Safety and immunogenicity of VGX-3100 formulations in a healthy young adult population.

HPV remains the most common sexually transmitted disease worldwide, despite improvements in awareness, screening, prophylactic vaccination uptake, and surgical treatment. VGX-3100 is an immunotherapy that uses electroporation to introduce DNA encoding for modified HPV-16 and HPV-18, E6-and E7 proteins into myocytes to stimulate an effector T cell response. We now report immunogenicity and safety of VGX-3100 for a refrigeration-stable formulation, which improves patient-care setting usability. This multi-arm, double-blinded, randomized trial enrolled 235 healthy men and women to receive either a refrigerated (RF) or frozen formulation (FF) of VGX-3100. Three doses were administered intramuscularly with electroporation at 0, 4, and 12 weeks. Non-inferiority of RF to FF was assessed by comparing the proportion of subjects who achieved a ≥2-fold increase from baseline to Week 14 in Spot Forming Units/106 PMBCs using an interferon-γ enzyme-linked immunospot assay. There were no related SAEs. Injection site reactions were the most common adverse event (54%, RF; 66%, FF) the majority of which resolved within a few minutes following administration. The primary endpoint was met with 89.9% of RF recipients and 97.2% of FF recipients reaching a ≥2-fold rise in SFU/106 PBMC, 2 weeks following the last dose; RF was statistically non-inferior to FF (p = .022). A systemic, immunologic approach has the potential to fill a critical gap in the ability to treat men and women with high grade HPV diseases. These safety and immunogenicity data are supportive of the continued development of a refrigerated formulation of VGX-3100.

A clinical evaluation to determine the safety, pharmacokinetics, and pharmacodynamics of an inositol-stabilized arginine silicate dietary supplement in healthy adult males.

PURPOSE: The purpose of this study was to characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of an oral inositol-stabilized arginine silicate dietary supplement. SUBJECTS AND METHODS: Ten healthy males, 26.7±5.4 years, took three 500 mg arginine silicate capsules (active product) for 14 days. The subjects attended test visits on Days 1 and 14. Fasting blood and saliva collections were performed predose and at 0.5 hours, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, and 6 hours postdose for plasma arginine, serum silicon, and salivary nitric oxide (NO) + nitrite. RESULTS: Day 1 PK parameters (adjusted for body weight) for arginine were peak serum concentration (C Max) 30.06±7.80 µg/mL, time it takes to reach peak serum concentration (t Max) 1.13±0.52 hours, and time required to reach half its original concentration (t 1/2) 15.93±9.55 hours and for silicon were C Max 2.99±0.63 µg/mL, t Max 2.44±2.05 hours, and t 1/2 34.56±16.56 hours. After Day 1 dose, arginine levels increased at 0.5 hours, 1 hour, 1.5 hours, 2 hours, 3 hours, and 5 hours (P<0.01) and silicon levels increased at 1 hour and 1.5 hours (P<0.05). After Day 14 dose, arginine levels increased at 0.5 hours, 1 hour, and 1.5 hours (P<0.05) and silicon levels increased at 1 hour, 1.5 hours, 2 hours, and 3 hours (P<0.01). After 14 days of use, baseline arginine trended toward being higher than baseline Day 1 (P=0.0645), and 4-hour postdose plasma arginine was significantly higher (P=0.0488) at Day 14 than Day 1. Although not a significant difference, NO, as measured as salivary nitrate, increased in four subjects and stayed the same in six subjects at 0.5 hours after the first dose (P=0.125). After 14 days of use, baseline NO levels increased in six subjects and stayed the same in four subjects; this shift was significant (P=0.031). CONCLUSION: The arginine silicate dietary supplement increases blood levels of arginine after a single dose within 30 minutes and blood levels of silicon for up to 1.5 hours. Blood levels of arginine, silicon, and NO (salivary nitrite) were elevated consistently after 14 days of use. The observed increase in baseline salivary nitrite is supporting information that there was some improvement in NO production. Further study on the effect of this supplement on NO production and the resulting physiological effect is warranted. Within the specific protocol of this study, the product was found to be safe.

A Prospective Randomized Double-Blind Study Evaluating UP165 and S-Adenosyl-l-Methionine on Depression, Anxiety and Psychological Well-Being.

The primary objective of this pilot clinical trial was to evaluate the effects of UP165 (derived from Zea mays L., commonly known as corn) over time. The secondary objective was the comparison for outcomes versusS-adenosyl-methionine (SAM-e). Subjects with mild depression or anxiety were given the Beck Depression Inventory second edition (BDI-II), the Beck Anxiety Inventory (BAI), and the Schwartz Outcome Scale (SOS-10). Forty-two subjects (21-65 years old) were randomized to eight-weeks of supplementation with UP165 or SAM-e with questionnaires being administered at randomization, week four and eight. Those receiving UP165 achieved significant reduction from baseline at weeks four and eight, respectively for the BDI-II, as well as a trend for reduction in BAI at week four and significance at week eight. There was a trend for improvement on the SOS at week four and significance at week eight. SAM-e demonstrated a trend for improvement on the BDI-II by week eight over the UP165 with no differences between the two for the BAI or the SOS. Overall, this study indicates that there may be benefit to UP165 for mood enhancement in those with mild depression or anxiety. Randomized placebo comparator trials appear warranted.

Efficacy and safety of Elaeis guineensis and Ficus deltoidea leaf extracts in adults with pre-diabetes.

BACKGROUND: Individuals with pre-diabetes (fasting glucose 100-125 mg/dl) are at increased risk of developing diabetes; 50% of U.S. adults aged ≥65 y had pre-diabetes in 2005-08. Extracts of the leaves of E. guineensis (a tropical plant producing edible oil), and F. deltoidea (a traditional tea) contain phenolic compounds that have hypoglycemic effects in vitro and in vivo. Therefore, a study of the efficacy and safety of these leaf extracts was undertaken. METHODS: Otherwise healthy adults with pre-diabetes (15m/15f; aged 21 to 65 y; BMI ≥25 and < 40 kg/m²) were assigned to one of 3 groups for 8 weeks: E. guineensis leaf extract 500 mg or 1000 mg or F. deltoidea leaf extract 1000 mg. Assessments at baseline and throughout the study included: fasting plasma glucose, insulin, OGTT, and HOMA-IR; body weight and waist circumference; vital signs, comprehensive metabolic and lipid panels. Statistical analyses included paired Student's t-test and ANCOVA or non-parametric tests when indicated. RESULTS: E. guineensis intervention for 8 weeks decreased fasting plasma glucose and insulin levels, glucose and insulin areas under the curve, and insulin resistance, and increased insulin sensitivity. The 500 mg dose of E. guineensis had a more consistent effect on reducing glycemia than the 1000 mg dose and the insulin findings at the two dose levels were somewhat inconsistent. Differences in the distribution of baseline insulin levels in the low and high dose groups may explain some of these observed differences in responses. F. deltoidea leaf extract had no effect on glycemia variables but both total and LDL cholesterol concentrations were significantly decreased in this group. There were no significant differences in change of weight; however waist circumference was significantly lower in the E. guineensis groups after intervention. At baseline and after 8 weeks of intervention, vital signs and safety lab tests were within normal limits and not significantly different between groups or due to intervention. CONCLUSIONS: These results suggest that the leaf extracts of E. guineensis and F. deltoidea may have positive effects on glucose and lipid levels and are safe for use in humans. Further study is required to determine the maximum effective dosages and the mechanisms of action.

Influence of methylsulfonylmethane on markers of exercise recovery and performance in healthy men: a pilot study.

BACKGROUND: Methylsulfonylmethane (MSM) has been reported to provide anti-inflammatory and antioxidant effects in both animal and man. Strenuous resistance exercise has the potential to induce both inflammation and oxidative stress. Using a pilot (proof of concept) study design, we determined the influence of MSM on markers of exercise recovery and performance in healthy men. METHODS: Eight, healthy men (27.1 ± 6.9 yrs old) who were considered to be moderately exercise-trained (exercising <150 minutes per week) were randomly assigned to ingest MSM at either 1.5 grams per day or 3.0 grams per day for 30 days (28 days before and 2 days following exercise). Before and after the 28 day intervention period, subjects performed 18 sets of knee extension exercise in an attempt to induce muscle damage (and to be used partly as a measure of exercise performance). Sets 1-15 were performed at a predetermined weight for 10 repetitions each, while sets 16-18 were performed to muscular failure. Muscle soreness (using a 5-point Likert scale), fatigue (using the fatigue-inertia subset of the Profile of Mood States), blood antioxidant status (glutathione and Trolox Equivalent Antioxidant Capacity [TEAC]), and blood homocysteine were measured before and after exercise, pre and post intervention. Exercise performance (total work performed during sets 16-18 of knee extension testing) was also measured pre and post intervention. RESULTS: Muscle soreness increased following exercise and a trend was noted for a reduction in muscle soreness with 3.0 grams versus 1.5 grams of MSM (p = 0.080), with a 1.0 point difference between dosages. Fatigue was slightly reduced with MSM (p = 0.073 with 3.0 grams; p = 0.087 for both dosages combined). TEAC increased significantly following exercise with 3.0 grams of MSM (p = 0.035), while homocysteine decreased following exercise for both dosages combined (p = 0.007). No significant effects were noted for glutathione or total work performed during knee extension testing (p > 0.05). CONCLUSION: MSM, especially when provided at 3.0 grams per day, may favorably influence selected markers of exercise recovery. More work is needed to extend these findings, in particular using a larger sample of subjects and the inclusion of additional markers of exercise recovery and performance.

Comparison of coconut water and a carbohydrate-electrolyte sport drink on measures of hydration and physical performance in exercise-trained men.

BACKGROUND: Sport drinks are ubiquitous within the recreational and competitive fitness and sporting world. Most are manufactured and artificially flavored carbohydrate-electrolyte beverages. Recently, attention has been given to coconut water, a natural alternative to manufactured sport drinks, with initial evidence indicating efficacy with regard to maintaining hydration. We compared coconut water and a carbohydrate-electrolyte sport drink on measures of hydration and physical performance in exercise-trained men. METHODS: Following a 60-minute bout of dehydrating treadmill exercise, 12 exercise-trained men (26.6 ± 5.7 yrs) received bottled water (BW), pure coconut water (VitaCoco®: CW), coconut water from concentrate (CWC), or a carbohydrate-electrolyte sport drink (SD) [a fluid amount based on body mass loss during the dehydrating exercise] on four occasions (separated by at least 5 days) in a random order, single blind (subject and not investigators), cross-over design. Hydration status (body mass, fluid retention, plasma osmolality, urine specific gravity) and performance (treadmill time to exhaustion; assessed after rehydration) were determined during the recovery period. Subjective measures of thirst, bloatedness, refreshed, stomach upset, and tiredness were also determined using a 5-point visual analog scale. RESULTS: Subjects lost approximately 1.7 kg (~2% of body mass) during the dehydrating exercise and regained this amount in a relatively similar manner following consumption of all conditions. No differences were noted between coconut water (CW or CWC) and SD for any measures of fluid retention (p > 0.05). Regarding exercise performance, no significant difference (p > 0.05) was noted between BW (11.9 ± 5.9 min), CW (12.3 ± 5.8 min), CWC (11.9 ± 6.0 min), and SD (12.8 ± 4.9 min). In general, subjects reported feeling more bloated and experienced greater stomach upset with the CW and CWC conditions. CONCLUSION: All tested beverages are capable of promoting rehydration and supporting subsequent exercise. Little difference is noted between the four tested conditions with regard to markers of hydration or exercise performance in a sample of young, healthy men. Additional study inclusive of a more demanding dehydration protocol, as well as a time trial test as the measure of exercise performance, may more specifically determine the efficacy of these beverages on enhancing hydration and performance following dehydrating exercise.

A prospective, randomized, double-blind, placebo-controlled parallel-group dual site trial to evaluate the effects of a Bacillus coagulans-based product on functional intestinal gas symptoms.

BACKGROUND: This randomized double blind placebo controlled dual site clinical trial compared a probiotic dietary supplement to placebo regarding effects on gastrointestinal symptoms in adults with post-prandial intestinal gas-related symptoms (abdominal pain, distention, flatulence) but no gastrointestinal (GI) diagnoses to explain the symptoms. METHODS: Sixty-one adults were enrolled (age 36.5 +/- 12.6 years; height 165.1 +/- 9.2 cm; weight 75.4 +/- 17.3 kg) and randomized to either Digestive Advantage Gas Defense Formula - (GanedenBC30 Bacillus coagulans GBI-30, 6086): n = 30; or Placebo: n = 31. Study subjects were evaluated every two weeks over a four-week period using validated questionnaires and standard biochemical safety testing. Outcome criteria of interest included change from baseline in Gastrointestinal Symptom Rating Scale (GSRS) abdominal pain, abdominal distention, flatus, and the Severity of Dyspepsia Assessment (SODA) bloating and gas subscores over four weeks of product use. RESULTS: Measured against the placebo, subjects in the probiotic group achieved significant improvements in GSRS abdominal pain subscore (p = 0.046) and the GSRS total score (p = 0.048), with a strong trend for improvement on the GSRS abdominal distension subscore (p = 0.061). A strong placebo effect was evident which could explain the lack of statistical significant differences between the groups for many of the efficacy variables. CONCLUSION: In conclusion, the Bacillus coagulans-based product was effective in improving the quality of life and reducing gastrointestinal symptoms in adults with post prandial intestinal gas-related symptoms and no GI diagnoses. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00881322.

A pilot trial comparing the availability of vitamins C, B6, and B12 from a vitamin-fortified water and food source in humans.

PRIMARY OBJECTIVE: In a cross-over randomized pilot study, the relative absorption of vitamins C, B(6) and B(12) were tested using a commercial vitamin-water (VW) and a standardized mixed meal (MM). METHODS AND PROCEDURES: Twelve adults (22.9+/-3.7 years), received the VW and the MM, randomly ordered, with a minimum 7-day washout period between. Blood was drawn pre-ingestion and over a post-ingestion period of 300+ min. Test meal quantities were formulated to contain equal amounts of vitamins B(6), B(12), and C as per the water label. Analysis revealed that a scaling factor had to be used to balance the actual content differences between test products. MAIN OUTCOMES AND RESULTS: Using the adjusted numbers for actual water vitamin concentration, there were no differences in the maximum concentration and the 5-h area under the curve for vitamins B(6), B(12) or C between the VW and the MM. CONCLUSIONS: VW was found to provide similar in vivo nutrition as the test MM at a caloric saving.

Effect of a proprietary Magnolia and Phellodendron extract on stress levels in healthy women: a pilot, double-blind, placebo-controlled clinical trial.

BACKGROUND: Recent research has established correlations between stress, anxiety, insomnia and excess body weight and these correlations have significant implications for health. This study measured the effects of a proprietary blend of extracts of Magnolia officinalis and Phellodendron amurense (Relora) on anxiety, stress and sleep in healthy premenopausal women. METHODS: This randomized, parallel, placebo controlled clinical study was conducted with healthy, overweight (BMI 25 to 34.9), premenopausal female adults, between the ages of 20 and 50 years, who typically eat more in response to stressful situations and scores above the national mean for women on self-reporting anxiety. The intervention was Relora (250 mg capsules) or identical placebo 3 times daily for 6 weeks. Anxiety as measured by the Spielberger STATE-TRAIT questionnaires, salivary amylase and cortisol levels, Likert Scales/Visual Analog Scores for sleep quality and latency, appetite, and clinical markers of safety. The study was conducted by Miami Research Associates, a clinical research organization in Miami, FL. RESULTS: The intent-to-treat population consisted of 40 subjects with 26 participants completing the study. There were no significant adverse events. Relora was effective, in comparison to placebo, in reducing temporary, transitory anxiety as measured by the Spielberger STATE anxiety questionnaire. It was not effective in reducing long-standing feelings of anxiety or depression as measured using the Spielberger TRAIT questionnaire. Other assessments conducted in this study including salivary cortisol and amylase levels, appetite, body morphology and sleep quality/latency were not significantly changed by Relora in comparison to placebo. CONCLUSION: This pilot study indicates that Relora may offer some relief for premenopausal women experiencing mild transitory anxiety. There were no safety concerns or significant adverse events observed in this study.

Effect of protein source and resistance training on body composition and sex hormones.

BACKGROUND: Evidence suggests an inverse relationship between soy protein intake and serum concentrations of male sex hormones. Anecdotal evidence indicates that these alterations in serum sex hormones may attenuate changes in lean body mass following resistance training. However, little empirical data exists regarding the effects of soy and milk-based proteins on circulating androgens and exercise induced body composition changes. METHODS: For 12 weeks 20 subjects were supplemented with 50 g per day of one of four different protein sources (Soy concentrate; Soy isolate; Soy isolate and whey blend, and Whey blend only) in combination with a resistance-training program. Body composition, testosterone, estradiol and sex hormone binding globulin (SHBG) were measured at baseline and week 12. RESULTS: Protein supplementation resulted in a significant increase in lean body mass independent of protein source (0.5 +/- 1.1 and 0.9 +/- 1.4 kg, p = 0.006, p = 0.007). No significant differences were observed between groups for total and free testosterone, SHBG, percentage body fat, BMI or body weight. The Testosterone/Estradiol ratio increased across all groups (+13.4, p = 0.005) and estradiol decreased (p = 0.002). Within group analysis showed significant increases in the Testosterone/Estradiol ratio in soy isolate + whey blend group (+16.3, p = 0.030). Estradiol was significantly lower in the whey blend group (-9.1 +/- 8.7 pg/ml, p = 0.033). CONCLUSION: This investigation shows that 12 week supplementation with soy protein does not decrease serum testosterone or inhibit lean body mass changes in subjects engaged in a resistance exercise program.