Safety, pharmacokinetics and pharmacodynamics of SBT-020 in patients with early stage Huntington's disease, a 2-part study.

AIMS: Huntington's disease (HD) is a neurodegenerative disease with cognitive, motor and psychiatric symptoms. Toxic accumulation of misfolded mutant huntingtin protein induces mitochondrial dysfunction, leading to a bioenergetic insufficiency in neuronal and muscle cells. We evaluated the safety, pharmacokinetics and pharmacodynamics of SBT-020, a novel compound to improve mitochondrial function, in a 2-part study in early stage HD patients. METHODS: Part 1 consisted of 7-day multiple ascending dose study to select the highest tolerable dose for Part 2, a 28-day multiple dose study. Mitochondrial function was measured in the visual cortex and calf muscle, using phosphorous magnetic resonance spectroscopy, and in circulating peripheral blood mononuclear cells. RESULTS: Treatment-emergent adverse events were mild and more present in the SBT-020 group. Injection site reactions occurred in 91% in Part 1 and 97% in Part 2. Mitochondrial function in calf muscle, peripheral blood mononuclear cells or visual cortex was not changed overall due to treatment with SBT-020. In a posthoc analysis, patients with a higher degree of mitochondrial dysfunction (below the median [∆Ψm < 3412 and τPCr > 42.5 s]) showed more improvement than patients with a relatively lower level of mitochondrial dysfunction. CONCLUSION: SBT-020 was safe at all doses, but no significant differences in any of the pharmacodynamic measurements between the treatment groups and placebo group could be demonstrated. The data suggest that the better than expected mitochondrial function in our patient population at baseline might explain the lack of effect of SBT-020.

Mitochondrial function, grip strength, and activity are related to recovery of mobility after a total knee arthroplasty.

Low muscle quality and a sedentary lifestyle are indicators for a slow recovery after a total knee arthroplasty (TKA). Mitochondrial function is an important part of muscle quality and a key driver of sarcopenia. However, it is not known whether it relates to recovery. In this pilot study, we monitored activity after TKA using a wrist mounted activity tracker and assessed the relation of mitochondrial function on the rate of recovery after TKA. Additionally, we compared the increase in activity as a way to measure recovery to traditional outcome measures. Patients were studied 2 weeks before TKA and up to 6 months after. Activity was monitored continuously. Baseline mitochondrial function (citrate synthase and complex [CP] 1-5 abundance of the electron transport chain) was determined on muscle tissue taken during TKA. Traditional outcome measures (Knee Injury and Osteoarthritis Outcome Score [KOOS], timed up-and-go [TUG] completion time, grip, and quadriceps strength) were performed 2 weeks before, 6 weeks after, and 6 months after TKA. Using a multivariate regression model with various clinical baseline parameters, the following were significantly related to recovery: CP5 abundance, grip strength, and activity (regression weights 0.13, 0.02, and 2.89, respectively). During recovery, activity correlated to the KOOS-activities of daily living (ADL) score (r = 0.55, p = 0.009) and TUG completion time (r = -0.61, p = 0.001). Mitochondrial function seems to be related to recovery, but so are activity and grip strength, all indicators of sarcopenia. Using activity trackers before and after TKA might give the surgeon valuable information on the expected recovery and the opportunity to intervene if recovery is low.

Brain Bio-Energetic State Does Not Correlate to Muscle Mitochondrial Function in Huntington's Disease.

BACKGROUND: Huntington's disease (HD) is a neurodegenerative disease with cognitive, motor and psychiatric symptoms. A toxic accumulation of misfolded mutant huntingtin protein (Htt) induces mitochondrial dysfunction, leading to a bioenergetic insufficiency in neuronal and muscle cells. Improving mitochondrial function has been proposed as an opportunity to treat HD, but it is not known how mitochondrial function in different tissues relates. OBJECTIVE: We explored associations between central and peripheral mitochondrial function in a group of mild to moderate staged HD patients. METHODS: We used phosphorous magnetic resonance spectroscopy (31P-MRS) to measure mitochondrial function in vivo in the calf muscle (peripheral) and the bio-energetic state in the visual cortex (central). Mitochondrial function was also assessed ex vivo in circulating peripheral blood mononuclear cells (PBMCs). Clinical function was determined by the Unified Huntington's Disease Rating Scale (UHDRS) total motor score. Pearson correlation coefficients were computed to assess the correlation between the different variables. RESULTS: We included 23 manifest HD patients for analysis. There was no significant correlation between central bio-energetics and peripheral mitochondrial function. Central mitochondrial function at rest correlated significantly to the UHDRS total motor score (R = -0.45 and -0.48), which increased in a subgroup with the largest number of CAG repeats. DISCUSSION: We did not observe a correlation between peripheral and central mitochondrial function. Central, but not peripheral, mitochondrial function correlated to clinical function. Muscle mitochondrial function is a promising biomarker to evaluate disease-modifying compounds that improve mitochondrial function, but Huntington researchers should use central mitochondrial function to demonstrate proof-of-pharmacology of disease-modifying compounds.

Publisher Correction: Mitochondrial function is impaired in the skeletal muscle of pre-frail elderly.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Mitochondrial function is impaired in the skeletal muscle of pre-frail elderly.

Aging is accompanied by a gradual decline in both muscle mass and strength over time, which can eventually lead to pathologies, such as frailty and sarcopenia. While these two conditions are well characterized, further investigation of the early biological signs present in pre-frail elderly is still needed to help identify strategies for preventative therapeutic intervention. The goal of the present clinical study was to evaluate the level of mitochondrial (dys)function in a well-defined population of pre-frail elderly (>60 years of age). Pre-frail elderly were compared with an age-matched population of active elderly. Muscle mitochondrial function was assessed in vivo using phosphorus magnetic resonance spectroscopy (31P-MRS) and a comprehensive set of biological biomarkers were measured ex vivo in vastus lateralis muscle biopsies. In pre-frail subjects, phosphocreatine recovery was impaired and mitochondrial respiratory complex protein and activity levels were significantly lower when compared with active elderly. Analysis of microarray data showed that mitochondrial genes were also significantly down-regulated in muscle of pre-frail compared to active elderly. These results show that mitochondrial impairment is a hallmark of pre-frailty development and the onset of decline in muscle function in the elderly.

Validation of a pharmacological model for mitochondrial dysfunction in healthy subjects using simvastatin: A randomized placebo-controlled proof-of-pharmacology study.

Proof-of-pharmacology models to study compounds in healthy subjects offer multiple advantages. Simvastatin is known to induce mitochondrial dysfunction at least partly by depletion of co-enzyme Q10. The goal of this study was to evaluate a model of simvastatin-induced mitochondrial dysfunction in healthy subjects and to determine whether mitochondrial dysfunction could be pharmacologically reversed by treatment with co-enzyme Q10 (ubiquinol). Subjects received simvastatin 40mg/day for 8 weeks. After 4 weeks, subjects were randomized to receive ubiquinol 300mg/day or placebo in a double-blinded fashion. Mitochondrial function was assessed by measuring the phosphocreatine recovery time (τ-PCr) using phosphorous Magnetic Resonance Spectroscopy (31P-MRS) after in-magnet exercise. After 4 weeks of simvastatin treatment, τ-PCr prolonged with 15.2% compared to baseline, (95%CI, 2.5-29.4%; P = 0.018, Fig. 3). After 8 weeks, τ-PCr further prolonged to 37.27s in the placebo group (prolongation of 18.5% compared to baseline, still significantly prolonged, 95%CI, 1.1-38.9%; P = 0.037), but shortened to 33.81s in the ubiquinol group (prolongation of 9.1% compared to baseline, no longer significantly prolonged, 95%CI, -7.9 to 29.2%; P = 0.31). At 8 weeks, there was no significant difference between groups (difference of 8.2%, 95%CI, -14.5 to 37.0%; P = 0.51). Simvastatin induces subclinical mitochondrial dysfunction in healthy subjects, which can be partly reversed by treatment with ubiquinol. This model of pharmacologically induced and reversed mitochondrial dysfunction can be used to study the effects of compounds that enhance mitochondrial function in healthy subjects.

Two-stage revision of an infected total hip arthroplasty: a follow-up of 136 patients.

BACKGROUND AND PURPOSE: Periprosthetic infection of a total hip arthroplasty (THA) is commonly treated with a two-stage revision procedure. After resection of the infected THA and placement of a cement spacer loaded with antibiotics, a THA is inserted at a second procedure to restore hip function and mobility. Revision surgery carries a significant risk of complications. This study focuses on hip function, rate of complications and reinfection after two-stage revision surgery for an infected THA. PATIENTS AND METHODS: From January 1996 to April 2010, 136 patients underwent revision surgery after removal of an infected THA. Follow-up ranged from 2 years to more than 15 years. Hip function was evaluated using the modified Harris Hip Score (mHHS) and the Hip disability and Osteoarthritis Outcome Score (HOOS). Visual Analogue Scale (VAS) measured pain. Annual follow-up included radiographs of the affected hip and blood sampling for inflammatory parameters. RESULTS: After revision surgery, average mHHS was 63% and average HOOS was 54%. VAS pain averaged 26.8 on a 100-point scale and 40% of patients had no pain. Prosthesis-related complications unrelated to sepsis occurred in 32%. Most common were periprosthetic fractures, leg length discrepancy and dislocation. Reinfection occurred in 13% of these patients and Coagulase Negative Staphylococcus (CNS) was isolated in 67%. CONCLUSION: Two-stage evision surgery is an accepted treatment for infected THAs. However, complications are common and hip function afterwards is modest. As previous studies have shown, CNS is an important microorganism in reinfection.