped mussel extract and omega-3 fatty acids), PernaTM Plus (green-lipped mussel extract, glucosamine sulfate, methylsulfonylmethane, manganese acid chelate).
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CLINICAL BOTTOM LINE/EFFECTIVENESS Brief Background
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r The green-lipped mussel (Perna canaliculus) is native to the New Zealand coast, and is a staple diet of the indigenous Maori culture (particularly those who live in coastal regions). r Interest in the health benefits of green-lipped mussel stemmed from the observation that coastal Maoris had lower incidence of arthritis than their European or inland Maori cohorts (Halpern & Georges, 2000). Thus, the anti-inflammatory effects of green-lipped mussel have been studied extensively in vitro, in vivo, and in clinical trials. r Green-lipped mussel products have been proposed as adjunct therapies for a number of inflammatory conditions (Ferreira, 2005) including asthma, osteoarthritis, and rheumatoid arthritis. r There is limited evidence for the use of green-lipped mussel for treating asthma, but the preliminary evidence is encouraging. Its most popular use, besides as food, is to help relieve joint pain and inflammatory joint disorders; while there is some evidence supporting the use of green-lipped mussel in treating osteoarthritis, the overall evidence for rheumatoid arthritis suggests inefficacy.
Scientific Evidence for Common/Studied Uses Indication
Evidence Grade
Asthma Osteoarthritis Rheumatoid arthritis
C C D
Natural Standard evidence-based validated grading rationaleTM
r Grades reflect the level of available scientific evidence in support of the efficacy of a given therapy for a specific indication.
r Expert opinion and folkloric precedent are not included in this assessment, and are reflected in a separate section of each review (“Strength of Expert Opinion and Historic/Folkloric Precedent”). r Evidence of harm is considered separately; the below grades apply only to evidence of benefit.
Ulbricht et al. Level of Evidence Grade
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A (Strong Scientific Evidence)
B (Good Scientific Evidence)
C (Unclear or conflicting scientific evidence)
D (Fair Negative Scientific Evidence)
F (Strong Negative Scientific Evidence) Lack of Evidence†
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Statistically significant evidence of benefit from >2 properly randomized trials (RCTs), OR evidence from one properly conducted RCT AND one properly conducted meta-analysis, OR evidence from multiple RCTs with a clear majority of the properly conducted trials showing statistically significant evidence of benefit AND with supporting evidence in basic science, animal studies, or theory. Statistically significant evidence of benefit from 1–2 properly randomized trials, OR evidence of benefit from >1 properly conducted meta-analysis OR evidence of benefit from >1 cohort/case-control/nonrandomized trials AND with supporting evidence in basic science, animal studies, or theory. Evidence of benefit from >1 small RCT(s) without adequate size, power, statistical significance, or quality of design by objective criteria, ∗ OR conflicting evidence from multiple RCTs without a clear majority of the properly conducted trials showing evidence of benefit or ineffectiveness, OR evidence of benefit from >1 cohort/case-control/nonrandomized trials AND without supporting evidence in basic science, animal studies, or theory, OR evidence of efficacy only from basic science, animal studies, or theory. Statistically significant negative evidence (i.e., lack of evidence of benefit) from cohort/case-control/nonrandomized trials, AND evidence in basic science, animal studies, or theory suggesting a lack of benefit. Statistically significant negative evidence (i.e., lack of evidence of benefit) from >1 properly randomized adequately powered trial(s) of high-quality design by objective criteria.* Unable to evaluate efficacy due to lack of adequate available human data.
∗ Objective criteria are derived from validated instruments for evaluating study quality, including the 5-point scale developed by Jadad et al., in which a score below 4 is considered to indicate lesser quality methodologically (Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Controlled Clinical Trials 1996; 17[1]:1–12). † Listed separately in reviews in the “Historical or Theoretical Uses which Lack Sufficient Evidence” section.
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Historical or Theoretical Uses Which Lack Sufficient Evidence
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r Abortifacient (uterine contraction stimulant) (Shiels & Whitehouse, 2000), ankylosing spondylitis, antihistamine, anti-inflammatory (Butters & Whitehouse, 2003; Halpern, 2000a; Halpern & Georges, 2000; McPhee et al., 2007; Meletis, 2000; Miller, Dodd, Ormrod, & Geddes, 1993; Miller & Ormrod, 1980; Shiels & Whitehouse, 2000; Whitehouse et al., 1997; Whitehouse, 2004; Yuan, Wahlqvist, He, Yang, & Li, 2006; ), atopic dermatitis, breast cancer (Anon, 1999 ), bursitis, cardiovascular disease (Sinclair, Murphy, & Li, 2000), connective tissue disorders, dysmenorrhea (Shiels & Whitehouse, 2000), eye disorders (retinal disorders) (Sinclair et al., 2000), inflammatory bowel disease (Tenikoff, Murphy, Le, Howe, & Howarth, 2005), inflammatory joint disease (Couch, Ormrod, Miller, & Watkins, 1982; Whitehouse, 2004), Lyme disease, mucositis (Torres et al., 2008), multiple sclerosis, nerve disorders (Sinclair et al., 2000), prostate cancer ( Anon, 1999 ), psoriasis, sports injuries, systemic lupus erythematosus (prevention) (Mani & Lawson, 2006), ulcers (NSAID-induced). Expert Opinion and Historic/Folkloric Precedent
r As a food or as a dietary supplement, green-lipped mussel is not regulated by the U.S. Food and Drug Administration (FDA). It is not listed in the FDA GRAS (Generally Recognized as Safe) list as a food additive. r The anti-inflammatory effects of green-lipped mussel have been studied extensively. Green-lipped mussel products have been proposed as adjunct therapies to a number of standard treatments for chronic inflammatory conditions (Ferreira, 2005). r Rigorous clinical trials that examine the purported 5-lipoxygenase R (5-LOX) inhibitory activity of Lyprinol green-lipped mussel extract (Whitehouse, 2002), as well as its purported ability to inhibit cyclooxygenase (COX) enzyme activity are warranted (Whitehouse, 2005). r Most of the anti-inflammatory activity of green-lipped mussel is believed to be in the lipid fraction. According to industry, the original freeze-dried powder preparations are up to 125 times less potent than stabilized lipid R extracts (such as Lyprinol ), and many currently available powders have little or no anti-inflammatory activity. The delipidated byproducts of the extraction process, which also have very little (if any) anti-inflammatory activity, have also been packaged and sold in low cost green-lipped mussel products (Halliday, 2008).
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Brief Safety Summary
r Likely safe: When eaten in moderation, due to its long history of use in the Maori diet (Halpern & Georges, 2000).
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r Possibly safe: When handling green-lipped mussels, although there have been occupational case reports of lung dysfunction and multiple respiratory symptoms in New Zealand mussel openers (Glass et al., 1998). r Possibly unsafe: When used in immunosuppressed patients, or in patients not vaccinated against the polio virus (Greening, Dawson, & Lewis, 2001). When used in patients with pulmonary disorders such as asthma (Emelyanov et al., 2002; Glass et al., 1998; Halpern, 2000b). r Likely unsafe: When used in patients with hepatitis or other hepatic disorders (MacKenzie et al., 2002; Miles et al., 2004; Suzuki, MacKenzie, Stirling, & Adamson, 2001); possible toxic hepatitis has been associated with Seatone in several case reports (Ahern, Milazzo, & Dymock, 1980; Croft, 1980; Fabrin, 1988). When used in patients with neurotoxicity (Ishida et al., 2004; Morohashi et al., 1999). When used in allergic patients (Glass et al., 1998). When used in patients who are pregnant or breastfeeding (Miller & Wu, 1984; Shiels & Whitehouse, 2000). r Note: Green-lipped mussel appears to be generally well tolerated in nonallergic people (Cho et al., 2003; Halpern & Georges, 2000), and secondary sources suggest that heavy metal contamination is usually not a concern (unlike oysters). However, the B4 analog of brevetoxin B (BTXB4), has been associated with neurotoxic shellfish poisoning (Ishida et al., 2004; Morohashi et al., 1999). Complete toxin profiles of green-lipped mussel may also include yessotoxins (YTXs), pectenotoxins (PTXs), and low levels of okadaic acid (OA) (MacKenzie et al., 2002; Miles et al., 2004; Suzuki et al., 2001). Possible toxic hepatitis has been associated with Seatone in several case reports (Ahern et al., 1980; Croft, 1980; Fabrin, 1988). DOSING/TOXICOLOGY General
r Recommended doses are based on those most commonly used in available trials or on historical practice. However, with natural products it often is not clear what the optimal doses are to balance efficacy and safety. Preparation of products may vary from manufacturer to manu-
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facturer, and from batch to batch within one manufacturer. Because it often is not clear what the active component(s) of a product is, standardization may not be possible, and the clinical effects of different brands may not be comparable.
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Standardization
r There is no well-known standardization for green-lipped mussel. Greenlipped mussels provide omega-3 fatty acids, and each capsule of R Lyprinol is standardized to contain 50 mg omega-3 fatty acids and 100 mg olive oil (Emelyanov et al., 2002). Dosing: Adult (age ≥18): Oral:
r General: According to Internet websites, oral green-lipped mussel supplementation typically consists of about 200 mg daily of lipid extract, or 1,000 mg daily of the powdered form. r Asthma: Two capsules of LyprinolR (containing 50 mg of omega3 polyunsaturated fatty acids and 100 mg olive oil per capsule) has been used twice daily for eight weeks for steroid-na¨ıve atopic asthma (Emelyanov et al., 2002). r Osteoarthritis: Green-lipped mussel has been used in the following doses to treat osteoarthritis: 1,050 mg mussel extract (three capsules) daily for 3–6 months (Gibson, Gibson, Conway, & Chappell, 1980), six capsules Seatone daily (no details given) for six months (Audeval R & Bouchacourt, 1986), 210 mg Lyprinol (or 1,150 mg mussel powder) daily for 3–6 months (Gibson & Gibson, 1998), or four capsules R Lyprinol daily (dose not specified) for two months followed by four R months of two capsules daily (Lau et al., 2004). Lyprinol was used as a 5-LOX inhibitor for osteoarthritis at a dosage of two capsules twice daily for 4–8 weeks (Cho et al., 2003). r Rheumatoid arthritis: Mussel extract capsules have been used daily for R 90 days (Gibson et al., 1980). A 210 mg Lyprinol has been used daily for three to six months (Gibson & Gibson, 1998). For inflammatory R rheumatoid arthritis, an unclear dose of Sanhelios Mussel Lyprinol Lipid Complex (a “special combination of Lyprinol and omega-3 fatty
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acids”) has been used for 12 weeks (Gruenwald, Graubaum, Hansen, & Grube, 2004). Children (age 1 SD r Medium: if 0.5 to 0.9 SD r Small: if 0.2 to 0.4 SD P = Pending Verification: In many cases, studies do not report the SD of change of the outcome measure. However, the change in the SD of the outcome measure (also known as effect size) can be calculated, and is derived by subtracting the mean (or mean difference) in the placebo/control group from the mean (or mean difference) in the treatment group, and dividing that quantity by the pooled SD (Effect size = [Mean Treatment – Mean Placebo]/SDp).
Absolute Risk Reduction This describes the difference between the percentage of people in the control/placebo group experiencing a specific outcome (control event rate), and the percentage of people in the experimental/therapy group experiencing that same outcome (experimental event rate). Mathematically, Absolute risk reduction (ARR) equals experimental event rate minus control event rate. ARR is better able to discriminate between large and small treatment effects than relative risk reduction (RRR), a calculation that is often cited in studies ([control event rate—experimental event rate]/control event rate). Many studies do not include adequate data to calculate the ARR, in which cases “NA” is entered into this column. P = pending verification.
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Number Needed to Treat
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This is the number of patients who would need to use the therapy under investigation, for the period of time described in the study, in order for one person to experience the specified benefit. It is calculated by dividing the ARR into 1 (1/ARR). P = pending verification. Comments When appropriate, this brief section may comment on design flaws (inadequately described subjects, lack of blinding, brief follow up, not intention-to treat, etc.), notable study design elements (crossover, etc.), dosing, and/or specifics of study group/sub-groups (age, gender, etc). More detailed description of studies is found in the “Evidence Discussion” section that follows the “Evidence Table” in Natural Standard reviews. EVIDENCE DISCUSSION Asthma
r Summary: Limited evidence suggests that green-lipped mussel supplementation may be of benefit in allergic diseases, such as atopic asthma. Additional research is needed before a recommendation can be made. r Randomized trials: Emelyanov et al. (2002) conducted a randomized controlled trial to assess the effects of green-lipped mussel lipid extract R (Lyprinol ) on airway inflammation in patients with steroid-na¨ıve atopic asthma (Emelyanov et al., 2002). The study analyzed 46 patients, aged between 18 and 56, with diagnoses of atopic asthma classified to the National Institutes of Health/World Health Organization (NIH/WHO) guidelines. Treatment consisted of two capsules of green-lipped mussel lipid extract, each containing 50 mg of omega-3 polyunsaturated fatty acids (eicosapentaenoic and docosahexaenoic acid) and 100 mg olive oil (Mac Lab, Melbourne, Australia); placebo capsules contained 150 mg of olive oil only. Treatment or placebo capsules were taken twice daily orally for eight weeks. All patients completed the study; treatment appeared to be well tolerated, with only two patients (one in each group) complaining of itch and three patients (one treatment, two placebo) complaining of metallic taste. Asthma symptoms were recorded by the patients in a journal; peak expiratory flow (PEF) and hydrogen peroxide
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(H2 O2 ) in expired breath condensate were assessed as measures of airway inflammation. Compared to the placebo group, treatment was associated with significantly decreased daytime wheeze and concentration of exhaled H2 O2 and increased morning PEF. This study was of strong methodological design, and suggested that green-lipped mussel supplementation may positively benefit patients with atopic asthma. This study was reviewed by Halpern and Georges (2000). Osteoarthritis
r Summary: There is conflicting evidence supporting the efficacy of green-lipped mussel supplementation for treating osteoarthritis, and there has been a good deal of controversy surrounding this topic (Gibson & Gibson, 1981b; Gibson & Gibson, 1981c; Gibson & Gibson, 1985; Author, 1981 ). Reliable evidence is needed to resolve the controversial efficacy of green-lipped mussel for this indication. r Preclinical evidence: In veterinary studies, green-lipped mussel preparations have been well tolerated, and shown to improve symptoms in arthritic dogs (Bierer & Bui, 2002; Bui & Bierer, 2003; Pollard, Guilford, Ankenbauer-Perkins, & Hedderley, 2006). r Systematic reviews: Brien et al. performed a systematic review of published literature regarding green-lipped mussel supplementation as a complementary treatment for osteoarthritis (Brien et al., 2008). Cochrane Library, Medline, Embase, Amed, Cinahl, Scopus, and NeLH databases were searched for clinical trials of adult patients with osteoarthritis of any joint. Studies considered included those that were randomized, quasi-randomized, comparative, placebo controlled, and/or crossover design. No studies were found that compared green-lipped mussel to standard treatment in osteoarthritis. However, four randomized controlled trials were identified. Three were placebo controlled (Audeval & Bouchacourt, 1986; Gibson et al., 1980; Lau et al., 2004), and one compared lipid extract of green-lipped mussel with stabilized mussel powder and was essentially an equivalence trial rather than a true randomized controlled trial (Gibson & Gibson, 1998). Altogether, these studies evaluated 201 subjects in total (male and female) with mean age of 68.8 (total group) (Gibson et al., 1980), 65 (extract group) or 66 (placebo group) (Audeval & Bouchacourt, 1986), 57.3 (green-lipped mussel extract group) or 52.8 (mussel powder group) (Gibson & Gib R son, 1998), and 62.1 (Lyprinol group) or 62.9 (placebo group) (Lau et al., 2004). Each of these studies used green-lipped mussel extract as
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an adjunct to conventional treatments of mild to moderate osteoarthritis. Doses used were as follows: 1,050 mg mussel extract taken orally daily for three to six months (Gibson et al., 1980), six capsules Seatone taken orally daily (no details given) for six months (Audeval & Boucha R court, 1986), 210 mg Lyprinol (or 1,150 mg mussel powder) taken orally daily for 3–6 months (Gibson & Gibson, 1998), and four cap R sules Lyprinol daily taken orally (dose not specified) for two months followed by four months of two capsules daily (Lau et al., 2004). Three of the studies reported adverse effect information: eight (12%) treatment group vs. one (2%) placebo group (Gibson et al., 1980), one (7%) in each treatment group (Gibson & Gibson, 1998), and three (7.5%) treatment group vs. one (2.5%) placebo group (Lau et al., 2004). Various outcome measures were used, including degree and duration of morning stiffness, visual analog scale (VAS) pain, joint mobility, and night pain. Each study reported overall benefits achieved with supplementation. Two studies were excluded from analysis due to inappropriate blinding and statistical analysis (Gibson et al., 1980; Gibson & Gibson, 1998). The remaining two studies (Audeval & Bouchacourt, 1986; Lau et al., 2004), which were of higher methodological quality, suggested that green-lipped mussel may offer greater clinical benefits than placebo for treating mild to moderate osteoarthritis. Citing credible evidence of anti-inflammatory activity of the omega-3 fatty acids in green-lipped mussel, which may underlie this purported benefit, the authors called for further research to determine the efficacy and optimal dosage of green-lipped mussel for osteoarthritis treatment. r Cobb and Ernst conducted a systematic review of clinical trials that tested the efficacy of green-lipped mussel supplementation in treating osteoarthritis (Cobb & Ernst, 2006). Systematic literature searches were performed to identify all published articles that examined green-lipped mussel supplementation in Medline, PubMed, Cochrane Library, and EMBASE (through February 2005). Two randomized controlled trials were identified that used green-lipped mussel for treating osteoarthritis (Audeval & Bouchacourt, 1986; Gibson et al., 1980). Two additional studies of lesser design strength were also evaluated: an equivalence trial R comparing Seatone powdered mussel extract with Lyprinol lipid extract (Gibson & Gibson, 1998), and an open-label trial of either PernaTM (500 mg green-lipped mussel extract and 100 mg alfalfa) or PernaTM Plus (500 mg green-lipped mussel extract, 300 mg glucosamine sulfate, 200 mg methylsulfonylmethane, and 5 mg manganese acid chelate) (Kendall et al., 2000). Data were systematically extracted by author
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and validated by a second author. Though the results largely supported the use of green-lipped mussel in osteoarthritis, methodological flaws, and inconsistent results preclude the recommendation of green-lipped mussel extract as a treatment for osteoarthritis. r Randomized trials: Lau et al. (2004) conducted a randomized, placebo R controlled, double-blind study to assess the efficacy of Lyprinol as an adjunct treatment for standard osteoarthritis therapy. Chinese patients (N= 80) with six-month diagnoses of knee osteoarthritis (without rheumatoid arthritis), and not taking omega-3 fatty acid supplements, R were randomized to receive either Lyprinol capsules (dose unclear) or placebo (olive oil capsules). Four capsules were taken daily orally for two months, followed by two capsules daily until the end of the study (week 24). Subjects ceased osteoarthritis medication one week before the trial, and continued to take 2 g acetaminophen daily taken orally throughout the trial. Additional acetaminophen was allowed as rescue medication. Randomization methods were not reported. This study was included in a systematic review by Brien et al. (2008). Five subjects R dropped out of the Lyprinol group: one cited lack of efficacy, one was later diagnosed with rheumatoid arthritis, and three developed adverse effects (nausea, abnormal liver function test, or heart failure). Eight subjects dropped out of the placebo: two refused to continue, three cited lack of efficacy, one required joint steroid injection, one developed abnormal liver function, and one did not comply. Outcome measures of osteoarthritis did not differ significantly between the two treatment R groups, except for patient global assessment (score reduced in Lyprinol group, but increased in placebo group). Although the data were inad R equate, the authors concluded that Lyprinol was well tolerated and associated with decreased pain perception. However, the clinical significance of this association remains unclear. r Audeval and Bouchacourt conducted a randomized controlled trial that examined Seatone as a treatment for knee osteoarthritis (Audeval & Bouchacourt, 1986). Parisian patients (53 total) were selected based on radiographic confirmation of osteoarthritis and clinically significant pain. Patients were excluded if debilitating symptoms were present or if intervening surgery was performed. Subjects took six capsules of Seatone or placebo (details unclear) taken orally daily for six months. A systematic review by Brien et al. (2008) cited inappropriate statistical analysis and assigned a Jadad score of 2; a separate systematic review by Cobb and Ernst (Cobb & Ernst, 2006) assigned a Jadad score of 4. Significant improvements in some outcome measures (pain, functional
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state, patient/physician global assessment) were observed in the treatment group, but not the placebo group. This study supported the use of Seatone in treating osteoarthritis; however, due to inappropriate statistical analysis and flaws in study design, the results should be interpreted with caution. r Gibson and Gibson conducted a randomized controlled trial of 38 patients with osteoarthritis (Gibson et al., 1980), which was included in two systematic reviews (Brien et al., 2008; Cobb & Ernst, 2006). Patients (who failed to respond to conventional treatment) were randomized to receive either capsules containing mussel extract (Seatone) or placebo (dried fish meal powder). Treatment or placebo was taken orally daily for 90 days, and outcome measures were assessed (joint stiffness, limbering up time, grip strength, joint tenderness, pain, functional efficiency, and walking speed. In the treatment group, six of the 16 patients showed improvement, as did three of the 22 patients in the placebo group. Reanalysis of the data by Brien et al. suggests a lack of benefit (Brien et al., 2008). In a second three-month phase of the study, all patients who responded well to the treatments (i.e., those who did not dropout) were given Seatone for an additional three months. This second phase was criticized for having lack of proper controls, as the subjects served as their own controls (Author, 1981 ); thus, the study was essentially a before-and-after comparison, rather than a true randomized controlled trial. Furthermore, the active treatment group was further divided into responders and nonresponders to Seatone, an unorthodox practice that potentially complicates the interpretation of the data (Author, 1981 ); this criticism was later acknowledged by the study authors (Gibson & Gibson, 1981a). The study was criticized by a later paper for improper blinding and statistical analysis (Huskisson et al., 1981). r Studies of lesser design strength: Cho et al. conducted a multicenter R clinical trial to evaluate the safety and clinical efficacy of Lyprinol green mussel extract as a 5-LOX inhibitor (Cho et al., 2003). In this study, 60 subjects with osteoarthritis of the knee and hip were adminis R tered two capsules of Lyprinol twice daily for four to eight weeks. No adverse events occurred during the trial. Outcome measures of efficacy were visual analog scale (VAS), Lequesne functional index, global assessment by patients, and global assessment by physician. After week four, 53% of patients experienced pain relief and improved joint function; this number increased to 80% after week eight. This prospective trial lacks several features of strong study design, such as randomization, placebo, and blinding.
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r Gibson and Gibson compared the effectiveness of green-lipped mussel
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R
powdered extract (Seatone) and lipid extract (Lyprinol ) in treating osteoarthritis and rheumatoid arthritis (Gibson & Gibson, 1998). In this study, 30 patients with osteoarthritis were randomized to receive either five capsules (1,150 mg) of Seatone daily, or three capsules (210 mg) R Lyprinol daily for three months. Thereafter, all subjects took lipid extract for an additional three months. There was no placebo group. Four subjects (two in each group) dropped out due to transportation difficulties. Outcome measures (patient and physician assessment) showed that 76% of rheumatoid and 70% of osteoarthritis patients experienced improved symptoms after three months. Three patients with rheumatoid arthritis, who responded particularly well to lipid treatment, were later described in a case series (Gibson, 2000). Because the number of capsules differed between the treatments (five vs. three capsules), the double-blind aspect of this study was questionable. The lack of a placebo arm further questions the validity of these results. This study was evaluated in two systematic reviews (Brien et al., 2008; Cobb & Ernst, 2006). r Kendall et al. (2000) conducted an uncontrolled evaluation (before and after comparison) of PernaTM (500 mg green-lipped mussel extract and 100 mg alfalfa) or PernaTM Plus (500 mg green-lipped mussel extract, 300 mg glucosamine sulfate, 200 mg methylsulfonylmethane, and 5 mg manganese acid chelate). This study followed 120 subjects with radiologically confirmed osteoarthritis over a one-year course of treatment. In 111 of 120 patients, NSAID intake was reported to be reduced by up to 50%; 83% of patients showed clinical improvement (assessed by physicians). This study was included in a systematic reviewed by Cobb and Ernst (Cobb & Ernst, 2006). Because the treatment was a combination product, it was excluded from the evidence table. Further analysis is needed to distinguish the effects of the individual constituents. Rheumatoid arthritis
r Summary: There is conflicting evidence supporting the efficacy of green-lipped mussel supplementation for treating rheumatoid arthritis, which has generated significant controversy (Gibson & Gibson, 1981b; Gibson & Gibson, 1981c; Gibson & Gibson, 1985; Author, 1981 ). Overall, the clinical evidence does not support the use of green-lipped mussel for treating rheumatoid arthritis. Other reviews of complementary rheumatic disease treatment found lack of evidence supporting the
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efficacy of green-lipped mussel (Jacobs, Rasker, Van Riel, Gribnau, & van de Putte, 1991; Darlington & Ramsey, 1994). Preclinical evidence: In veterinary studies, green-lipped mussel preparations have been well tolerated, and shown to improve symptoms in arthritic dogs (Bierer & Bui, 2002; Bui & Bierer, 2003; Pollard et al., 2006). Systematic reviews: Cobb and Ernst conducted a systematic review of the literature to examine green-lipped mussel supplementation in the treatment of osteoarthritis and rheumatoid arthritis (Cobb & Ernst, 2006). Systematic literature searches were performed to identify all published articles that examined green-lipped mussel supplementation in Medline, PubMed, Cochrane Library, and EMBASE (through February 2005). Five randomized controlled trials were identified that used green-lipped mussel for treating osteoarthritis (Audeval & Bouchacourt, 1986; Gibson et al., 1980). One additional equivalence trial compared R Seatone powdered mussel extract with Lyprinol lipid extract (Gibson & Gibson, 1998). Dosage information was unclear for these studies. Data were systematically extracted by author and validated by a second author. Four studies (Caughey, et al., 1983; Highton & McArthur, 1975; Huskisson et al., 1981; Larkin et al., 1985) found no significant difference between green-lipped mussel and placebo. The overall lack of effect precludes the recommendation for using green-lipped mussel extract as a treatment for rheumatoid arthritis. Randomized trials: Larkin et al. (1985) conducted a randomized controlled trial to examine the purported effectiveness of Seatone greenlipped mussel extract in treating rheumatoid arthritis. Subjects (N= 35), who were refractory to standard treatment, were randomized to receive either Seatone (20 patients) or placebo (15 patients). The active treatment consisted of one 230 mg Seatone capsule, taken four times daily orally for six months. The placebo was prepared to be indistinguishable from the active treatment. After six months of treatment, there were no statistically significant improvements in laboratory or clinical parameters of rheumatoid arthritis. There was a strong placebo effect; in fact, none of the patients in the placebo group reported worsening symptoms, yet six of the original 20 patients in the Seatone group felt worse after treatment. Though the randomization method was unclear, this study is otherwise of strong methodological design, and did not support the efficacy of green-lipped mussel in the treatment of rheumatoid arthritis. Highton and McArthur (1975) published the first clinical study examining the effect of green-lipped mussel extract on rheumatoid arthritis.
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In this double-blind crossover trial, six subjects were randomized to receive either Seatone capsules (containing green-lipped mussel powder) or placebo (identical placebo). There were no significant between-group differences in any of the outcome measures tested (pain, grip strength, articular index, limbering-up time, or walking time). All five subjects completing the study increased acetaminophen use, and showed no preference for treatment (Seatone) or placebo. This early study did not support the efficacy of Seatone in treating rheumatic disease. r Caughey et al. conducted a randomized controlled trial to test freezedried extracts of green-lipped mussel as a treatment for rheumatoid arthritis (Caughey et al., 1983). The study recruited 47 patients with rheumatoid arthritis, who were to discontinue other therapies before the experimental treatment. All subjects then started a naproxen regimen (750 mg daily for weeks 1–6, followed by placebo naproxen for weeks 7–23). The subjects were additionally randomized to receive either green-lipped mussel capsules 1,050 mg daily or identical placebo for 12 weeks. No significant difference was observed in any of the outcome measures between treatment arms (pain, grip strength, articular index, and morning stiffness). After withdrawal of naproxen, there was a high dropout rate due to joint pain (15 of 22 patients from the Seatone group and 15 of 19 patients from the placebo group). This study was included in a systematic review by Cobb and Ernst (2006) and suggests a lack of effect of Seatone in rheumatoid arthritis. r Huskisson et al. (1981) conducted a randomized, placebo controlled, crossover trial to test whether Seatone green-lipped mussel extract was superior to placebo for treating rheumatoid arthritis. Subjects (N= 30) were randomized to receive either Seatone (300 mg capsule, three times daily) or an identical foul-smelling placebo. Treatment (or placebo) was given for four weeks, followed by crossover to the alternate arm. Three patients in the treatment group dropped out due to side effects; one had headaches; another had diarrhea and headaches; the third suffered constipation. One patient dropped out of the placebo group for reasons unrelated to the study. All subjects responded to an advertisement for a Seatone clinical trial and thought they were taking Seatone; this was reflected in the strong placebo effect. Outcome measurements (pain, morning stiffness, articular index, proximal interphalangeal joint size, and analgesic consumption) were similar between active and placebo treatments. The method of randomization and blinding status were not stated in this brief report. A strong placebo effect was observed; it was noted that one patient on placebo was “so enthusiastic” about her treatment that she discontinued physiotherapy for rheumatoid arthritis.
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r Gibson and Gibson conducted a randomized controlled trial of 28 patients with rheumatoid arthritis (Gibson et al., 1980), which was included in a systematic review by Cobb and Ernst (2006). Patients (who failed to respond to conventional treatment) were randomized to receive either capsules containing mussel extract (Seatone) or placebo (dried fish meal powder). Treatment or placebo was taken orally daily for 90 days, and outcome measures were assessed (joint stiffness, limbering up time, grip strength, joint tenderness, pain, functional efficiency, and walking speed). In the treatment group, 10% reported a transient worsening of symptoms; no other adverse events were experienced. However, 68% of rheumatoid arthritis patients experienced overall improvements. In a second three-month phase of the study, all patients who responded well to the treatments (i.e., those who did not drop out) were given Seatone for an additional three months. This second phase was criticized for having lack of proper controls, as the subjects served as their own controls (Author, 1981 ). Furthermore, the active treatment group was further divided into responders and nonresponders to Seatone, an unorthodox practice that potentially complicates the interpretation of the data (Author, 1981 ); this criticism was later acknowledged by the study authors (Gibson & Gibson, 1981a). The study was criticized by a later paper for improper blinding and statistical analysis (Huskisson et al., 1981). A parallel study evaluated 38 osteoarthritis patients, which was re-analyzed by Brien et al. and found to suggest lack of benefit (Brien et al., 2008). r Studies of lesser design strength: Gibson and Gibson conducted a R double-blind equivalence study which examined Lyprinol green-lipped mussel extract in the treatment of rheumatoid arthritis (38); this study was systematically reviewed by Cobb and Ernst (Cobb & Ernst, 2006). R Thirty patients were randomized to receive either 210 mg Lyprinol (three capsules, N= 15) or 1,150 mg of stabilized mussel powder (five capsules, N= 15). Treatment (or placebo) was taken orally daily for R three months, followed by three months of Lyprinol treatment for all subjects. Adverse events were mild and rare (one case each of fluid retention and transient nausea). Outcome measures included articular index of joint tenderness (AI), morning stiffness or limbering-up-time (LUT), grip strength, VAS of pain, and functional index (FI). After the three-month treatment, 76% of rheumatoid arthritis patients reported benefits in AI, LUT, and FI. This study also examined 30 patients with osteoarthritis, reviewed by Brien et al. (2008). Because the number of capsules differed between the treatments (five vs. three capsules), the
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double-blind aspect of this study was questionable. The lack of a placebo arm further questions the validity of these results. r Gruenwald et al. (2004) conducted a clinical trial to evaluate the efficacy of a mussel-lipid preparation on inflammatory rheumatoid arthritis. Subjects in the trial had diagnoses of rheumatoid joint disorders with at least moderate pain and morning stiffness. Potential subjects were excluded if they were pregnant, breastfeeding, or had severe symptoms of rheumatism requiring immediate treatment. Adult men and women (50 total) took one Sanhelios Mussel Lyprinol Lipid Complex capsule, containing 458 mg of fish oil concentrate (50% EPA and 50% DHA) and 35 mg Lyprinol, twice daily (morning and evening) for two days; thereafter, the dosage was increased to two capsules twice daily. Treatment lasted for 12 weeks. Seven mild adverse events were noted. One case of mild nausea and vomiting was attributed to the treatment, and suggested to be due to fish oil aversion; this nausea improved by the end of the trial. The majority of patients and physicians (98%) assessed the tolerability of the study medication as “very good” or “good.” Of the 50 subjects, 34 required drug therapy before the study; by the end of the study, 21 were able to reduce medication, and 13 terminated drug therapy completely. One patient withdrew from the study at day 70; reasons for withdrawal were not specified. At the conclusion of the study, 38% of the patients were reported to be symptom-free. At six weeks, morning stiffness was reduced significantly in the treatment group from baseline measures of 13.7 ± 5.9 min by 1.3 ± 5.2 min (9.5%, p = .005). At the end of the trial (12 weeks), morning stiffness was reduced by 2.1 ± 3.8 min (15.3%, p ≤ .001). Number of painful joints was reduced significantly from 4.18 ± 2.80 at baseline by 0.30 ± 0.81 joints (7.2%, p = .012) after 6 weeks and 0.60 ± 1.18 joints (14.4%, P = .001) after 12 weeks. The number of swollen joints was reduced significantly from 2.62 ± 2.29 at baseline by 0.36 ± 0.78 joints (13.7%, p = 0.002) after six weeks and 0.68 ± 1.00 joints (26.0%, p = .001) after 12 weeks. The number of painful small joints was significantly reduced after 6 weeks (9.3%; p = .022) and after 12 weeks (18.6%; p = .002). Pain intensity, evaluated using a five-point scale (0 = no pain; 4 = very severe pain) was reduced successively during the course of the trial. According to physician assessments, the pain intensity decreased from moderate or severe to mild in 44% (n = 22) of treated patients by the completion of the study; 38% (n = 19) of patients reported this level of pain reduction. Patients with severe pain decreased from 60% at baseline to 25% at the end of the study. Limitations of the study include lack of a control group (and thus lack of randomization or blinding); thus, it is difficult to
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attribute any of the observed effects to Lyprinol or the other constituents of the treatment capsules. PRODUCTS STUDIED
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Brands Used in Statistically Significant Clinical Trials
r LyprinolR (Cho et al., 2003; Emelyanov et al., 2002; Lau et al., 2004; McPhee et al., 2007); PernaTM and PernaTM Plus (DaVinci Laboratories, R USA) (Kendall et al., 2000), Sanhelios Mussel Lyprinol Lipid Complex (Gruenwald et al., 2004); Seatone (Audeval & Bouchacourt, 1986; Gibson et al., 1980; Gibson & Gibson, 1998). Four studies (Caughey, et al., 1983; Highton & McArthur, 1975; Huskisson et al., 1981; Larkin et al., 1985) found no significant difference between Seatone and placebo. REFERENCES Ahern MJ, Milazzo SC, Dymock R. Granulomatous hepatitis and Seatone. Med J Aust. 1980;2(3):151–152. Audeval B, Bouchacourt P. Etude contrˆol´ee, en double aveugle contre placebo, de l’extrait de moule Perna canaliculus (moule aux orles verts) dans la gonarthose (Double blind, placebo-controlled study of the mussel Perna canaliculus (New Zealand green-lipped mussel) in arthritis of the knee). La Gazette. 1986;93:111– 116. Bierer TL, Bui LM. Improvement of arthritic signs in dogs fed green-lipped mussel (Perna canaliculus). J Nutr. 2002;132(6 Suppl 2):1634S–1636S. 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. Brooks PM. Side effects from Seatone. Med J Aust. 1980;2(3):158. Bui LM, Bierer TL. Influence of green lipped mussels (Perna canaliculus) in alleviating signs of arthritis in dogs. Vet Ther. 2003;4(4):397–407. Butters DE, Whitehouse MW. Treating inflammation: some (needless) difficulties for gaining acceptance of effective natural products and traditional medicines. Inflammopharmacology. 2003;11(1):97–110. Caughey DE, Grigor RR, Caughey EB, Young P, Gow PJ, Stewart AW. Perna canaliculus in the treatment of rheumatoid arthritis. Eur J Rheumatol Inflamm. 1983;6(2):197–200. Cho SH, Jung YB, Seong SC, Park HB, Byun KY, Lee DC, Song, E. K., Son, J. H. 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. Eur Ann Allergy Clin Immunol. 2003;35(6):212–216.
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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. Couch RA, Ormrod DJ, Miller TE, Watkins WB. Anti-inflammatory activity in fractionated extracts of the green-lipped mussel. N Z Med J. 1982;95(720):803–806. Croft JE. Granulomatous hepatitis and Seatone. Med J Aust. 1980;2(7):401– 402. Darlington LG, Ramsey NW. Review of dietary therapy for rheumatoid arthritis. Compr Ther. 1994;20(9):490–494. Dugas B. Lyprinol inhibits LTB4 production by human monocytes. Allerg Immunol (Paris). 2000;32(7):284–289. 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. Fabrin B. Possible toxic hepatitis after intake of an alternative preparation. Ugeskr Laeger. 1988;150(24):1474–1475. Ferreira SH. Proposal to use pentoxifylline and Lyprinol therapy for chronic inflammatory diseases. Inflammopharmacology. 2005;13(5–6):429–430. Gibson SL. The effect of a lipid extract of the New Zealand green-lipped mussel in three cases of arthritis. J Altern Complement Med. 2000;6(4):351–354. Gibson RG, Gibson SL. Green-lipped mussel extract in arthritis. Lancet. 1981a;1(8217):439. Gibson RG, Gibson SL. Seatone in arthritis. Br Med J (Clin Res Ed). 1981b; 282(6278):1795. Gibson RG, Gibson SL. New Zealand green-lipped mussel extract (Seatone) in rheumatoid arthritis. N Z Med J. 1981c;94(688):67–68. Gibson RG, Gibson SL. Seatone in rheumatoid arthritis. Ann Rheum Dis. 1985;44(9):645–646. Gibson SL, Gibson RG. The treatment of arthritis with a lipid extract of Perna canaliculus: a randomised trial. Comp Ther Med. 1998;6:122–126. Gibson RG, Gibson SL, Conway V, Chappell D. Perna canaliculus in the treatment of arthritis. Practitioner. 1980;224(1347):955–960. 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(2):163–168. Green-lipped mussel extract in arthritis. Lancet. 1981;1(8211):85. Greening GE, Dawson J, Lewis G. Survival of poliovirus in New Zealand greenlipped mussels, Perna canaliculus, on refrigerated and frozen storage. J Food Prot. 2001;64(6):881–884. Gruenwald J, Graubaum H, Hansen K, Grube B. Efficacy and tolerability of a combination of LYPRINOL and high concentrations of EPA and DHA in inflammatory rheumatoid disorders. Adv Ther. 2004;21(3):197–201. Halliday J. Not all green lipped mussel extracts are created equal. NutraIngredients.com Europe. Nutra Ingredients – Europe 2008. Halpern GM. An anti-inflammatory from the South Seas: Lyprinol. Allerg Immunol (Paris). 2000a;32(7):259–260.
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Halpern GM. Anti-inflammatory effects of a stabilized lipid extract of Perna canaliculus (Lyprinol). Allerg.Immunol (Paris). 2000b;32(7):272–278. Halpern C, Georges M. Anti-inflammatory effects of a stabilized lipid extract of Perna canaliculus (Lyprinol). Townsend Lett Dr Patients. 2000;(202):109–113. Highton TC, McArthur AW. Pilot study on the effect of New Zealand green mussel on rheumatoid arthritis. N Z Med J. 1975;81(535):261–262. Huskisson EC, Scott J, Bryans R. Seatone is ineffective in rheumatoid arthritis. Br Med J (Clin Res Ed). 1981;282(6273):1358–1359. Ishida H, Nozawa A, Nukaya H, Rhodes L, McNabb P, Holland PT, Tsuji, K. Confirmation of brevetoxin metabolism in cockle, Austrovenus stutchburyi, and greenshell mussel, Perna canaliculus, associated with New Zealand neurotoxic shellfish poisoning, by controlled exposure to Karenia brevis culture. Toxicon. 2004;43(6):701– 712. Jacobs JW, Rasker JJ, Van Riel PL, Gribnau FW, van de Putte LB. Alternative treatment methods in rheumatic diseases; a literature review. Ned Tijdschr Geneeskd. 1991;135(8):317–322. Kendall RV, Lawson JW, Hurley LA. New research and a clinical report on the use of Perna canaliculus in the management of arthritis. Townsend Lett Dr Patients. 2000;204(98):111. Kosuge T, Tsuji K, Ishida H, Yamaguchi T. Isolation of an anti-histaminic substance from green-lipped mussel (Perna canaliculus). Chem Pharm Bull (Tokyo). 1986;34(11):4825–4828. Larkin JG, Capell HA, Sturrock RD. Seatone in rheumatoid arthritis: a six-month placebo-controlled study. Ann Rheum Dis. 1985;44(3):199–201. Lau S, Chiu PK, Chu EMY, Cheng IYW, Tang WM, Man RYK, Halpern, G. M. Treatment of knee osteoarthritis with Lyprinol, lipid extract of the green-lipped mussel – a double-blind placebo-controlled study. Prog Nutr. 2004;61(17):17–31. 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. MacKenzie L, Holland P, McNabb P, Beuzenberg V, Selwood A, Suzuki T. Complex toxin profiles in phytoplankton and Greenshell mussels (Perna canaliculus), revealed by LC-MS/MS analysis. Toxicon. 2002;40(9):1321–1330. 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. McPhee S, Hodges LD, Wright PF, Wynne PM, Kalafatis N, Harney DW, Macrides, T. A. Anti-cyclooxygenase effects of lipid extracts from the New Zealand greenlipped mussel, Perna canaliculus. Comp Biochem Physiol B Biochem Mol Biol. 2007;146(3):346–356. Meletis CD. Natural relief for inflammation of sprains, strains, and arthritis. Alt Comp Ther. (England) 2000;6:141–144. Miles CO, Wilkins AL, Munday R, Dines MH, Hawkes AD, Briggs LR, Sandvik, M., Jensen, D. J., Cooney, J. M., Holland, P. T., Quilliam, M. A., MacKenzie, A. L., Beuzenberg, V., Towers, N. R. Isolation of pectenotoxin-2 from Dinophysis acuta and its conversion to pectenotoxin-2 seco acid, and preliminary assessment of their acute toxicities. Toxicon. 2004;43(1):1–9.
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Miller TE, Ormrod D. The anti-inflammatory activity of Perna canaliculus (NZ green lipped mussel). N Z Med J. 1980;92(667):187–193. Miller TE, Dodd J, Ormrod DJ, Geddes R. Anti-inflammatory activity of glycogen extracted from Perna canaliculus (NZ green-lipped mussel). Agents Actions. 1993;38 Spec No:C139–C142. Miller T, Wu H. In vivo evidence for prostaglandin inhibitory activity in New Zealand green-lipped mussel extract. N Z Med J. 1984;97(757):355–357. Morohashi A, Satake M, Naoki H, Kaspar HF, Oshima Y, Yasumoto T. Brevetoxin B4 isolated from greenshell mussels Perna canaliculus, the major toxin involved in neurotoxic shellfish poisoning in New Zealand. Nat Toxins. 1999;7(2):45–48. 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. New Zealand green-lipped mussel extract (Seatone) and rheumatoid arthritis. N Z Med J. 1981;93(684):343. Anon. Aussies to test Lyprinol. International Council for Health Freedom Newsletter 1999;3(3/4):45. Pollard B, Guilford WG, Ankenbauer-Perkins KL, Hedderley D. Clinical efficacy and tolerance of an extract of green-lipped mussel (Perna canaliculus) in dogs presumptively diagnosed with degenerative joint disease. N Z Vet J. 2006;54(3):114–118. Scotti PD, Dearing SC, Greenwood DR, Newcomb RD. Pernin: a novel, selfaggregating 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. Shiels IA, Whitehouse MW. Lyprinol: anti-inflammatory and uterine-relaxant activities in rats, with special reference to a model for dysmenorrhoea. Allerg Immunol (Paris). 2000;32(7):279–283. Sinclair AJ, Murphy KJ, Li D. Marine lipids: overview “news insights and lipid composition of Lyprinol”. Allerg Immunol (Paris). 2000;32(7):261–271. Singh M, Hodges LD, Wright PF, Cheah DM, Wynne PM, Kalafatis N, Macrides, T. A. 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. Suzuki T, MacKenzie L, Stirling D, Adamson J. Pectenotoxin-2 seco acid: a toxin converted from pectenotoxin-2 by the New Zealand Greenshell mussel, Perna canaliculus. Toxicon. 2001;39(4):507–514. Tenikoff D, Murphy KJ, Le M, Howe PR, Howarth GS. Lyprinol (stabilised lipid extract of New Zealand green-lipped mussel): a potential preventative treatment modality for inflammatory bowel disease. J Gastroenterol. 2005;40(4):361–365. 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. 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.
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Whitehouse MW. Call for a trial of Lyprinol, an over-the-counter 5-lipoxygenase inhibitor: comment on the article by Kowal-Bielecka et al. Arthritis Rheum. 2002;46(7):1977–1978. Whitehouse MW. Anti-TNF-alpha therapy for chronic inflammation: reconsidering pentoxifylline as an alternative to therapeutic protein drugs. Inflammopharmacology. 2004;12(3):223–227. Whitehouse MW. Prostanoids as friends, not foes: further evidence from the interference by cycloxygenase-inhibitory drugs when inducing tolerance to experimental arthritigens in rats. Inflammopharmacology. 2005;12(5–6):481–492. Whitehouse MW, Macrides TA, Kalafatis N, Betts WH, Haynes DR, Broadbent J. Anti-inflammatory activity of a lipid fraction (lyprinol) from the NZ green-lipped mussel. Inflammopharmacology. 1997;5(3):237–246. Wolyniak CJ, Brenna T, Murphy KJ, Sinclair AJ. Gas chromatography-chemical ionization-mass spectrometric fatty acid analysis of a commercial supercritical carbon dioxide lipid extract from New Zealand green-lipped mussel (Perna canaliculus). Lipids. 2005;40(4):355–360. Yuan G, Wahlqvist ML, He G, Yang M, Li D. Natural products and anti-inflammatory activity. Asia Pac J Clin Nutr. 2006;15(2):143–152.
doi: 10.1080/19390210802690191
