Dataset Information

Pharmacokinetics of Repeated Oral Dosing with Coenzyme Q10 in Cavalier King Charles Spaniels with Myxomatous Mitral Valve Disease.

ABSTRACT: Coenzyme Q10 (Q10) is a mitochondrial cofactor and an antioxidant with the potential to combat oxidative stress in heart failure. This study aims to determine the pharmacokinetics of repeated oral dosing of Q10 in Cavalier King Charles Spaniels (CKCS) with spontaneous myxomatous mitral valve disease (MMVD) and to evaluate echocardiographic parameters, circulating cardiac biomarkers, and quality of life (QoL) after treatment. The study is a randomized, placebo-controlled, single-blinded crossover study. Nineteen CKCS with MMVD were randomized to receive 100 mg Q10 (ubiquinone) bi-daily for three weeks, then placebo (or in reverse order). Clinical examination, blood sampling, echocardiography, and QoL assessment were performed before and after each treatment phase. Q10 plasma concentrations were determined in plasma using a validated high-performance liquid chromatography method using electrochemical detection (HPLC-ECD). Eighteen CKCS were included in the analyses. Total plasma concentration of Q10 increased significantly (p < 0.0001) from baseline (median, 0.92 µg/mL; interquartile range (IQR), 0.70-1.26) to after treatment (median, 3.51 µg/mL; IQR, 2.30-6.88). Thirteen dogs reached the threshold of a total plasma Q10 concentration of ?2.0 µg/mL. The average half-life (T1/2) of Q10 was 2.95 days (IQR, 1.75-4.02). No significant differences were observed in clinical MMVD severity, and the owner perceived QoL between Q10 and placebo treatment. The solubilized Q10 formulation was well-tolerated in the dogs. Individual variation in plasma concentrations was observed following oral treatment. A long-term placebo-controlled trial is warranted in dogs with MMVD to determine long-term efficacy on the clinical severity of MMVD.

SUBMITTER: Christiansen LB

PROVIDER: S-EPMC7555137 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Pharmacokinetics of Repeated Oral Dosing with Coenzyme Q10 in Cavalier King Charles Spaniels with Myxomatous Mitral Valve Disease.

Christiansen Liselotte B LB Morsing Malene K MK Reimann Maria Josefine MJ Martinussen Torben T Birlie Zita Z Schou-Pedersen Anne Marie V AMV Lykkesfeldt Jens J Olsen Lisbeth H LH

Antioxidants (Basel, Switzerland) 20200904 9

Coenzyme Q10 (Q10) is a mitochondrial cofactor and an antioxidant with the potential to combat oxidative stress in heart failure. This study aims to determine the pharmacokinetics of repeated oral dosing of Q10 in Cavalier King Charles Spaniels (CKCS) with spontaneous myxomatous mitral valve disease (MMVD) and to evaluate echocardiographic parameters, circulating cardiac biomarkers, and quality of life (QoL) after treatment. The study is a randomized, placebo-controlled, single-blinded crossover ...[more]

PMID: 32899633

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Project description:There is a growing interest in developing new molecular markers of heart disease in young dogs affected by myxomatous mitral valve disease. The study aimed to measure 3 circulating microRNAs and their application as potential biomarkers in the plasma of Cavalier King Charles Spaniels with early asymptomatic myxomatous mitral valve disease. The hypothesis is that healthy Cavalier King Charles Spaniels have different microRNA expression profiles than affected dogs in American College of Veterinary Internal Medicine (ACVIM) stage B1. The profiles can differ within the same class among subjects of different ages. This is a prospective cross-sectional study. Thirty-three Cavalier King Charles Spaniels in ACVIM stage B1 were divided into three groups (11 younger than 3 years, 11 older than 3 years and younger than 7 years, and 11 older than 7 years), and 11 healthy (ACVIM stage A) dogs of the same breed were included as the control group. Three circulating microRNAs (miR-1-3p, miR30b-5p, and miR-128-3p) were measured by quantitative real-time PCR using TaqMan® probes. Diagnostic performance was evaluated by calculating the area under the receiver operating curve (AUC). MiR-30b-5p was significantly higher in ACVIM B1 dogs than in ACVIM A subjects, and the area under the receiver operating curve was 0.79. According to the age of dogs, the amount of miR-30b-5p was statistically significantly higher in group B1<3y (2.3 folds, P = 0.034), B1 3-7y (2.2 folds, P = 0.028), and B1>7y (2.7 folds, P = 0.018) than in group A. The area under the receiver operating curves were fair in discriminating between group B1<3y and group A (AUC 0.780), between B1 3-7y and A (AUC 0.78), and good in discriminating between group B1>7y and A (AUC 0.822). Identifying dogs with early asymptomatic myxomatous mitral valve disease through the evaluation of miR-30b-5p represents an intriguing possibility that certainly merits further research. Studies enrolling a larger number of dogs with preclinical stages of myxomatous mitral valve disease are needed to expand further and validate conclusively the preliminary findings from this report.

Project description:BackgroundAlmost all elderly dogs develop myxomatous mitral valve disease by the end of their life, but the cavalier King Charles spaniel (CKCS) has a heightened susceptibility, frequently resulting in death at a young age and suggesting that there is a genetic component to the condition in this breed. Transcriptional profiling can reveal the impact of genetic variation through differences in gene expression levels. The aim of this study was to determine whether expression patterns were different in mitral valves showing myxomatous degeneration from CKCS dogs compared to valves from non-CKCS dogs.ResultsGene expression patterns in three groups of canine valves resulted in distinct separation of normal valves, diseased valves from CKCS and diseased valves from other breeds; the latter were more similar to the normal valves than were the valves from CKCS. Gene expression patterns in diseased valves from CKCS dogs were quite different from those in the valves from other dogs, both affected and normal. Patterns in all diseased valves (from CKCS and other breeds) were also somewhat different from normal non-diseased samples. Analysis of differentially expressed genes showed enrichment in GO terms relating to cardiac development and function and to calcium signalling canonical pathway in the genes down-regulated in the diseased valves from CKCS, compared to normal valves and to diseased valves from other breeds. F2 (prothrombin) (CKCS diseased valves compared to normal) and MEF2C pathway activation (CKCS diseased valves compared to non-CKCS diseased valves) had the strongest association with the gene changes. A large number of genes that were differentially expressed in the CKCS diseased valves compared with normal valves and diseased valves from other breeds were associated with cardiomyocytes including CASQ2, TNNI3 and RYR2.ConclusionTranscriptomic profiling identified gene expression changes in CKCS diseased valves that were not present in age and disease severity-matched non-CKCS valves. These genes are associated with cardiomyocytes, coagulation and extra-cellular matrix remodelling. Identification of genes that vary in the CKCS will allow exploration of genetic variation to understand the aetiology of the disease in this breed, and ultimately development of breeding strategies to eliminate this disease from the breed.

Project description:BACKGROUND:Syringomyelia (SM) is a debilitating condition in the cavalier King Charles spaniel (CKCS) that results in neuropathic pain and diminished quality of life. Von Frey aesthesiometry (VFA) is a method of mechanical quantitative sensory testing that provides an objective sensory threshold (ST) value and can be used to quantify neuropathic pain (NP) and monitor response to therapy. The utility of VFA has been previously established in client-owned dogs with acute spinal cord injury but the technique has not been evaluated in dogs with SM. The goal of this study was to evaluate ST, as determined by VFA, in dogs with and without SM, to assess the utility of VFA in quantifying NP in SM-affected dogs. We hypothesized the SM-affected CKCS would have lower ST values, consistent with hyperesthesia, when compared to control CKCS. Additionally, we hypothesized that ST values in SM-affected dogs would be inversely correlated with syrinx size on MRI and with owner-derived clinical sign scores. RESULTS:ST values for the thoracic and pelvic limbs differed significantly between the SM-affected and control CKCS (p?=?0.027; p?=?0.0396 respectively). Median ST value (range) for the thoracic limbs was 184.1?g (120.9-552) for control dogs, and 139.9?g (52.6-250.9) for SM-affected dogs. The median ST value (range) for the pelvic limbs was 164.9?g (100.8-260.3) in control dogs and 129.8?g (57.95-168.4) in SM-affected dogs. The ST values in SM-affected dogs did not correlate with syrinx height on MRI (r?=?0.314; p?=?0.137). Owner-reported clinical sign scores showed an inverse correlation with pelvic limb ST values, where dogs with lower ST values (hyperesthesia) were reported by their owners to display more frequent and severe clinical signs (r?=?-?0.657; p?=?0.022). CONCLUSION:ST values were lower in SM-affected CKCS compared to control dogs, suggesting the presence of neuropathic pain. Dogs with lower ST pelvic limb values were perceived by their owners to have more severe clinical signs classically associated with SM. Our results suggest that VFA might offer quantitative assessment of neuropathic pain in SM-affected dogs and could be useful for monitoring response to therapy in future clinical studies.

Dataset Information

Pharmacokinetics of Repeated Oral Dosing with Coenzyme Q10 in Cavalier King Charles Spaniels with Myxomatous Mitral Valve Disease.

Publications

Pharmacokinetics of Repeated Oral Dosing with Coenzyme Q10 in Cavalier King Charles Spaniels with Myxomatous Mitral Valve Disease.

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