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The "blue shark", Prionace glauca (class: Chondrichthyes), is a pelagic shark species commonly found in tropical and temperate oceans. This shark is mainly sold in Asian countries as food and as traditional Chinese medicine. According to the Red List of the International Union for the Conservation of Nature, P. glauca is classified as low-risk to near endangered. P. glauca cartilage contains collagen type II, which makes it suitable as a bioactive ingredient in cosmeceutical products. This study evaluated the effects of a gel containing various concentrations (0.125-5%) of lyophilized hydrolyzed P. glauca cartilage on the human inner wrist skin compared to a placebo (base). A skin properties evaluation test was conducted before and after applying various concentrations (0.125-5%) of the P. glauca cartilage gel for 10 and 20 min on the inner wrists of participants using a skin analyzer that determined the moisture level, oil level, texture level, complexion level, and the 3D level. Adding lyophilized hydrolyzed shark cartilage (LHSC) significantly improved the moisture, texture, and complexion of the skin while controlling oil and providing a wrinkle-smoothing effect. The result indicated that LHSC formulations were prepared at different concentrations, and they had significantly enhanced effects on skin hydration and elasticity (texture) and the smoothing of wrinkles (3D level). The LHSC also effectively controlled oil secretion and the complexion.

Cancer patients use health foods (HFs) as complementary and alternative medicine, although the details of their adverse events (AEs) are unclear. We searched three databases [PubMed, "Igaku Chuo Zasshi", and Information System on Safety and Effectiveness for Health Foods website (https://hfnet.nibiohn.go.jp/)] for case reports on AEs related to HF intake in cancer patients published before October 2018. Of the matched reports, 76 studies and 92 patients (31 in Japan, 61 overseas) that met the selection criteria were included in this review. Thus, the severity of AEs and outcomes were not related to either the concomitant use of HF with cancer chemotherapy or cancer stages of patients. AEs caused by HF intake itself accounted for 87%, while drug-HF interaction accounted for 11%. According to the Common Terminology Criteria for Adverse Events (CTCAE) classification, 70% of patients whose grades were identified had severe cases (grades 3 to 5). In Japanese patients, hepatic and respiratory disorders accounted for 52% of the severe cases. Cases were predominantly developed as a result of an allergic mechanism, and mushroom products were mostly used. Overseas, serious cases were induced by products that were already indicated for safety problems. Moreover, notable AEs were recognized, such as hypercalcemia, which were caused by intake of HF containing calcium, vitamin D, and shark cartilage, and bacterial infection caused by probiotic products. Analyzing the details of AEs related to HF intake can help health professionals and cancer patients prevent health hazards.

During the past decade, use of complementary and alternative medicine (CAM) by the American public increased from 34% in 1990 to 42% in 1995 with related out-of-pocket expenditures estimated at $27 billion. Among cancer patients, use of CAM ranges between 30 and 75% worldwide and includes dietary approaches, herbals and other biologically based treatments such as melatonin, mushrooms, shark cartilage and high dose vitamins and minerals. Concerns about herb-nutrient-drug interactions and product quality and standardization emphasize the need for rigorous research. In 1998, Congress mandated the creation of the National Center for Complementary and Alternative Medicine (NCCAM) to conduct and support such research of CAM therapies. The NCCAM portfolio for oncology is rapidly growing. As of July 2001, 26 projects are underway, two specialized centers are funded for cancer research and four botanical centers are cofunded with the Office of Dietary Supplements. Investigations are targeting herbals and complex herbal formulas; single dietary supplements and complex dietary regimens; biological agents; and mind-body, body-based and frontier approaches. Of these, biopharmacologic and herbal therapies are a major focus of research. The NCCAM portfolio illustrates how research of CAM, particularly studies of biopharmacologic and herbal approaches for cancer, is developing systematically and rigorously.

The present work shows an antinociceptive and dose-dependent effect of shark cartilage hydrosoluble fraction (HF) on writhing and formalin tests in mice. The effect was not altered by thalidomide, a known inhibitor of tumor necrosis factor-alfa (TNF-alfa) synthesis. Similarly, the antinociceptive effect did not change in the presence of naloxone, indicating that the opioid system is not involved. However, the effect observed was blocked by L-arginine, a NO synthesis substrate, and it was potentiated by L-NAME, suggesting a role of the NO system in the shark cartilage antinociceptive effect. Effects similar to those seen with the HF were detected with peak II from gel filtration chromatography. The increase in vascular permeability induced by serotonin in rats was significantly abolished by the HF at the dose of 2 mg/kg, p.o., and again it was not potentiated by thalidomide. The observed blockade in the vascular permeability increase induced by histamine was detected only with a higher dose (10 mg/kg, p.o.).

191. Drugs R D. 2004;5(2):83-9. doi: 10.2165/00126839-200405020-00003. AE 941. [No authors listed] AE 941 [Arthrovas, Neoretna, Psovascar] is shark cartilage extract that inhibits angiogenesis. AE 941 acts by blocking the two main pathways that contribute to the process of angiogenesis, matrix metalloproteases and the vascular endothelial growth factor signalling pathway. When initial development of AE 941 was being conducted, AEterna assigned the various indications different trademarks. Neovastat was used for oncology, Psovascar was used for dermatology, Neoretna was used for ophthalmology and Arthrovas was used for rheumatology. However, it is unclear if these trademarks will be used in the future and AEterna appears to only be using the Neovastat trademark in its current publications regardless of the indication. AEterna Laboratories signed commercialisation agreements with Grupo Ferrer Internacional SA of Spain and Medac GmbH of Germany in February 2001. Under the terms of the agreement, AEterna has granted exclusive commercialisation and distribution rights to AE 941 in oncology to Grupo Ferrer Internacional for the Southern European countries of France, Belgium, Spain, Greece, Portugal and Italy. It also has rights in Central and South America. Medac GmbH will have marketing rights in Germany, the UK, Scandinavia, Switzerland, Austria, Ireland, the Netherlands and Eastern Europe. In October 2002, AEterna Laboratories announced that it had signed an agreement with Australian healthcare products and services company Mayne Group for marketing AE 941 (as Neovastat) in Australia, New Zealand, Canada and Mexico. In March 2003, AEterna Laboratories announced it has signed an agreement with Korean based LG Life Sciences Ltd for marketing AE 941 (as Neovastat) in South Korea. The agreement provides AEterna with upfront and milestone payments, as well as a return on manufacturing and sales of AE 941. AEterna Laboratories had granted Alcon Laboratories an exclusive worldwide licence for AE 941 for ophthalmic products. However, this licence has been terminated. In 1999, AEterna secured funding for AE 941, part of which is from Technology Partnerships Canada (TPC),

Erratum in Toxins (Basel). 2018 May 10;10(5):E191. doi: 10.3390/toxins10050191. The neurotoxin β-N-methylamino-l-alanine (BMAA), a non-protein amino acid produced by terrestrial and aquatic cyanobacteria and by micro-algae, has been suggested to play a role as an environmental factor in the neurodegenerative disease Amyotrophic Lateral Sclerosis-Parkinsonism-Dementia complex (ALS-PDC). The ubiquitous presence of BMAA in aquatic environments and organisms along the food chain potentially makes it public health concerns. However, the BMAA-associated human health risk remains difficult to rigorously assess due to analytical challenges associated with the detection and quantification of BMAA and its natural isomers, 2,4-diamino butyric acid (DAB), β-amino-N-methyl-alanine (BAMA) and N-(2-aminoethyl) glycine (AEG). This systematic review, reporting the current knowledge on the presence of BMAA and isomers in aquatic environments and human food sources, was based on a selection and a score numbering of the scientific literature according to various qualitative and quantitative criteria concerning the chemical analytical methods used. Results from the best-graded studies show that marine bivalves are to date the matrix containing the higher amount of BMAA, far more than most fish muscles, but with an exception for shark cartilage. This review discusses the available data in terms of their use for human health risk assessment and identifies knowledge gaps requiring further investigations.

OBJECTIVE: To evaluate inflammatory responses induced via intra-articular recombinant human interleukin (IL)-1beta treatment in horses receiving a dietary nutraceutical (DN; composed of mussel, shark cartilage, abalone, and Biota orientalis lipid extract) and assess the clinical effects of long-term DN administration. ANIMALS: 22 healthy horses. PROCEDURES: 12 horses were fed 0, 15, 45, or 75 mg of DN (3 horses/treatment) daily for 84 days. General health and clinicopathologic variables were monitored at intervals. Ten other horses received 0 or 15 g of DN/d (5 horses/treatment) for 29 days (beginning day -14). One intercarpal joint in each horse was injected twice with IL-1beta (10 and 100 ng on days 0 and 1, respectively), and the contralateral joint was similarly injected with saline (0.9% NaCl) solution. Synovial fluid prostaglandin E(2) (PGE(2)), sulfated glycosaminoglycan (GAG), nitric oxide (NO), and protein concentrations and leukocyte counts were analyzed before and at intervals after injections. RESULTS: Administration of the DN (up to 75 g/d) to horses for 84 days did not induce any adverse effects. In the other experiment, synovial fluid PGE(2), GAG, and protein concentrations and leukocyte count increased after intra-articular injections of IL-1beta (compared with effects of saline solution injections) in horses that received no DN; NO concentration was not affected. In horses that were fed the DN, intra-articular IL-1beta injections did not induce significant increases in synovial fluid PGE(2) and GAG concentrations. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that administration of the DN may be useful in preventing inflammation associated with arthritis and degenerative joint disease in horses.

Randomized controlled trials are generally regarded as the standard of study designs to determine potential causality. The inclusion of a placebo group in these trials, when appropriate, is generally needed to access the efficacy of a drug or dietary supplement. The recent increasing use of dietary supplements and herbal medications by patients makes it imperative to reevaluate the past findings of clinical studies. Several large-scale trials of dietary supplements have been tested in various populations to determine their effect on cancer prevention. Other trials have focused on patients already diagnosed with cancer. In the latter case, it is difficult to involve a placebo because of the serious nature of the disease. Nevertheless, much has been gleaned from these trials directly and indirectly. Overall, when analyzing primary endpoints in these trials, the results have been discouraging and even support the nonuse of certain supplements because of potential adverse effects. Other secondary endpoints in these same trials have revealed some potential encouraging and discouraging data. Individuals who currently qualify for the potential use of dietary supplements for cancer may be restricted to those who have a deficiency in a certain compound despite adequate dietary sources or lifestyle changes. Those individuals with a smoking history or other unhealthy lifestyle seem to have the most to gain or lose from taking certain dietary supplements for cancer. The time seems more than ripe to evaluate past adequate trials with supplements, such as beta-carotene, N-acetyl-cysteine, selenium, shark cartilage, vitamin C, vitamin E, and others. Again, these studies have been disappointing, but they provide insight for the clinician and patient of what to potentially expect when using these supplements for cancer. In addition, indirect trials for other conditions (cardiovascular) may provide future insight into possible results for future cancer prevention trials.

OBJECTIVE: To develop a method of collecting, organizing, and analyzing information on nutrient and nonnutrient dietary supplement use by women at risk for breast cancer recurrence as a component of nutrition assessment and monitoring, and to describe the characteristics associated with dietary supplement use in this population at enrollment in a clinical trial to prevent breast cancer recurrence. DESIGN: Cross-sectional descriptive study design. SUBJECTS: Women diagnosed with breast cancer within the previous 4 years (n=435). ANALYSIS: Dietary supplements reported in four 24-hour dietary recalls were categorized according to primary nutrient and nonnutrient contents. Prevalence of dietary supplement use is described. Associations between supplement use and demographic and participant characteristics were examined using chi(2) analysis and logistic regression. RESULTS: Dietary supplement use was reported by 80.9% of the women. Increased likelihood of supplement use was associated with demographic (eg, older age, higher level of education, white race vs other ethnic groups) and personal (eg, lower body mass index, moderate alcohol consumption) characteristics. Use of vitamin C and related compounds, other nutrients (eg, n-3 fatty acids, evening primrose oil), and herbal products was inversely associated with months since diagnosis; use of miscellaneous supplements (eg, shark cartilage) was directly associated with more advanced stage at diagnosis. APPLICATIONS: Monitoring dietary supplement use is an important aspect of nutrition assessment, especially in populations with chronic health conditions or medical diagnoses. Demographic and personal characteristics, time passed since diagnosis, and stage of cancer at diagnosis are predictive of dietary supplement use by women at risk for breast cancer recurrence. Associations in this population may be present in other groups that are the object of nutrition intervention efforts.

Comment in J Natl Cancer Inst. 2010 Jun 16;102(12):834-5. doi: 10.1093/jnci/djq196. BACKGROUND AE-941 is a standardized aqueous shark cartilage extract with antiangiogenic properties that has previously been evaluated in phase I and II clinical trials. Our objective was to determine the effect of adding AE-941 to chemoradiotherapy on overall survival of patients with unresectable stage III non-small cell lung cancer (NSCLC). METHODS A randomized, double-blinded, placebo-controlled, phase III clinical trial was designed to test the efficacy of AE-941 in unresectable stage III NSCLC patients who were treated with chemoradiotherapy. Between June 5, 2000, and February 6, 2006, 379 eligible patients were enrolled in community and academic oncology centers across the United States and Canada. In February 2006, the trial was closed to new patient entry before meeting the target sample size because of insufficient accrual. All subjects received induction chemotherapy followed by concurrent chemotherapy with chest radiotherapy. Each participating center administered one of the two chemotherapy regimens, either carboplatin and paclitaxel, or cisplatin and vinorelbine. The primary endpoint was overall survival, and secondary endpoints were time to progression, progression-free survival, tumor response rate, and toxic effects. Event-time distributions were estimated by the Kaplan-Meier method. All statistical tests were two-sided. RESULTS There was no statistically significant difference in overall survival between the chemoradiotherapy plus AE-941 group (n = 188; median survival = 14.4 months, 95% confidence interval = 12.6 to 17.9 months) and the chemoradiotherapy plus placebo group (n = 191; median survival = 15.6 months, 95% confidence interval = 13.8 to 18.1 months) (P = .73). Time to progression, progression-free survival, and tumor response rates were not statistically significantly different between the AE-941 and the placebo groups. No differences between the two groups were observed in common grade 3 or higher toxic effects attributable to chemoradiotherapy. CONCLUSIONS The addition of AE-941 to chemoradiotherapy did not improve overall survival in patients with

192. J Natl Cancer Inst. 2010 Jun 16;102(12):834-5. doi: 10.1093/jnci/djq196. Epub 2010 May 26. The challenge of rational development of complex natural products as cancer therapeutics. White J. Comment on J Natl Cancer Inst. 2010 Jun 16;102(12):859-65. doi: 10.1093/jnci/djq179.

193. Med Monatsschr Pharm. 2007 Sep;30(9):351. [Shark cartilage extract. No effect on bronchial carcinoma]. [Article in German] [No authors listed]

PURPOSE: We analyzed prognostic factors, described survival and generated a prognostic model in patients with metastatic renal cell carcinoma in whom immunotherapy failed and who were potentially eligible for novel agents. MATERIALS AND METHODS: An analysis of the relationship between clinical features and survival was performed in 300 patients with advanced renal cell carcinoma in whom immunotherapy had failed and who were subsequently treated as part of a single, phase III clinical trial with the anti-angiogenic agent Neovastat (shark cartilage extract AE 941). Clinical features were first examined univariately and a stepwise modeling approach based on Cox proportional hazard regression was then performed to generate a multivariate model. RESULTS: Median and progression-free survival (prognostic factors) for the whole cohort was 12.6 and 2 months, respectively. Prognostic features associated with shorter survival on multivariate analysis were the number of metastatic sites (greater than 1), time from nephrectomy to metastatic disease (less than 2 years), high alkaline phosphatase, abnormal corrected serum Ca and high lactate dehydrogenase (greater than 1.5 x the upper limit of normal). Four prognostic subgroups were identified by counting the number of adverse prognostic factors. Median survival in patients with zero adverse prognostic factors was 15.6 months compared to 11.7 months in patients with 1, 8.5 months in patients with 2 and 3.5 months in patients with 3 or more. CONCLUSIONS: We identified 4 risk groups to predict survival in previously treated patients with renal cell carcinoma. This model was based on data from what is to our knowledge the largest experience in this population. It should be used in clinical trial design, risk stratification and patient counseling.

BACKGROUND: Shark cartilage has been a popular complementary or alternative medicine intervention. The basis for this popularity is the claim that sharks rarely get cancer because of the high proportion of cartilage in the shark's body. However, early studies were equivocal. Therefore, a clinical trial was conducted to look at the impact of shark cartilage in patients with advanced cancer. The primary goal of this trial was to determine whether a shark cartilage product improved overall survival for patients with advanced cancer who were getting standard care. Secondary research goals were to evaluate toxicities, tolerability, and quality of life associated with this shark cartilage product. METHODS: The study was a two-arm, randomized, placebo-controlled, double-blind, clinical trial. Patients with incurable breast or colorectal carcinoma had to have good performance status and organ function. Patients could be receiving chemotherapy. Patients were all to receive standard care and then to be randomly selected to receive either a shark cartilage product or an identical-appearing and smelling placebo 3 to 4 times each day. RESULTS: Data on a total of 83 evaluable patients were analyzed. There was no difference in overall survival between patients receiving standard care plus a shark cartilage product versus standard care plus placebo. Likewise, there was no suggestion of improvement in quality of life for patients receiving the shark cartilage, compared with those receiving placebo. CONCLUSION: This trial was unable to demonstrate any suggestion of efficacy for this shark cartilage product in patients with advanced cancer.

194. MMW Fortschr Med. 2004 Apr 22;146(17):8, 10. [From shark cartilage to hypnosis. Conservative medicine against cancer?]. [Article in German] Arnheim K. Comment in MMW Fortschr Med. 2004 May 20;146(21):17.

There is considerable evidence to support an immunopathogenic basis of psoriasis. However, changes such as altered angiogenesis have also been implicated in the pathogenesis of psoriasis. AE-941 (Neovastat; Aeterna Laboratories, Quebec City Quebec, Canada) is a naturally occurring product currently in clinical investigation that blocks two main mechanisms of angiogenesis activation, namely, vascular endothelial growth factor and matrix metalloproteinase. We hypothesized that psoriasis could be modulated by inhibiting the neovascularization of psoriatic plaques. We conducted a randomized dose-comparison trial to evaluate the safety and potential therapeutic benefit of AE-941, administered orally to patients with psoriasis. Forty-nine patients with psoriasis were enrolled and assigned to receive AE-941 at 30, 60, 120, or 240 mL/d for 12 weeks. Patients were followed up for another 12-week period. Improvement in the Psoriasis Area and Severity Index (PASI) score was observed in 50%, 41.7%, and 30.8% of the patients receiving 240, 120, and 60 mL/d, respectively. No patients receiving a dosage 30 mL/d showed a PASI score improvement. A statistically significant improvement with increasing dose was observed for the PASI score, severity of itch, and the physician's global assessment. The most commonly reported nonserious drug-related adverse events affected the gastrointestinal system in 12 of 49 patients (primarily nausea, diarrhea, vomiting, flatulence, and constipation) and the skin and appendages in 4 of 49 patients (primarily acne and rash). This randomized phase I/II study provides evidence that the antiangiogenic agent AE-941 offers a new therapeutic approach to the management of psoriasis.

Numerous inhibitors of angiogenesis are currently under study in lung cancer. Four trials of adjuvant interferon after chemotherapy for small cell lung cancer (SCLC) were negative. Several metalloproteinase inhibitors (MMPIs) are now in study in SCLC and non-small cell lung cancer (NSCLC). Two large randomized trials have closed recently in which Marimastat 10 mg bid was compared to placebo in responding patients with SCLC. Two randomized studies of Prinomastat versus placebo with combination chemotherapy in advanced NSCLC have also completed accrual. The results of these trials are not yet available, but should be reported in mid-2001. A Phase III trial of BMS-275291, a broad-spectrum MMPI in combination with paclitaxel and carboplatin is open for patients with advanced NSCLC. Neovastat, a standardized shark cartilage extract is under study in inoperable Stage III NSCLC. VEG-F gene expression is increased in many tumors including NSCLC, and may act as a paracrine mediator of growth. A randomized Phase II trial of paclitaxel and carboplatin with or without a recombinant humanized anti-VEG-F has been undertaken in NSCLC. Modestly better response and survival were seen with anti-VEG-F and a large Phase III trial is planned. Numerous receptor tyrosine kinases (TK) have been found to be directly or indirectly involved in angiogenesis including Flk-1, Flt-l, Tie-1 and Tie-2. SU5416 is a small molecular TK inhibitor and potent inhibitor of VEG-F-mediated Flk-1 receptor signaling. Another TK inhibitor SU6668 blocks VEG-F, bFGF and PDGF receptor signaling. It is orally available, and it may be evaluated in lung cancer trials in the near future. ZD4190 is an inhibitor of KDR/Flk-1 that may be evaluated in SCLC. Thalidomide has recently been shown in pre-clinical models to be anti-angiogenic. A randomized trial of paclitaxel/carboplatin and radiation with or without thalidomide is open for patients with Stage IIIB NSCLC in the United States. Numerous other anti-angiogenesis agents are in early clinical trials, but have not been evaluated in lung cancer yet.

Comment in Med J Aust. 2001 Jun 4;174(11):611-2. doi: 10.5694/j.1326-5377.2001.tb143462.x. Med J Aust. 2001 Sep 17;175(6):342-3. doi: 10.5694/j.1326-5377.2001.tb143610.x. Complementary and alternative medicine (CAM) is frequently used by cancer patients, and many oncologists have limited knowledge of CAM. This article provides a brief, evidence-based introduction to several CAM treatments relevant in the context of cancer. "Alternative" diets, chiropractic, coffee enemas, ozone therapy, and shark cartilage seem to have little to offer cancer patients. The evidence for or against homoeopathy and spiritual healing is at present inconclusive. Acupuncture, aromatherapy, and meditation may be useful for nausea/vomiting, for mild relaxation, and for pain/anxiety, respectively. Herbal treatments offer no reasonable prospect of a cure (mistletoe), but could be useful as palliative treatments (eg, for depression [St John's wort] or anxiety [kava]). Our knowledge regarding the potential benefit and harm of CAM is insufficient.

Ratings systems and awards for medical Web sites have proliferated, but the validity and utility of the systems has not been well established. This study examined the effect of awards on the perceived credibility and retention of health information on a Web page. We recruited study participants from Internet newsgroups and presented them with information on the claimed health benefits of shark cartilage. Participants were randomized to receive health information with and without a medical award present on the page. We subsequently asked them to evaluate the credibility of the Web page and posed multiple-choice questions regarding the content of the pages. 137 completed responses were included for analysis. Our results show that the presentation of awards has no significant effect on the credibility or retention of health information on a Web page. Significantly, the highly educated participants in our study found inaccurate and misleading information on shark cartilage to be slightly believable.

BACKGROUND: The antiangiogenic properties of shark cartilage extracts have been demonstrated in animal models but there are no data in human subjects. MATERIALS AND METHODS: A placebo or one of two doses of a liquid shark cartilage extract was orally administered daily, from Day 1 to Day 23 of the study protocol, to 29 healthy male volunteers randomized into three groups. On Day 12, a polyvinyl alcohol sponge threaded in a perforated silicone tubing was inserted subcutaneously on the anterior side of the arm and removed on Day 23. Evaluation of endothelial cell density, with factor VIII immunostaining, an indirect measurement of angiogenesis, was performed on histological sections of the implant using a semiquantitative numerical scale ranging from 1 (low density) to 5 (high density). The hydroxyproline content of the sponges was measured by HPLC. RESULTS: The mean endothelial cell density was significantly lower in groups that had received the liquid cartilage extract: grades 2.24 +/- 0.10, 2.47 +/- 0.10, and 3.15 +/- 0.11 for 7 and 21 ml liquid cartilage extract and placebo, respectively (P < 0.01 for both comparisons). No grade 1 was observed in the placebo group, whereas 9 treated subjects received a grade 1. Hydroxyproline content of the sponges did not differ between groups and there was no significant correlation between hydroxyproline content and endothelial cell density in the sponges. CONCLUSIONS: These results demonstrate that the liquid cartilage extract contains an antiangiogenic component bioavailable in humans by oral administration. This is the first report of an inhibition of wound angiogenesis in healthy men. Copyright 1999 Academic Press.