Scientific Name(s): Sphyrna lewini (Hammerhead Shark), Squalus acanthias (spiny dogfish shark)
Common Name(s): Hammerhead shark, Shark cartilage, Spiny dogfish shark
Shark cartilage is prepared from the cartilage of freshly caught sharks in the Pacific Ocean, predominantly from the spiny dogfish shark (S. acanthias) and the hammerhead shark (S. lewini).1 One of the main processing plants for dogfish shark is in Costa Rica. The cartilage is cut from the shark, cleaned, shredded, and dried. The finely ground cartilage is uniformly pulverized in a 200 mesh screen, sterilized, and encapsulated. Gelatin capsules contain shark cartilage 740 mg, usually without additives or fillers, and are claimed to be "all natural." Shark cartilage is also available in 200 and 500 g capsules (eg, Cartilade).2, 3
Shark cartilage is composed of approximately 40% protein (troponin-I, tetranectin-type protein, collagenase, cartilage-derived inhibitor, and tissue inhibitor of metalloproteinases), 5% to 20% glycosaminoglycans (chondroitin sulfate-D, chondroitin-6-sulfate, keratin sulfate), calcium salts, and glycoproteins (sphyrnastatin-1 and 2, galactosamines, glucosamine).4 Several studies have been conducted using various shark species. Sphyrnastatins 1 and 2 from the hammerhead shark have been isolated and characterized.5 The isolation of a protein from reef shark (Carcharhinus springeri) cartilage that bears a striking resemblance to human tetranectin was reported.6 A broad-spectrum steroidal antibiotic from the dogfish shark has been discovered and named "squalamine"; chemically, it is 3-beta-N-1-(N-[3–(4–aminobutyl)]-1,3-diamino-propane)-7 alpha, 24 zeta-dihydroxy-5 alpha-cholestane 24-sulfate.7
Uses and Pharmacology
Shark cartilage may be useful in inflammatory conditions such as rheumatoid arthritis, psoriatic arthritis, and, in some cases, osteoarthritis. Specifically, it may be beneficial due to its anti-angiogenic effects as well as the presence of high levels of anti-inflammatory mucopolysaccharides such as glucosamine sulfate and chondroitin sulfate. Improvements in inflammation may be noticed as soon as 1 to 2 weeks after initiating treatment with shark cartilage; however, if no improvement occurs, patients should be advised to continue treatment for 6 to 8 weeks before a decision is made to discontinue.8
Animal and in vitro data
Shark cartilage polysaccharide given to rats at 9 mg/day for 24 days exerted beneficial effects in a model of rheumatoid arthritis (RA). Supplementation reduced paw swelling, inhibited IL-6 and IL-12 secretion, and improved radiologic change of the bone. While shark cartilage was not better than methotrexate on these parameters, the inflammatory process in RA rats without treatment led to increases in levels of the proinflammatory cytokines IL-6 and IL-12.9 Similarly, another murine model found that shark cartilage attenuated inflammation when dosed at 3 mg/kg/day orally for 2 weeks.10 However, in an in vitro study, shark cartilage stimulated production of proinflammatory cytokines and chemokines, as well as activated signaling pathways; in vivo, this could lead to exacerbations of inflammatory diseases such as irritable bowel syndrome.11
A topical combination preparation containing glucosamine sulfate 30 mg/g, chondroitin sulfate 50 mg/g, and shark cartilage 140 mg/g applied for an 8-week period improved visual analog scores for pain compared with placebo at 4 and 8 weeks in patients with osteoarthritis of the knee.12
In a study examining the role of AE-941 in psoriasis, AE-941 was effective in preventing skin irritation, suggesting anti-inflammatory properties.13
There have been many claims regarding the role of shark cartilage as a cure for cancer. The fact that sharks rarely get cancer has led to the theory that because sharks are cartilaginous fish, and cartilage is avascular and contains agents that inhibit vascularization (angiogenesis, promotion of new blood vessels needed for tumor growth and metastasis), the cartilage from sharks can, therefore, cure cancer. The inhibited vascularization theoretically prevents formation of tumors; hence, in humans, use may inhibit tumor angiogenesis and thus possibly cure cancer.2 AE-941, a mixture of water-soluble components from shark cartilage developed by Aeterna Laboratories, inhibits the activation of angiogenesis through vascular endothelial growth factor and matrix metalloproteinase (MMP), particularly MMP-2, -9, -12, and -13.14, 15, 16 It also induces apoptosis in endothelial cells.16
Animal and in vitro data
Some of the earliest published data on use of shark cartilage for anticancer effects come from an experimental cornea model in rabbits. Pellets of shark cartilage derived from basking sharks (Cetorhinus maximus) were placed into rabbit corneas, along with V2 carcinoma cells. At 19 days, corneas treated with shark cartilage did not contain any 3-dimensional tumors, unlike the control corneas.17 The study authors suggested that further exploration in experimental models is needed to determine the angiogenesis inhibitory effects of shark cartilage.
An acidic ethanol-precipitate fraction of shark cartilage was associated with reduced incidence and number of adenocarcinomas in the pancreatic ducts of hamsters. Additionally, this fraction inhibited MMP-9.18
In a survey of long-term lymphoma survivors (6 to 20 years), 7% (95% confidence interval, 2% to 17%) of patients reported shark cartilage use.19 In late 1992, incomplete and nonreplicated clinical studies (unpublished) conducted in Havana, Cuba, purported to show some benefit in terminally ill cancer patients. The National Cancer Institute reviewed these studies and decided against researching shark cartilage.2
A case report described clinical and histological regression of early-stage cutaneous Kaposi sarcoma in a 45-year-old man positive for human herpesvirus-8 and negative for HIV. Initially, the patient received a 3-month course of ganciclovir with no clinical resolution. Shark cartilage supplementation was then initiated at 3,750 mg divided twice daily for the first 3 months. After 3 months, the Kaposi sarcoma lesion had decreased in size. The dose was increased to 4,500 mg divided 3 times daily for the remainder of the approximately 3-year treatment period.20 In a phase 2, open-label study of 144 patients with refractory renal cell carcinoma, the effects of AE-941 on survival were assessed. Patients were given either AE-941 60 mL/day or 240 mL/day orally, divided twice daily. Patients treated with the 240 mL/day dose had a longer median survival time (16.3 months) compared with those receiving 60 mL/day (7.1 months; P=0.01).21
In a 2005 two-armed, randomized, double-blind, placebo-controlled clinical trial in patients with incurable breast or colorectal cancer (N=88), shark cartilage powder (BeneFin) was initiated at 24 g and titrated upward as tolerated every 3 days, towards a goal of 96 g given in 3 or 4 divided doses. Results demonstrated no improvement in survival or quality of life (QOL) in patients who received shark cartilage compared with placebo; in fact, QOL variables were confirmed to be significantly worse with shark cartilage supplementation at weeks 2 and 3 (P=0.005 and P=0.05, respectively). For the 24 patients who remained in the study at month 3, QOL, measured using the Symptom Distress Scale, was significantly better in the shark cartilage group (P=0.04), with Linear Analogue Self-Assessment test scores indicating higher emotional and spiritual well-being (P=0.05 and P=0.01, respectively). However, given the very low number of patients in each arm at month 3, results should be interpreted with caution. The most frequent severe toxicities experienced in the shark cartilage group and not observed in the placebo group included diarrhea, dyspnea, leukopenia, neutropenia, and bone pain; most adverse effects were mild to moderate.22
In a randomized, double-blind, placebo-controlled, phase 3 trial of patients with stage III non–small cell lung cancer treated with chemoradiotherapy, the addition of shark cartilage did not improve overall patient survival compared with placebo. In addition, time to progression, progression-free survival, and tumor response rates were not different between shark cartilage and placebo groups. It should be noted that the study was closed before reaching the targeted sample size due to insufficient accrual of patients.23
In a study of patients with advanced cancer (breast, colorectal, lung, prostate, non-Hodgkin lymphoma, brain, and unknown tumor), shark cartilage was inactive and had no beneficial effects on QOL.24
AE-941 has received orphan status designation by the US Food and Drug Administration for the treatment of renal cell carcinoma.25
AE-941 may be beneficial in the management of psoriasis by inhibiting the neovascularization of psoriatic plaques.
Animal and in vitro data
In chick embryos, AE-941 inhibited neovascularization and types 1 and 4 collagenase activity in a concentration-dependent manner.13
In a phase 1/2, open-label clinical trial, the effects of AE-941 were assessed in 49 patients with plaque psoriasis. Patients were randomized to receive an AE-941 regimen of 30, 60, 120, or 240 mL/day orally twice daily for 12 weeks, with an additional 12-week follow up period. Only 12 of the 49 patients completed the entire 24-week study. Psoriasis Area and Severity Index (PASI) score improved by 20% or greater in 30.8%, 41.7%, and 50% of patients receiving 60, 120, and 240 mL/day, respectively, of AE-941. Those receiving 30 mL/day did not show an improvement in PASI score.14 The high withdrawal/dropout rate in this study limits interpretation of the data.
In another study examining the potential role of AE-941 in psoriasis, investigators applied shark cartilage to the ventral forearms, followed by Balsam of Peru, a skin irritant. AE-941 prevented skin irritation at all doses tested, suggesting anti-inflammatory properties.13
Research has identified the broad-spectrum aminosterol antibiotic squalamine in the dogfish shark. Squalamine has shown bactericidal activity against both gram-negative and gram-positive bacteria. It is also fungicidal and induces activity against protozoa.7 This discovery implicated a unique steroid acting as a potential host-defense agent in vertebrates and provided for a new family of broad-spectrum antibiotics.
In an in vitro study, shark cartilage served as a scavenger against reactive oxygen species and protected cells against inactivation and mutagenesis, suggesting potential antioxidant effects.26
Following colonic anastomosis in rabbits, administration of shark cartilage increased connective tissue and vascularization without impacting microbial growth or translocation. Bursting pressure (139.29 mm Hg vs 85 mm Hg) and hydroxyproline levels (4.59±0.26 g/mg tissue vs 2.55±0.21 g/mg tissue) were higher in the shark cartilage group compared with controls (P<0.05 for both comparisons). Shark cartilage positively impacted collage synthesis and promoted better vascularization in the anastomosis regions, thereby increasing the strength of the anastomosis.27
An in vitro study demonstrated that shark cartilage possesses plasmin-independent fibrinolytic activity. Shark cartilage decreased clot firmness; however, there was no impact on clotting time and kinetic parameters.28
In an in vitro study, a fraction of shark cartilage–derived protein exerted immunostimulatory effects on the cytotoxic activity of natural killer cells.29
Due to shark cartilage's antiangiogenic effects, improved or stabilized visual acuity has been reported in a small cohort of patients with macular degeneration.4 Additional studies are needed before recommendations can be made regarding the use of shark cartilage in macular degeneration.
Uric acid–lowering effects
In a murine model, the basic peptide fraction of shark cartilage was found to exert uric acid–lowering activity.30 At least one of the peptides, Tyr- Leu-Asp-Asn-Tyr, maintains antihyperuricemic activity when administered orally.31
Commercial doses range from 0.5 to 4.5 g/day, given in 2 to 6 divided doses.1
Oral shark cartilage preparations should be taken on an empty stomach, and acidic fruit juices should be avoided for 15 to 30 minutes before and after administration.4
80 to 100 g/day or 1 to 1.3 g/kg/day of ground extract in 2 to 4 divided doses.4 Doses of the shark cartilage derivative AE-941, used in clinical trials, have ranged from 30 to 240 mL/day or 20 mg/kg twice daily.4 In one trial, a liquid shark cartilage extract was dosed at 7 and 21 mL daily.32 In patients with incurable breast and colorectal cancer, a powder formulation (BeneFin) was initially dosed at 24 g/day and titrated upward every 3 days to a target dose of 96 g/day, administered in divided doses 3 to 4 times a day.33
0.2 to 2 g/kg/day in 2 to 3 divided doses.4
0.4 to 0.5 g/kg/day for 4 weeks, with dosage reduced to 0.2 to 0.3 g/kg/day for 4 additional weeks if skin lesions improve. Topical preparations containing shark cartilage 5% to 30% are also available.4
Pregnancy / Lactation
Coadministration of shark cartilage with other drugs (eg, calcium supplements, thiazide diuretics) may increase calcium levels.4
The most commonly reported adverse effects are mild to moderate and include GI distress and nausea.4 Taste alterations have also been noted.21 Because shark cartilage supplements often contain high levels of calcium (eg, elemental calcium 600 to 780 mg daily), hypercalcemia may occur, particularly in patients with cancer. In 2 case reports of patients with cancer, it was suggested that episodes of symptomatic hypercalcemia were associated with shark cartilage supplementation, especially when used in combination with multivitamins that provide additional calcium and vitamin D.34
A case of immunoglobulin E–mediated allergic occupational asthma has been documented in a 29-year-old man who worked in a dietetic product production facility. Symptoms included chest tightness, cough, and dyspnea that required management with bronchodilators and several hospital admissions. Peak expiratory flow rate decreased by more than 20% during work periods and, along with other symptoms, improved on the weekends and holidays.35 Another case report described a 38-year-old white man working in a facility that ground shark cartilage. After about 10 months of exposure, he reported dyspnea, coughing, and wheezing, symptoms associated with shark cartilage exposure, and was diagnosed with asthma. Six months later, he reported shortness of breath at work and died; the autopsy report indicated the presence of mucus casts and numerous emphysematous blebs, and confirmed asthma as the cause of death.36 This case is confounded by the patient's smoking history but may be linked to occupational exposure to shark cartilage.
A case report described a 57-year-old man with hepatitis presumed to be induced by shark cartilage. He reported a 3-week history of nausea, vomiting, diarrhea, and anorexia and was found to have elevated liver enzyme, bilirubin, and alkaline phosphatase levels. He had begun taking shark cartilage 10 weeks prior to hospitalization but had reportedly discontinued taking the supplements a few days before his symptoms began due to an odor from the supplements. Six weeks following discharge, he had normal liver function.37
In an analysis of calcium supplements in Korea, shark cartilage–containing calcium supplements were among the highest in mercury and cadmium content, with levels that could be toxic in pediatric and elderly populations.38 In another study testing 16 shark cartilage products, 15 of the 16 contained BMAA (a neurotoxin found in the fins of several species of shark and potentially linked to degenerative brain disease) at concentrations ranging from 86 to 265 mcg/g; mercury content was low in these shark fin products.39 Caution should be used.
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