Resistance strength training exercise in children with spinal muscular atrophy.

INTRODUCTION: Preliminary evidence in adults with spinal muscular atrophy (SMA) and in SMA animal models suggests exercise has potential benefits in improving or stabilizing muscle strength and motor function. METHODS: We evaluated feasibility, safety, and effects on strength and motor function of a home-based, supervised progressive resistance strength training exercise program in children with SMA types II and III. Up to 14 bilateral proximal muscles were exercised 3 times weekly for 12 weeks. RESULTS: Nine children with SMA, aged 10.4 ± 3.8 years, completed the resistance training exercise program. Ninety percent of visits occurred per protocol. Training sessions were pain-free (99.8%), and no study-related adverse events occurred. Trends in improved strength and motor function were observed. CONCLUSIONS: A 12-week supervised, home-based, 3-day/week progressive resistance training exercise program is feasible, safe, and well tolerated in children with SMA. These findings can inform future studies of exercise in SMA.

Plyometric training: effectiveness and optimal duration for children with unilateral cerebral palsy.

PURPOSE: To evaluate the optimal duration and effects of plyometric training on the gross motor abilities of 3 boys with unilateral spastic cerebral palsy (9 years 11 months, 10 years, and 8 years 9 months). METHODS: This was a multiple-baseline, multiple-probe, single-subject experiment. The intervention followed the National Strength and Conditioning Association's guidelines for youth. The Gross Motor Function Measure 66, 10×5-m sprint, 20-m run, throw ball, broad jump, and vertical jump tests were used to evaluate gross motor abilities, agility, running speed, and power. RESULTS: Improvements were found in upper extremity power, Gross Motor Function Measure 66 scores, and agility. Findings for lower extremity power and running speed were inconsistent. Training duration ranged from 8 to 14 weeks. CONCLUSIONS: This study suggests that plyometric training improves gross motor ability, agility, and upper extremity power in boys with unilateral cerebral palsy. Treatment duration should be determined by an individual's capacity, the task, and the outcome measure.

Effects of a plyometric training program for 3 children with neurofibromatosis type 1.

BACKGROUND AND PURPOSE: To evaluate the feasibility and safety of plyometric training and to determine the effects on motor proficiency. CASE DESCRIPTION: Three children with neurofibromatosis type 1, aged 5, 7, and 10 years, selected for representative ages, sexes, abilities, and outcomes participated in a 10-week plyometric training program. Outcome measures included throwing and jumping distance, performance on a self-selected goal, the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, and the Children's Assessment of Participation and Enjoyment. OUTCOMES: All participants safely completed the program. Improvements were seen in distance and consistency of throwing and jumping, performance on the self-selected goal, and bilateral coordination composite scores. Increased diversity, but not intensity of physical activity, was observed. DISCUSSION: A safe plyometric training program was implemented, resulting in gains in motor performance. It may be important to address personal and environmental barriers to physical activity participation to improve intensity of physical activity.

Effects of food on a gastrically degraded drug: azithromycin fast-dissolving gelatin capsules and HPMC capsules.

PURPOSE: Commercial azithromycin gelatin capsules (Zithromax®) are known to be bioequivalent to commercial azithromycin tablets (Zithromax®) when dosed in the fasted state. These capsules exhibit a reduced bioavailability when dosed in the fed state, while tablets do not. This gelatin capsule negative food effect was previously proposed to be due to slow and/or delayed capsule disintegration in the fed stomach, resulting in extended exposure of the drug to gastric acid, leading to degradation to des-cladinose-azithromycin (DCA). Azithromycin gelatin capsules were formulated with "superdisintegrants" to provide fast-dissolving capsules, and HPMC capsule shells were substituted for gelatin capsule shells, in an effort to eliminate the food effect. METHODS: Healthy volunteers were dosed with these dosage forms under fasted and fed conditions; pharmacokinetics were evaluated. DCA pharmacokinetics were also evaluated for the HPMC capsule subjects. In vitro disintegration of azithromycin HPMC capsules in media containing food was evaluated and compared with commercial tablets and commercial gelatin capsules. RESULT: When the two fast-dissolving capsule formulations were dosed to fed subjects, the azithromycin AUC was 38.9% and 52.1% lower than after fasted-state dosing. When HPMC capsules were dosed to fed subjects, the azithromycin AUC was 65.5% lower than after fasted-state dosing. For HPMC capsules, the absolute fasting-state to fed-state decrease in azithromycin AUC (on a molar basis) was similar to the increase in DCA AUC. In vitro capsule disintegration studies revealed extended disintegration times for commercial azithromycin gelatin capsules and HPMC capsules in media containing the liquid foods milk and Ensure®. CONCLUSION: Interaction of azithromycin gelatin and HPMC capsules with food results in slowed disintegration in vitro and decreased bioavailability in vivo. Concurrent measurement of serum azithromycin and the acid-degradation product DCA demonstrates that the loss of azithromycin bioavailability in the fed state is largely (and probably entirely) due to gastric degradation to DCA. Capsules can provide a useful and elegant dosage form for almost all drugs, but may result in a negative food effect for drugs as acid-labile as azithromycin.

Functional decline in children undergoing selective dorsal rhizotomy after age 10.

AIM: To compare function and gait in a group of children older than most children who received selective dorsal rhizotomy (SDR) with age- and function-matched peers who received either orthopedic surgery or no surgical intervention. METHOD: A retrospective study examined ambulatory children with diplegic cerebral palsy, aged between 10 years and 20 years and categorized in Gross Motor Function Classification System (GMFCS) levels I or II. Three groups were considered: (1) children who had selective dorsal rhizotomy (n=8; two females, six males; mean age 15y 4mo at SDR, 16y 8mo at follow-up); (2) children who had orthopedic surgery (n=9; three females, six males; mean age 14y 6mo at SDR, 15y 1mo at follow-up), and (3) children who had no surgical intervention (n=9; two females, seven males; mean age 15y 6mo at follow-up). Longitudinal measures of gait analysis (velocity, gait deviation index, and gait variable scores) and gross motor function (GMFCS level, Gross Motor Function Measure scores, and centiles) were examined. RESULTS: No significant differences were found between changes in gait comparing rhizotomy with orthopedic surgery; however, the group who received orthopedic surgery demonstrated improved gait compared with the group without surgical intervention. Longitudinal comparisons of gross motor function demonstrated a decrease in the group who received SDR. Between-group analysis of outcomes also demonstrated worse outcomes of the SDR group compared with the orthopedic surgery group and with the no surgical intervention group. INTERPRETATION: Rhizotomy in older children was associated with functional declines compared with similar children who had no surgery and with those who underwent orthopedic surgery. This suggests that age greater than 10 years might be a contraindication for SDR if the goal is to improve motor skills.

A systematic review: plyometric training programs for young children.

The purpose of this systematic review was to evaluate the efficacy and safety of plyometric training for improving motor performance in young children; to determine if this type of training could be used to improve the strength, running speed, agility, and jumping ability of children with low motor competence; and to examine the extent and quality of the current research literature. Primary research articles were selected if they (a) described the outcomes of a plyometric exercise intervention; (b) included measures of strength, balance, running speed, jumping ability, or agility; (c) included prepubertal children 5-14 years of age; and (d) used a randomized control trial or quasiexperimental design. Seven articles met the inclusion criteria for the final review. The 7 studies were judged to be of low quality (values of 4-6). Plyometric training had a large effect on improving the ability to run and jump. Preliminary evidence suggests plyometric training also had a large effect on increasing kicking distance, balance, and agility. The current evidence suggests that a twice a week program for 8-10 weeks beginning at 50-60 jumps a session and increasing exercise load weekly results in the largest changes in running and jumping performance. An alternative program for children who do not have the capability or tolerance for a twice a week program would be a low-intensity program for a longer duration. The research suggests that plyometric training is safe for children when parents provide consent, children agree to participate, and safety guidelines are built into the intervention.

Motor proficiency in children with neurofibromatosis type 1.

PURPOSE: Neurofibromatosis type 1 (NF1) is a genetic disorder with associated musculoskeletal abnormalities, tumors, and developmental delays. The purpose of this study was to investigate and characterize the motor proficiency of children with NF1. METHODS: Children with NF1 were assessed using the Bruininks-Oseretsky Test (BOT 2) instrument. The NF1 group scores were compared with age and sex-matched test norms. RESULTS: Twenty-six children participated in the study. The NF1 group had statistically significant lower scores (P < .05) for the total motor composite (Z = -1.62) and 7 of the 8 subtests. Nineteen percent (n = 5) scored in the average category, 54% (n = 14) scored in the below-average category, and 27% (n = 7) scored in the well-below-average category. CONCLUSIONS: Children with NF1 have significantly lower motor proficiency than the BOT 2 normative scores. The results indicate the BOT 2 is useful in identifying and characterizing delays in motor proficiency for children with NF1.

N-methylation and N-formylation of a secondary amine drug (varenicline) in an osmotic tablet.

Significant degradation of the amine-based smoking cessation drug varenicline tartrate in an early development phase osmotic, controlled-release (CR) formulation yields predominantly two products: N-methylvarenicline (NMV) and N-formylvarenicline (NFV). NMV is produced by reaction of the amine moiety with both formaldehyde and formic acid in an Eschweiler-Clarke reaction, while NFV is formed by reaction of formic acid alone with varenicline. This represents the first report of these reactions occurring on storage of solid pharmaceutical formulations. Both formaldehyde and formic acid are formed from oxidative degradation of polyethylene glycol (PEG) used in an osmotic coating through a process heavily dependent on the physical state of the PEG. When the concentration of PEG in the coating is sufficiently low, the PEG remains phase compatible with the other component of the coating (cellulose acetate) such that its degradation (and the resulting drug reactivity) is effectively eliminated. Antioxidants in the coating and oxygen scavengers in the packaging also serve to prevent the PEG degradation, and consequently provide for drug stability.

Activity and participation in children with neurofibromatosis type 1.

We describe activity and participation in children and youth with neurofibromatosis type 1 (NF1), and compared an intervention and control group after a strengthening program using the Pediatric Outcomes Data Collection Instrument (PODCI) and the Children's Assessment of Participation and Enjoyment (CAPE). Questionnaires were filled out by parents at baseline, 12-weeks, and 1-year. The intervention group performed a strengthening program twice a week for ten weeks, followed by a 9-month independent program. Thirty-six participants (18 control, 18 intervention) between the ages of 5- and 18-years (mean 10.6 years, SD 4.6 years) were enrolled, and 34 completed the 1-year assessment. There were significant differences between formal and informal participation (p<0.0001) in baseline CAPE scores for the entire cohort. At 12 weeks, PODCI upper extremity function improved in intervention and decreased in controls (p=0.040), while happiness declined in intervention and increased in control (p=0.003). There were no significant differences between control and intervention groups in any of the CAPE or PODCI change scores from baseline to 1-year. Upper extremity function, sport and physical function, comfort/pain and happiness PODCI scores were lower than normative values. The NF1 cohort had low participation in formal active physical and skill-based activities. The companionship and location dimensions suggest participation occurs with family and other relatives in the home or a relative's home and reflects a pattern of social isolation from peers.

Postural control in children with and without neurofibromatosis type 1.

Previous research has evaluated the motor proficiency of children with neurofibromatosis type 1 (NF1) and found delays on the balance subtest. However the balance subtest was found to have low sensitivity for identifying balance impairments. This study examines the differences in postural control between children with NF1 and peers with typical development using a force plate. A single limb stance test on a force plate was completed for all participants. The force plate variables, center of pressure maximum distance in the anterior/posterior direction (COPmax A/P) and center of pressure velocity (COPvel A/P) were compared between groups. The NF1 group's performance was significantly poorer than the control group in both COPmax A/P (p=.01) and COPvel A/P (p=.01). When separated into specific age ranges, only the children in the NF1 group between 5 and 12years of age demonstrated statistically significant differences in the COP variables. The COP variables for the 13- to 18-year-old group were not significantly different. These results indicate that young children with NF1 have poor postural control. However, postural control appears to improve with maturation.

Analysis of the relationships that body composition and muscular strength have with oxygen cost of walking in children with cerebral palsy.

OBJECTIVE: To investigate whether body composition and lower extremity strength relate to oxygen cost of walking in children with cerebral palsy (CP), and to evaluate the relative contributions of these measures to explain variation in oxygen cost seen in this population. METHODS: A total of 116 children with spastic diplegic CP, Gross Motor Function Classification System levels I-III, aged 8-18 participated. Strength, body composition (body mass index (BMI) and percent body fat) and oxygen cost were recorded. Pearson correlations assessed relationships between variables of body composition and strength to oxygen cost. Forward stepwise linear regression analyzed variance explained by strength and body composition measures. Oxygen data were analyzed by weight status classifications using one-way analysis of variance with significance set at p<0.05. RESULTS: Total strength (r=-0.27) and total extensor strength (r=-0.27) had fair inverse relationships with oxygen cost. Total extensor strength explained 7.5% (r(2)=0.075, beta=-0.274, p<0.01) of the variance in oxygen cost. Body composition did not explain significant variance in oxygen cost, however significant differences were found in oxygen consumption (p=0.003) and walking velocity (p=0.042) based on BMI weight classifications. CONCLUSIONS: For ambulatory children with CP, oxygen cost during walking can be partially explained by total extensor strength and not body composition. However, those categorized as obese may adjust to a slower walking speed to keep their oxygen cost sustainable, which may further affect their ability to keep up with typically developing peers and possibly lead to greater fatigue.

Lower extremity strength and hopping and jumping ground reaction forces in children with neurofibromatosis type 1.

The purpose of this study was to (1) extend the research findings of decreased muscular force production in grip strength to the lower extremity strength of children with NF1 and (2) to determine if there was a relationship between isometric strength and functional activities in children with NF1. Force production was assessed using a hand held dynamometer (HHD) and a functional task (hopping and jumping) on a force plate. Data from twenty-six children with NF1 were compared to data from 48 typically developing children of similar sex, weight and height. Children with NF1 demonstrated statistically significant lower force production with HHD (p<0.01) during hip extension, but similar force production for knee extension and ankle plantar flexion compared to the control group. A relationship existed between the ground reaction forces at take-off from both hopping and jumping and the force generated from knee extensor strength in the NF1 group. The addition of a functional task to hand held dynamometry is useful for determining a relationship between common clinical measures and functional activities.

Evaluation of a single leg stance balance test in children.

Balance is a major determinate of gait. In high functioning individuals without significant vestibular or vision impairments, a ceiling effect may be present when using a double limb support protocol to assess balance function. For these populations, a single leg stance protocol may be more suitable. 47 typically developing (TD) subjects and 10 patients with CEV performed a single leg stance test on a force plate. The center of pressure (COP) was determined and several COP derived variables were calculated. Included measurements were: standard deviation, maximum excursion, area, average radial displacement, path velocity and frequency of the COP. Directional components of suitable variables were used to analyze anterior/posterior and medial/lateral contributions. Correlations with age of TD subjects indicated that all balance variables except frequency were significantly correlated. Most parameters were highly inter-correlated. Age adjusted COP balance variables also correlated to the Bruininks-Oseretsky balance subtest. Highest correlations were determined by the maximum excursion and velocity of the COP in the anterior/posterior direction. Statistical comparisons between the CEV group and a 4-6 TD group indicated significant differences between groups for most COP balance parameters. These results indicated that a single limb balance assessment may be a useful assessment for determining balance impairments in higher functioning children with orthopedic impairments.

Characterizing the structure of pharmaceutical granules obtained by wet granulation with varying amounts of water via Raman chemical imaging.

A pharmaceutical formulation containing metformin hydrochloride (MET), hydroxypropyl cellulose (HPC), and microcrystalline cellulose (MCC) was wet granulated with varying amounts of water and the structure of the obtained granules was characterized by Raman chemical mapping. Univariate Raman mapping was found to be satisfactory for producing the images of the two components of interest (HPC and MCC). In addition to the images, the average Raman spectra from the maps as well as the micro-Raman spectra from the hot pixels were analyzed. HPC is found to strongly respond to the addition of water, with its domain dissipating and Raman bands becoming weaker as the water addition increases. MCC is also responsive to water, reacting similarly to HPC but to a much smaller extent and only for the largest amounts of water. Granules made with increasing water content also have improved tabletting properties and flow.

Use of the antioxidant BHT in asymmetric membrane tablet coatings to stabilize the core to the acid catalyzed peroxide oxidation of a thioether drug.

The application of a controlled-release asymmetric membrane (AM) coating containing cellulose acetate and polyethylene glycol 3350 (PEG3350) to a stable osmotic tablet core resulted in the oxidative degradation of active ingredient located in the core. It was hypothesized that the production of hydroperoxides from PEG3350 in the coating was responsible for the electrophilic oxidation of drug to the sulfoxide degradation product. The type and solubility of carboxylic acid excipient used to formulate the drug release profile of the osmotic tablet significantly influenced the amount of oxidation. By adding the antioxidant butylated hydroxytoluene (BHT) to the coating, oxidation was significantly inhibited in tablets placed on accelerated stability. Of three additives that were used to prevent oxidation [BHT, ferrous sulfate, and ethylenediaminetetraacetic acid (EDTA)], BHT was shown to be the most effective at preventing sulfoxide formation. The BHT was also shown to be more effective in the coating rather than in the core due to its location closer to the source of the oxidizing species, PEG3350, in the coating.