Revisiting the Definition of 'Healthy' Participants in Substantiation of Structure/Function Claims for Dietary Supplements.

Concepts and definitions of 'healthy' have been evolving within clinical treatment algorithms as well as reference standards such as Body Mass Index and Dietary Reference Intakes. Consumers' perception of the word 'healthy' is also changing to reflect longer life span, need to stay active and in a good state of mental well-being while managing multiple diseases. Guidelines from the US Food and Drug Administration indicate that substantiating evidence for support of Structure/Function (S/F) claims for dietary supplements is best derived from clinical research conducted in a 'healthy' population. S/F claims cannot be represented to diagnose, treat, cure or prevent any disease. However, in this context, the term 'healthy' is non-descriptive and largely interpreted as an absence of disease. Guidelines for treatment of disease have been broadened to include biomarkers of disease risk such that the pool of 'healthy' volunteers eligible to be enrolled in clinical trials for S/F claim substantiation is greatly diminished. This perspective presents the challenges faced by the food and dietary supplement industry and by researcher efforts designed to substantiate S/F claims and suggest the phrase 'physiologically stable' or 'apparently healthy' as descriptions better suited to replace the term 'healthy.'

Paraxanthine safety and comparison to caffeine.

Introduction: Caffeine, one of the most ubiquitous ingredients found in beverages and other ingested food products, has a long history of safe use. As a member of the methylxanthine class of stimulants, caffeine is not devoid of unwanted side effects at any serving level. Caffeine safety has been the subject of a safety workshop by FDA and the Institute of Medicine in the past decade. Thus, investigation into an alternate stimulant with similar pharmacology but improved safety is warranted. Paraxanthine (1,7-dimethylxanthine) is the predominant metabolite of caffeine in humans with similar stimulant properties. The few toxicity studies that are available for paraxanthine suggest that the molecule is relatively safe, although thorough characterization of its safety is required prior to widespread incorporation into foods/beverages. Methods: The aim of this study was to evaluate the toxicity of paraxanthine (Rarebird, Inc.) relative to caffeine through a battery of toxicological studies conducted in accordance with international guidelines. These studies evaluated the potential mutagenicity (bacterial reverse mutation, in vitro mammalian chromosomal aberration), genetic toxicity (in vitro mammalian cell gene mutation) and acute, sub-acute and sub-chronic oral toxicity of paraxanthine in Sprague Dawley rats. Results/Discussion: There was no evidence of genetic toxicity or mutagenicity in the in vitro studies. An acute oral LD50 of 829.20 mg/kg body weight (bw) was established. There was no mortality or treatment-related adverse effects in the 14-day repeat dose oral toxicity study, wherein rats received low, mid, or high doses of paraxanthine (50, 100, or 150 mg/kg bw, n = 5 rats/sex/group). The same findings were observed in the subchronic repeat-dose 90-day oral toxicity study at daily doses of paraxanthine of 100, 150, or 185 mg/kg bw which were compared to caffeine at 150 or 185 mg/kg bw (n = 10 animals/sex/group). However, mortality was reported in two animals in the high dose caffeine-treated animals. Therefore, the no observed adverse effect level (NOAEL) from the 90-day study was determined to be 150 mg/kg bw for caffeine and 185 mg/kg bw for paraxanthine for both male and female Sprague Dawley rats. These findings may suggest that paraxanthine could be a safer alternative to caffeine in humans.

Topical Minoxidil: Systematic Review and Meta-Analysis of Its Efficacy in Androgenetic Alopecia.

Topical minoxidil has become a mainstay in the treatment of androgenetic alopecia (AGA). Despite being a longstanding treatment for AGA, relatively few reviews of its efficacy have been published. The current study sought to synthesize the available efficacy data by performing a systematic review of the literature and conducting random-effects pairwise meta-analyses for the outcomes percent increase in hair count from baseline, investigator assessment, and patient self-assessment. Results showed that minoxidil is more effective than placebo in promoting total and nonvellus hair growth (mean difference [MD], 16.68; 95% confidence interval [CI], 9.34-24.03 and MD, 20.90; 95% CI, 9.07-32.74). A significantly higher proportion of participants in the minoxidil group had greater hair growth than participants in the placebo group as judged by both investigators and self-reports (relative risk [RR], 2.28; 95% CI, 1.58-3.31 and RR, 1.56; 95% CI, 1.34-1.80). Despite significant clinical efficacy, cosmetically acceptable results are present in only a subset of patients. Compliance is thought to be a major limiting factor and is being addressed by novel formulations and combinations.

The efficacy and safety of 5α-reductase inhibitors in androgenetic alopecia: a network meta-analysis and benefit-risk assessment of finasteride and dutasteride.

INTRODUCTION: In the light of post-marketing reports of persistent sexual dysfunction with the use of finasteride, analysis of the extent of risk associated with 5α-reductase inhibitor treatment for androgenetic alopecia (AGA) is warranted. This study sought to evaluate the efficacy of 5α-reductase inhibitors using the outcomes hair count, global photographic assessment and patient self-assessment and evaluate the benefits of treatment versus the risk of global sexual dysfunction. METHODS: A systematic review identified all relevant randomized controlled trials of finasteride 1 mg, 5 mg and dutasteride 0.5 mg. The efficacy outcome hair count was analyzed using pair-wise meta-analysis, while the efficacy outcomes global photographic assessment and patient self-assessment as well as the safety outcome global sexual dysfunction were analyzed through network meta-analyses. A benefit-risk assessment was also performed. RESULTS: The active interventions were not significantly different than each other in efficacy and were not significantly different from placebo in eliciting sexual dysfunction. Benefit-risk analysis resulted in an arbitrary ranking due to the lack of statistically significant difference between active treatments. DISCUSSION: Analysis results reiterate the efficacy and safety of 5α-reductase inhibitors for the treatment of AGA and may support the approval of dutasteride 0.5 mg as an additional treatment option, following further study.