Increased cardiac involvement in Fabry disease using blood-corrected native T1 mapping

Fabry disease (FD) is a rare lysosomal storage disorder resulting in myocardial sphingolipid accumulation which is detectable by cardiovascular magnetic resonance as low native T1. However, myocardial T1 contains signal from intramyocardial blood which affects variability and consequently measurement precision and accuracy. Correction of myocardial T1 by blood T1 increases precision. We therefore deployed a multicenter study of FD patients (n = 218) and healthy controls (n = 117) to investigate if blood-correction of myocardial native T1 increases the number of FD patients with low T1, and thus reclassifies FD patients as having cardiac involvement. Cardiac involvement was defined as a native T1 value 2 standard deviations below site-specific means in healthy controls for both corrected and uncorrected measures. Overall low T1 was 135/218 (62%) uncorrected vs. 145/218 (67%) corrected (p = 0.02). With blood-correction, 13/83 previously normal patients were reclassified to low T1. This reclassification appears clinically relevant as 6/13 (46%) of reclassified had focal late gadolinium enhancement or left ventricular hypertrophy as signs of cardiac involvement. Blood-correction of myocardial native T1 increases the proportion of FD subjects with low myocardial T1, with blood-corrected results tracking other markers of cardiac involvement. Blood-correction may potentially offer earlier detection and therapy initiation, but merits further prospective studies

Obesity-Related Oxidative Stress: the Impact of Physical Activity and Diet Manipulation

Obesity-related oxidative stress, the imbalance between pro-oxidants and antioxidants (e.g., nitric oxide), has been linked to metabolic and cardiovascular disease, including endothelial dysfunction and atherosclerosis. Reactive oxygen species (ROS) are essential for physiological functions including gene expression, cellular growth, infection defense, and modulating endothelial function. However, elevated ROS and/or diminished antioxidant capacity leading to oxidative stress can lead to dysfunction. Physical activity also results in an acute state of oxidative stress. However, it is likely that chronic physical activity provides a stimulus for favorable oxidative adaptations and enhanced physiological performance and physical health, although distinct responses between aerobic and anaerobic activities warrant further investigation. Studies support the benefits of dietary modification as well as exercise interventions in alleviating oxidative stress susceptibility. Since obese individuals tend to demonstrate elevated markers of oxidative stress, the implications for this population are significant. Therefore, in this review our aim is to discuss (i) the role of oxidative stress and inflammation as associated with obesity-related diseases, (ii) the potential concerns and benefits of exercise-mediated oxidative stress, and (iii) the advantageous role of dietary modification, including acute or chronic caloric restriction and vitamin D supplementation

Blood-brain equilibration kinetics of levo-alpha-acetyl-methadol using a chronically instrumented sheep preparation

© 2006 British Pharmacological SocietyThe delayed onset and long duration of action of the opioid agonist levo--acetyl-methadol (LAAM) has been attributed to the formation of active metabolites. However, at present, little is known about the time course of blood–brain equilibration of LAAM itself. The cerebral kinetics of LAAM were quantified using physiologically based kinetic models and a conscious chronically instrumented sheep preparation. Seven sheep were administered 4 min intravenous infusions of 30 mg LAAM. Concentrations of LAAM and N-demethylated metabolites (nor-LAAM and di-nor-LAAM) in whole blood (0–75 min) were measured using a validated HPLC assay. LAAM did not alter cerebral blood flow, mean arterial pressure or cause significant respiratory depression. Cardiac output was similar to baseline at 4 min, but decreased by 30% at 10 min and remained at this level for the duration of the 75 min study period. Cerebral kinetics were best described by a membrane-limited model, with a relatively slow blood–brain tissue equilibration half-life of 22 min due to intermediate permeability (56 ml min-1) and a large cerebral distribution volume (724 ml). In conclusion, pharmacokinetic–pharmacodynamic modelling of LAAM should account for the large equilibration delay between brain and blood caused by slow equilibration kinetics. This may account for some of the delay in onset of effect previously attributed to the delayed appearance of active metabolites in blood.David J. R. Foster, Mette L. Jensen, Richard N. Upton, Andrew A. Somogyi, Cliff Grant and Allison Martine

Swelling behavior and release properties of pH-sensitive hydrogels based on methacrylic derivatives

peer reviewedThe purpose of this study is to develop novel intestinal-specific drug delivery systems with pH sensitive swelling and drug release properties. Methacrylic-type polymeric prodrugs were synthesized by free radical copolymerization of methacrylic acid, poly(ethyleneglycol monomethyl ether methacrylate) and a methacrylic derivative of N-(4-hydroxyphenyl)-2-(4-methoxyphenyl) acetamide in the presence of ethylene glycol dimethacrylate as crosslinking agent. The effect of copolymer composition on the swelling behavior and hydrolytic degradation were studied in simulated gastric (SGF, pH 1.2) and intestinal fluids (SIF, pH 7.0). The dynamic swelling behavior of these hydrogels was investigated to determine the mechanism of water transport through these hydrogels. The mechanism of water transport through the gels was significantly affected by the pH of the swelling medium and became more relaxation-controlled in a swelling medium of pH 7.0. The swelling and hydrolytic behaviors of hydrogels were dependent on the content of methacrylic acid (MAA) groups and caused a decrease and increase in gel swelling in SGF and SIF, respectively. Drug release studies showed that the increasing content of MAA acid in the copolymer enhances hydrolysis in SIF. These results suggest that pH-sensitive systems could be useful for preparation of a muccoadhesive system and controlled release of N-(4-hydroxyphenyl)-2-(4-methoxyphenyl) acetamide