Related substances: Related dietary supplements include bovine cartilage, chondroitin sulfate, and glucosamine. The safety of these substances was not thoroughly reviewed for this prototype monograph.

Since antiangiogenic activity has been suggested as the mechanism of action of shark cartilage preparations and in vitro studies have shown antiangiogenic potential, it is relevant to consider safety cautions in place for other compounds with antiangiogenic activity (i.e., functional relatedness as described in Chapter 6). Indeed, there is a potential for adverse side effects when angiogenesis is inhibited. For example, thalidomide, a known teratogen, has antiangiogenic activity. Clinical trials using other antiangiogenic agents have reported a wide variety of adverse effects, including neurotoxic effects.

Other information: Squalamine, a potential contaminant during processing, has been associated with reversible nonserious side effects (when administered by intravenous infusion to subjects with advanced-stage cancer).

There is a substantial lack of safety data for shark cartilage both clinically and in animal toxicity studies, including a lack of any serious adverse event reports. In the context of the large numbers of individuals that have been exposed, the lack of serious acute adverse event reports may be indicative of no serious overt acute toxicity. However, chronic toxicity has not been systematically evaluated. Shark cartilage does not appear to be associated with any serious adverse events, even when taken chronically in gram quantities; however, nonserious side effects have been reported. Nonserious side effects, especially nausea and vomiting, may motivate the individual to discontinue consumption. It should be noted that most clinical trials involved critically ill individuals and thus these gastrointestinal disturbances may be associated with other clinical circumstances or treatments. The incidence of these nonserious side effects is in the range of side effects expected in a placebo group. Although the available evidence does not indicate sufficient evidence for concern about shark cartilage as a dietary supplement ingredient, there has not been a systematic and scientific safety evaluation of shark cartilage.

Antiangiogenesis: There is a body of evidence that some shark cartilage preparations, when tested in vitro, contain a substance that has antiangiogenic properties. A common assay used to demonstrate angiogenicity (i.e.,