Nutritional co-therapy with 1,3-butanediol and multi-ingredient antioxidants enhances autophagic clearance in Pompe disease.

Alglucosidase alpha is an orphan drug approved for enzyme replacement therapy (ERT) in Pompe disease (PD); however, its efficacy is limited in skeletal muscle because of a partial blockage of autophagic flux that hinders intracellular trafficking and enzyme delivery. Adjunctive therapies that enhance autophagic flux and protect mitochondrial integrity may alleviate autophagic blockage and oxidative stress and thereby improve ERT efficacy in PD. In this study, we compared the benefits of ERT combined with a ketogenic diet (ERT-KETO), daily administration of an oral ketone precursor (1,3-butanediol; ERT-BD), a multi-ingredient antioxidant diet (ERT-MITO; CoQ10, α-lipoic acid, vitamin E, beetroot extract, HMB, creatine, and citrulline), or co-therapy with the ketone precursor and multi-ingredient antioxidants (ERT-BD-MITO) on skeletal muscle pathology in GAA-KO mice. We found that two months of 1,3-BD administration raised circulatory ketone levels to ≥1.2 mM, attenuated autophagic buildup in type 2 muscle fibers, and preserved muscle strength and function in ERT-treated GAA-KO mice. Collectively, ERT-BD was more effective vs. standard ERT and ERT-KETO in terms of autophagic clearance, dampening of oxidative stress, and muscle maintenance. However, the addition of multi-ingredient antioxidants (ERT-BD-MITO) provided the most consistent benefits across all outcome measures and normalized mitochondrial protein expression in GAA-KO mice. We therefore conclude that nutritional co-therapy with 1,3-butanediol and multi-ingredient antioxidants may provide an alternative to ketogenic diets for inducing ketosis and enhancing autophagic flux in PD patients.

A Five-Ingredient Nutritional Supplement and Home-Based Resistance Exercise Improve Lean Mass and Strength in Free-Living Elderly.

Old age is associated with lower physical activity levels, suboptimal protein intake, and desensitization to anabolic stimuli, predisposing for age-related muscle loss (sarcopenia). Although resistance exercise (RE) and protein supplementation partially protect against sarcopenia under controlled conditions, the efficacy of home-based, unsupervised RE (HBRE) and multi-ingredient supplementation (MIS) is largely unknown. In this randomized, placebo-controlled and double-blind trial, we examined the effects of HBRE/MIS on muscle mass, strength, and function in free-living, older men. Thirty-two sedentary men underwent twelve weeks of home-based resistance band training (3 d/week), in combination with daily intake of a novel five-nutrient supplement ('Muscle5'; M5, n = 16, 77.4 ± 2.8 y) containing whey, micellar casein, creatine, vitamin D, and omega-3 fatty acids, or an isocaloric/isonitrogenous placebo (PLA; n = 16, 74.4 ± 1.3 y), containing collagen and sunflower oil. Appendicular and total lean mass (ASM; +3%, TLM; +2%), lean mass to fat ratios (ASM/% body fat; +6%, TLM/% body fat; +5%), maximal strength (grip; +8%, leg press; +17%), and function (5-Times Sit-to-Stand time; -9%) were significantly improved in the M5 group following HBRE/MIS therapy (pre vs. post tests; p < 0.05). Fast-twitch muscle fiber cross-sectional areas of the quadriceps muscle were also significantly increased in the M5 group post intervention (Type IIa; +30.9%, Type IIx, +28.5%, p < 0.05). Sub-group analysis indicated even greater gains in total lean mass in sarcopenic individuals following HBRE/MIS therapy (TLM; +1.65 kg/+3.4%, p < 0.05). We conclude that the Muscle5 supplement is a safe, well-tolerated, and effective complement to low-intensity, home-based resistance exercise and improves lean mass, strength, and overall muscle quality in old age.

Protocol for evaluating the effects of a foot-ankle therapeutic exercise program on daily activity, foot-ankle functionality, and biomechanics in people with diabetic polyneuropathy: a randomized controlled trial.

BACKGROUND: Diabetic polyneuropathy (DPN) negatively affects foot and ankle function (strength and flexibility), which itself affects the daily physical activity and quality of life of patients. A physical therapy protocol aiming to strengthen the intrinsic and extrinsic foot muscles and increase flexibility may be a promising approach to improve lower-extremity function, prevent further complications, and improve autonomy for daily living activities in these patients. Thus, the inclusion of a specific foot-related exercises focused on the main musculoskeletal impairments may have additional effects to the conventional interventions in the diabetic foot. METHODS/DESIGN: A prospective, parallel-group, outcome-assessor blinded, randomized controlled trial (RCT) will be conducted in 77 patients with DPN who will be randomly allocated to usual care (control arm) or usual care with supervised foot-ankle exercises aiming to increase strengh and flexibility twice a week for 12 weeks and remotely supervised foot-ankle exercises for a year through a web software. Patients will be evaluated 5 times in a 1 year period regarding daily physical activity level, self-selected and fast gait speeds (primary outcomes), foot ulcer incidence, ulcer risk classification, neuropathy testing, passive ankle range of motion, quality of life, foot health and functionality, foot muscle strength, plantar pressure, and foot-ankle kinematics and kinetics during gait. DISCUSSION: This study aims to assess the effect of a foot-ankle strength and flexibility program on a wide range of musculoskeletal, activity-related, biomechanical, and clinical outcomes in DPN patients. We intend to demonstrate evidence that the year-long training program is effective in increasing gait speed and daily physical activity level and in improving quality of life; foot strength, functionality, and mobility; and biomechanics while walking. The results will be published as soon as they are available. TRIAL REGISTRATION: This study has been registered at ClinicalTrials.gov as NCT02790931 (June 6, 2016) under the name "Effects of foot muscle strengthening in daily activity in diabetic neuropathic patients".

De la farmacocinética a la farmacodinámica, ¿estamos listos para los software 3D? / From pharmacokinetics to pharmacodynamics -Are we ready for 3D software?

Abstract The relationship between the dose and plasma concentration of a drug is determined by pharmacokinetics. However, difficulties arise when more than one drug is administered simultaneously. There is currently a gap in the teaching model when trying to convey the significance of pharmacodynamic interactions. In this article the authors reflect on the importance of developing a software that simplifies the pharmacokinetic concepts of two drugs, turning them into one single variable in space as a function of time. Together with depth of anesthesia monitoring and the pain control variables, this model will bring pharmacokinetics and pharmacodynamics together and provide a teaching tool for improved understanding of these concepts.

Resumen La relación entre la dosis y la concentración plasmática de un fármaco está determinada por la farmacocinética. Sin embargo, se presentan dificultades cuando hay más de un medicamento administrado de forma simultánea. En la actualidad hay un vacío en el modelo de enseñanza cuando se pretende difundir la importancia de las interacciones farmacodinámicas. En el presente artículo los autores hacen una reflexión sobre la importancia de poder construir un software que simplifique los conceptos farmacocinéticos de dos medicamentos, convirtiéndolos en una sola variable de espacio en función del tiempo. Este modelo permitiría, junto con la monitorización de la profundidad anestésica y las variables de control del dolor, acoplar la farmacocinética a la farmacodinámica, y brindaría una herramienta de educación para la comprensión de estos conceptos.

Microencapsulation of xylitol by double emulsion followed by complex coacervation.

The objective of this study was to produce and characterise xylitol microcapsules for use in foods, in order to prolong the sweetness and cooling effect provided by this ingredient. Complex coacervation was employed as the microencapsulation method. A preliminary double emulsion step was performed due to the hydrophilicity of xylitol. The microcapsules obtained were characterised in terms of particle size and morphology (optical, confocal and scanning electron microscopy), solubility, sorption isotherms, FTIR, encapsulation efficiency and release study. The microcapsules of xylitol showed desirable characteristics for use in foods, such as a particle size below 109 µm, low solubility and complete encapsulation of the core by the wall material. The encapsulation efficiency ranged from 31% to 71%, being higher in treatments with higher concentrations of polymers. Release of over 70% of the microencapsulated xylitol in artificial saliva occurred within 20 min.

Effect of different dosage and administration schedules of folic acid on blood folate levels in a population of Honduran women of reproductive age.

BACKGROUND: Observational studies and clinical trials have shown conclusive evidence that periconceptional folic acid supplementation prevents up to 70 % of neural tube defects (NTD). The Honduran government wanted to implement a supplementation programme of folic acid but needed to assess the relative effects of two dosages of folic acid. OBJECTIVE: To determine the effect of two dosages of folic acid on blood folate levels in Honduran female factory workers aged 18 to 49 years. DESIGN: This was a randomized, double-blind control supplementation trial conducted in Choloma, Honduras. A total of 140 eligible women were randomly assigned to two dosage groups and followed up for 12 weeks. One group received a daily dosage of 1 mg folic acid and the other a once weekly dosage of 5 mg. Serum folate and red blood cell folate levels were determined by radioassay at baseline, 6 weeks and 12 weeks. RESULTS: Serum folate levels increased from 6.3 (se 0.2) to 14.9 (se 0.6) ng/ml (P < 0.0001) in women assigned to the 1 mg/d group and from 6.9 (se 0.3) to 10.1 (se 0.4) ng/ml (P < 0.0001) in those assigned to the 5 mg/week group. Red blood cell folate concentrations also increased significantly in both groups, albeit more slowly. Educational level, age and BMI were not associated with the changes in serum and red blood cell folate levels during the supplementation period. However, a differential effect on serum folate levels by dosage group and time was observed. CONCLUSIONS: Although both folate supplementation regimens increased serum and red blood cell folate levels significantly among the women studied, blood folate levels that are considered to be protective of NTD were reached faster with the daily dosage of 1 mg folic acid.

Simultaneous modeling of the pharmacokinetics and pharmacodynamics of midazolam and diazepam.

The pharmacokinetics and pharmacodynamics of midazolam and diazepam were compared after intravenous infusions of 0.03 and 0.07 mg/kg midazolam and 0.1 and 0.2 mg/kg diazepam on four separate occasions in 12 healthy male subjects in a randomized four-way crossover design. The Digit Symbol Substitution Test (DSST) was used as a measure of drug effect. Subjects performed three practice tests before dosing to account for any effects caused by familiarization ("learning curve") with the testing procedure. Pharmacokinetic and pharmacodynamic data were simultaneously fitted to a semiparametric model. In this model, a pharmacokinetic model related dose to plasma concentrations, a link model related plasma concentrations to the concentration at the effect site, and a pharmacodynamic model related the effect site concentration to the observed effect. The plasma-effect site equilibrium half-life was approximately 2 1/2 times longer for midazolam than for diazepam, which is in good agreement with previously published data. Based on the estimated effect site concentration at which half of the maximal effect was reached, midazolam had approximately a sixfold greater intrinsic potency than diazepam. This difference in potency was also observed in a previous study that used transformed electroencephalographic (EEG) data to assess pharmacodynamic activity. The findings reported here with a clinically relevant pharmacodynamic marker (DSST) confirm the utility of surrogate drug effect measures such as EEG. This work also shows the feasibility of conducting pharmacokinetic pharmacodynamic analysis during the drug development process.

The influence of orlistat on the pharmacokinetics and pharmacodynamics of glyburide in healthy volunteers.

To assess the influence of orlistat on the pharmacokinetics and pharmacodynamics (the blood glucose-lowering effect) of glyburide, an open-label, placebo-controlled, randomized, two-way crossover study was done in 12 healthy male volunteers. Each subject received single 5-mg oral doses of glyburide (Micronase; The Upjohn Company, Kalamazoo, MI) on the fifth day of treatment with placebo (treatment A) and 80-mg orlistat (treatment B) three times a day for 4 1/3 days; the two treatments were separated by a five-day washout period. Serial blood samples were collected before and at appropriate intervals after each glyburide dose to determine plasma concentrations and blood glucose levels. Values of Cmax and AUC of glyburide showed an equality of the two treatments by the analysis of variance. There was an apparent correlation between blood glucose level and the logarithm of plasma glyburide concentration; this relationship appeared to not be altered when glyburide was administered with orlistat. In conclusion, orlistat administered at doses of 80-mg three times daily does not significantly alter the pharmacokinetics and blood glucose-lowering effect of a single 5-mg oral dose of glyburide in healthy volunteers.