The Bioequivalence of Tafamidis 61-mg Free Acid Capsules and Tafamidis Meglumine 4 × 20-mg Capsules in Healthy Volunteers.

Tafamidis, a non-nonsteroidal anti-inflammatory benzoxazole derivative, acts as a transthyretin (TTR) stabilizer to slow progression of TTR amyloidosis (ATTR). Tafamidis meglumine, available as 20-mg capsules, is approved in more than 40 countries worldwide for the treatment of adults with early-stage symptomatic ATTR polyneuropathy. This agent, administered as an 80-mg, once-daily dose (4 × 20-mg capsules), is approved in the United States, Japan, Canada, and Brazil for the treatment of hereditary and wild-type ATTR cardiomyopathy in adults. An alternative single solid oral dosage formulation (tafamidis 61-mg free acid capsules) was developed and introduced for patient convenience (approved in the United States, United Arab Emirates, and European Union). In this single-center, open-label, randomized, 2-period, 2-sequence, crossover, multiple-dose phase 1 study, the rate and extent of absorption were compared between tafamidis 61-mg free acid capsules (test) and tafamidis meglumine 80-mg (4 × 20-mg) capsules (reference) after 7 days of repeated oral dosing under fasted conditions in 30 healthy volunteers. Ratios of adjusted geometric means (90%CI) for the test/reference formulations were 102.3 (98.0-106.8) for area under the concentration-time profile over the dosing interval and 94.1 (89.1-99.4) for the maximum observed concentration, satisfying prespecified bioequivalence acceptance criteria (90%CI, 80-125). Both tafamidis regimens had an acceptable safety/tolerability profile in this population.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Effects of PF-06751979, a Potent and Selective Oral BACE1 Inhibitor: Results from Phase I Studies in Healthy Adults and Healthy Older Subjects.

PF-06751979 is a selective inhibitor of the beta-site amyloid precursor protein cleaving enzyme-1, which is a key aspartyl protease in the generation of amyloid-ß (Aß) peptides, thought to be critical for the cerebral degeneration observed in Alzheimer's disease. Two Phase I studies (NCT02509117, NCT02793232) investigated the safety/tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PF-06751979. Single-ascending doses up to 540 mg and multiple-ascending doses up to 275 mg once daily (QD) in healthy adults, and multiple doses of 50 mg or 125 mg QD in healthy older subjects were assessed. PF-06751979 was well tolerated at all doses given, and all treatment-related adverse events (AEs) were mild to moderate. PK parameters remained consistent across the PF-06751979 QD dosing regimens, and no notable food effects were observed. PD analysis showed that PF-06751979 reduced the cerebrospinal fluid (CSF) and plasma levels of Aß peptides in a dose-dependent manner, with the greatest reductions observed in subjects treated with 275 mg QD (approximately 92% and 93% reduction in CSF Aß1-40 and Aß1-42 observed at 24 h after Day 14 dose, respectively). A drug interaction study (NCT03126721) using midazolam indicated that there was no clinically meaningful effect of multiple doses of PF-06751979 100 mg QD on the PK of single-dose midazolam in healthy adults. Overall, these data suggest that PF-06751979 with daily dosing is favorable for further clinical development.

Effects of a Six-Month Local Vibration Training on Bone Density, Muscle Strength, Muscle Mass, and Physical Performance in Postmenopausal Women.

The aim of the study was to investigate the effect of 6 months' local vibration training on bone mineral density (BMD), muscle strength, muscle mass, and physical performance in postmenopausal women (66-88 years). The study was organized as a randomized controlled trial for postmenopausal women who lived in daily care service flats and rest homes. Thirty-five postmenopausal women were randomly assigned to either a vibration (n = 17) or a control group (n = 18). The vibration group received 6-month local vibration treatment with frequency between 30 and 45 Hz and acceleration between 1.71 and 3.58g. The vibration was applied on the midthigh and around the hip in supine-lying position once per day, 5 d·wk. The participants of the control group continued their usual activities and were not involved in any additional training program. The primary outcome variables were the isometric and dynamic quadriceps muscle strength and the BMD of the hip. We assessed the muscle mass of the quadriceps and physical performance. Additionally, the feasibility, side effects, and compliance were evaluated after 6 months of local vibration training. Overall, the results showed a net benefit of 13.84% in isometric muscle strength at 60° knee angle in favor of the vibration group compared with controls (p < 0.01). No changes in BMD, muscle mass, or physical performance were found in both groups (p > 0.05). Six months of local vibration training improved some aspects of muscle strength but had no effect on BMD, muscle mass, and physical performance in postmenopausal women. The specific vibration protocol used in this study can be considered as safe and suitable for a local vibration training program.

Vibration training for upper body: transmission of platform vibrations through cables.

The aim of the present study was to evaluate the vibration transmission from a vibration platform through Vectran cables to the upper body and its relationship to induced muscular activation. Fifteen clinically healthy participants performed 3 different arm exercises-biceps curl, triceps curl, and lateral raise. Vibration transmission to the upper body was assessed over a wide range of accelerations (from 1.90 to 5.98 g) and frequencies (from 25 to 40 Hz). To assess the vibration transmission, 7 triaxial accelerometers were attached from the hand up to the head, and the root-mean-square of acceleration signal of each site-specific body point was calculated. Muscular activity of biceps brachii, triceps brachii, deltoid, and upper trapezius was recorded. The results showed a significant attenuation of the platform accelerations transmitted through the Vectran cables to the upper body. Handle vibration ranged between 27 and 44% of the acceleration delivered by the platform depending on platform vibration parameters (acceleration/frequency). Vibration increased the muscle activity of biceps brachii, triceps brachii, deltoid, and upper trapezius muscles significantly only during biceps curl exercises. No frequency or acceleration effect was found on the size of the muscle response. The results of the present study suggest that a cable-pulley resistance system on a vibration platform channels the vibration safely from the platform to the arms and induces additional muscle activation in some arm muscles when biceps curl exercises are performed.

Effects of intensive whole-body vibration training on muscle strength and balance in adults with chronic stroke: a randomized controlled pilot study.

OBJECTIVES: To investigate the effects of a 6-week whole body vibration (WBV) training program in patients with chronic stroke. DESIGN: Randomized controlled pilot trial with 6 weeks' follow-up. SETTING: University hospital. PARTICIPANTS: Adults with chronic stroke (N=15) were randomly assigned to an intervention (n=7) or a control group (n=8). INTERVENTIONS: Supervised, intensive WBV training. The vibration group performed a variety of static and dynamic squat exercises on a vibration platform with vibration amplitudes of 1.7 and 2.5mm and frequencies of 35 and 40Hz. The vibration lasted 30 to 60 seconds, with 5 to 17 repetitions per exercise 3 times weekly for 6 weeks. Participants in the control group continued their usual activities and were not involved in any additional training program. MAIN OUTCOME MEASURES: The primary outcome variable was the isometric and isokinetic muscle strength of the quadriceps (isokinetic dynamometer). Additionally, hamstrings muscle strength, static and dynamic postural control (dynamic posturography), and muscle spasticity (Ashworth Scale) were assessed. RESULTS: Compliance with the vibration intervention was excellent, and the participants completed all 18 training sessions. Vibration frequencies of both 35 and 40Hz were well tolerated by the patients, and no adverse effects resulting from the vibration were noted. Overall, the effect of intensive WBV intervention resulted in significant between-group differences in favor of the vibration group only in isometric knee extension strength (knee angle, 60°) (P=.022) after 6 weeks of intervention and in isokinetic knee extension strength (velocity, 240°/s) after a 6-week follow-up period (P=.005), both for the paretic leg. Postural control improved after 6 weeks of vibration in the intervention group when the patients had normal vision and a sway-referenced support surface (P<.05). Muscle spasticity was not affected by vibration (P>.05). CONCLUSIONS: These preliminary results suggest that intensive WBV might potentially be a safe and feasible way to increase some aspect of lower limb muscle strength and postural control in adults with chronic stroke. Further studies should focus on evaluating how the training protocol should be administered to achieve the best possible outcome, as well as comparing this training protocol to other interventions.

Transmission of whole-body vibration and its effect on muscle activation.

The aim of current study was to measure the transmission of whole-body vibration through the entire body and to relate this to body posture and induced muscular activation. Eight clinically healthy subjects performed 3 static body postures-high squat (135°), deep squat (110°), and erect stance, whereas vibration transmission was assessed over a wide range of accelerations (from 0.33 to 7.98 g) and frequencies (from 30 to 50 Hz). To assess the vibration transmission, 9 triaxial accelerometers were attached from the ankle up to the head and the root mean square of acceleration signal of each site-specific body point was calculated. Additionally, muscle activity from 7 lower limb muscles was recorded. The results showed a significant attenuation of the platform accelerations transmitted from the feet to the head. Compared with erect stance, knee bent posture significantly diminished vibration transmission at the hip, spine, and the head (p < 0.05). Vibration transmission to the spine was significantly lower in deep vs. high squat (p < 0.05), suggesting that further knee bending may reduce the risk of overloading the spine. Vibration increased the muscle activity in most leg and hip muscles during both squat postures, although, on average, no clear dose-response relationship between the acceleration and/or frequency and muscle response was found. The muscular activation of vastus medialis and rectus femoris showed clear negative correlation to the vibration transmission at the sternum. The specific vibration parameters used in the present study can be considered as safe and suitable for a training program. Moreover, the present results contribute to optimize the most advantageous whole-body vibration protocol and to determine the beneficial effects on muscle and bone.