1.
Caffeine, CYP1A2 Genotype, and Endurance Performance in Athletes.
Guest, N, Corey, P, Vescovi, J, El-Sohemy, A
Medicine and science in sports and exercise. 2018;(8):1570-1578
Abstract
PURPOSE Many studies have examined the effect of caffeine on exercise performance, but findings have not always been consistent. The objective of this study was to determine whether variation in the CYP1A2 gene, which affects caffeine metabolism, modifies the ergogenic effects of caffeine in a 10-km cycling time trial. METHODS Competitive male athletes (n = 101; age = 25 ± 4 yr) completed the time trial under three conditions: 0, 2, or 4 mg of caffeine per kilogram body mass, using a split-plot randomized, double-blinded, placebo-controlled design. DNA was isolated from saliva and genotyped for the -163A > C polymorphism in the CYP1A2 gene (rs762551). RESULTS Overall, 4 mg·kg caffeine decreased cycling time by 3% (mean ± SEM) versus placebo (17.6 ± 0.1 vs 18.1 ± 0.1 min, P = 0.01). However, a significant (P <0.0001) caffeine-gene interaction was observed. Among those with the AA genotype, cycling time decreased by 4.8% at 2 mg·kg (17.0 ± 0.3 vs 17.8 ± 0.4 min, P = 0.0005) and by 6.8% at 4 mg·kg (16.6 ± 0.3 vs 17.8 ± 0.4 min, P < 0.0001). In those with the CC genotype, 4 mg·kg increased cycling time by 13.7% versus placebo (20.8 ± 0.8 vs 18.3 ± 0.5 min, P = 0.04). No effects were observed among those with the AC genotype. CONCLUSION Our findings show that both 2 and 4 mg·kg caffeine improve 10-km cycling time, but only in those with the AA genotype. Caffeine had no effect in those with the AC genotype and diminished performance at 4 mg·kg in those with the CC genotype. CYP1A2 genotype should be considered when deciding whether an athlete should use caffeine for enhancing endurance performance.
2.
UX007 for the treatment of long chain-fatty acid oxidation disorders: Safety and efficacy in children and adults following 24weeks of treatment.
Vockley, J, Burton, B, Berry, GT, Longo, N, Phillips, J, Sanchez-Valle, A, Tanpaiboon, P, Grunewald, S, Murphy, E, Humphrey, R, et al
Molecular genetics and metabolism. 2017;(4):370-377
Abstract
BACKGROUND Long-chain fatty acid oxidation disorders (LC-FAOD) lead to accumulation of high concentrations of potentially toxic fatty acid intermediates. Newborn screening and early intervention have reduced mortality, but most patients continue to experience frequent hospitalizations and significant morbidity despite treatment. The deficient energy state can cause serious liver, muscle, and heart disease, and may be associated with an increased risk of sudden death. Triheptanoin is a medium odd-chain fatty acid. Anaplerotic metabolites of triheptanoin have the potential to replace deficient tricarboxylic acid (TCA) cycle intermediates, resulting in net glucose production as a novel energy source for the treatment of LC-FAOD. STUDY DESIGN A single-arm, open-label, multicenter Phase 2 safety and efficacy study evaluated patients with severe LC-FAOD evidenced by ongoing related musculoskeletal, cardiac, and/or hepatic events despite treatment. After a four-week run-in on current regimen, investigational triheptanoin (UX007) was titrated to a target dose of 25-35% of total daily caloric intake. Patients were evaluated on several age/condition-eligible endpoints, including submaximal exercise tests to assess muscle function/endurance (12-minute walk test; 12MWT) and exercise tolerance (cycle ergometry), and health related quality of life (HR-QoL). Results through 24weeks of treatment are presented; total study duration is 78weeks. RESULTS Twenty-nine patients (0.8 to 58years) were enrolled; most qualified based on severe musculoskeletal disease. Twenty-five patients (86%) completed the 24-week treatment period. At Week 18, eligible patients (n=8) demonstrated a 28% increase (LS mean=+181.9 meters; p=0.087) from baseline (673.4meters) in 12MWT distance. At Week 24, eligible patients (n=7) showed a 60% increase in watts generated (LS mean=+409.3W; p=0.149) over baseline (744.6W) for the exercise tolerance test. Improvements in exercise tests were supported by significant improvements from baseline in the adult (n=5) self-reported SF-12v2 physical component summary score (LS mean=+8.9; p<0.001). No difference from baseline was seen in pediatric parent-reported (n=5) scores (SF-10) at Week 24. Eighteen patients (62%) had treatment-related adverse events, predominantly gastrointestinal (55%), mild-to-moderate in severity, similar to that seen with prior treatment with medium chain triglyceride (MCT) oil. One patient experienced a treatment-related serious adverse event of gastroenteritis. One patient discontinued from study due to diarrhea of moderate severity; the majority of patients (25/29; 86%) elected to continue treatment in the extension period. CONCLUSIONS In patients with severe LC-FAOD, UX007 interim study results demonstrated improved exercise endurance and tolerance, and were associated with positive changes in self-reported HR-QoL.