4. Discussion
This is the first well-designed comparison of pterostilbene in a dose-ranging controlled human trial. There appears to be no direct effect of pterostilbene on measures of hepatic or renal function. The proposed mechanism of action of pterostilbene is PPAR-α agonism [4]. Currently available FDA-approved PPAR-α agonists (e.g., fenofibrate or pioglitazone) have both renal and hepatic dose adjustments required. Fenofibrate has reported increases in serum creatinine from baseline by 12% as an ADR [14]. Despite a high prevalence of a combination with statin, pterostilbene did not demonstrate any biochemical hepatic ADRs. There does not appear to be a need for such precautions with pterostilbene in doses up to 250 mg/day.
No patients taking statins reported myopathy. Myopathy was reported in patients not taking statins in both low-dose groups on 3 occasions. The lack of myopathy in the high-dose group and in statin users decreases the likelihood of this ADR in relation to pterostilbene. Though a drug-drug interaction with statins appears unlikely, possible drug-drug interactions with other medication classes warrant further investigation.
There is unlikely an association of pterostilbene with gastrointestinal ADR (with or without food) or itching as both reported ADRs occurred to a low extent in only the placebo and high dose groups.
While <20% of completers reported any dietary changes during the trial, increased appetite was reported in all three pterostilbene arms, but not placebo. Although detailed changes in weight will be reported separately, there was no overall trend towards an increase in body weight. Participants reporting this ADR () all gained weight (average 1.7 pounds). A possible mechanism is cross-selective PPAR-γ activation of pterostilbene. This unique response in a small subgroup of patients warrants periodic weight monitoring and further investigation.
The slight decrease in bicarbonate could indicate a minor acidic effect of pterostilbene in the blood. This is an expected outcome due to the general acidic nature of phenols, such as pterostilbene. This finding does indicate that the encapsulated method of delivery used in this trial appears to be sufficient for blood absorption in humans.
Some limitations include a small trial population in one region of the United States over approximately 7 weeks. Also, the total daily dose was restricted to 250 mg and no patient reported overuse. While there are no obvious signs of toxicity at this maximum dose, the potential for toxicity cannot be excluded at higher doses.
Neither complete blood count nor urinalysis was performed. Urine was collected for oxidative stress comparison only. Results of a previous short-term healthy volunteer trial demonstrated no baseline changes in blood count when evaluating a pterostilbene-rich extract [8]. The risk of hematological or urinary ADRs was not demonstrated in animal models or a common ADR with currently available PPAR-α agonists. There was also no electrocardiogram (ECG) performed due to budgetary constraints. Additional evaluation of ECG monitoring is warranted considering that the target patient population is at-risk for cardiovascular disease and previous dietary supplements have demonstrated QTc prolongation (i.e., Ephedra) [15].
In the United States, dietary supplements are not specifically monitored by a regulating body for assessment of quality. Unfortunately, some dietary supplements may contain varying and even absent amounts of listed active ingredients [16]. In this trial, purity was confirmed in a blinded, randomized manner.
5. Conclusion
Pterostilbene is generally safe for use in humans at doses up to 250 mg per day. Pterostilbene is well-tolerated at a twice daily dosing frequency.
Acknowledgments
This trial was supported by a grant through ChromaDex, Inc. ChromaDex, Inc. had no role in the collection or interpretation/analysis of data. The safety results were reported at the International Society of Antioxidants in Nutrition and Health (ISANH) 6th World Congress on Polyphenols Applications: Paris Polyphenols 2012. The authors would like to thank the pharmacy residents and students that participated in the data collection phase of this trial (Clinicaltrials.gov identifier NCT 01267227).
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