Use of groundwater lifetime expectancy for the performance assessment of a deep geologic waste repository: 1. Theory, illustrations, and implications

Long-term solutions for the disposal of toxic wastes usually involve isolation of the wastes in a deep subsurface geologic environment. In the case of spent nuclear fuel, if radionuclide leakage occurs from the engineered barrier, the geological medium represents the ultimate barrier that is relied upon to ensure safety. Consequently, an evaluation of radionuclide travel times from a repository to the biosphere is critically important in a performance assessment analysis. In this study, we develop a travel time framework based on the concept of groundwater lifetime expectancy as a safety indicator. Lifetime expectancy characterizes the time that radionuclides will spend in the subsurface after their release from the repository and prior to discharging into the biosphere. The probability density function of lifetime expectancy is computed throughout the host rock by solving the backward-in-time solute transport adjoint equation subject to a properly posed set of boundary conditions. It can then be used to define optimal repository locations. The risk associated with selected sites can be evaluated by simulating an appropriate contaminant release history. The utility of the method is illustrated by means of analytical and numerical examples, which focus on the effect of fracture networks on the uncertainty of evaluated lifetime expectancy.Comment: 11 pages, 8 figures; Water Resources Research, Vol. 44, 200

Rimeporide as a first- in-class NHE-1 inhibitor: Results of a phase Ib trial in young patients with Duchenne Muscular Dystrophy

Rimeporide, a first-in-class sodium/proton exchanger Type 1 inhibitor (NHE-1 inhibitor) is repositioned by EspeRare for patients with Duchenne Muscular Dystrophy (DMD). Historically, NHE-1 inhibitors were developed for cardiac therapeutic interventions. There is considerable overlap in the pathophysiological mechanisms in Congestive Heart Failure (CHF) and in cardiomyopathy in DMD, therefore NHE-1 inhibition could be a promising pharmacological approach to the cardiac dysfunctions observed in DMD. Extensive preclinical data was collected in various animal models including dystrophin-deficient (mdx) mice to characterise Rimeporide’s anti-fibrotic and anti-inflammatory properties and there is evidence that NHE-1 inhibitors could play a significant role in modifying DMD cardiac and also skeletal pathologies, as the NHE-1 isoform is ubiquitous. We report here the first study with Rimeporide in DMD patients. This 4-week treatment, open label phase Ib, multiple oral ascending dose study, enrolled 20 ambulant boys with DMD (6–11 years), with outcomes including safety, pharmacokinetic (PK) and pharmacodynamic (PD) biomarkers. Rimeporide was safe and well-tolerated at all doses. PK evaluations showed that Rimeporide was well absorbed orally reaching pharmacological concentrations from the lowest dose, with exposure increasing linearly with dose and with no evidence of accumulation upon repeated dosing. Exploratory PD biomarkers showed positive effect upon a 4-week treatment, supporting its therapeutic potential in patients with DMD, primarily as a cardioprotective treatment, and provide rationale for further efficacy studies

Rimeporide as a first- in-class NHE-1 inhibitor: results of a phase Ib trial in young patients with Duchenne Muscular Dystrophy

Rimeporide, a first-in-class sodium/proton exchanger Type 1 inhibitor (NHE-1 inhibitor) is repositioned by EspeRare for patients with Duchenne Muscular Dystrophy (DMD). Historically, NHE-1 inhibitors were developed for cardiac therapeutic interventions. There is considerable overlap in the pathophysiological mechanisms in Congestive Heart Failure (CHF) and in cardiomyopathy in DMD, therefore NHE-1 inhibition could be a promising pharmacological approach to the cardiac dysfunctions observed in DMD. Extensive preclinical data was collected in various animal models including dystrophin-deficient (mdx) mice to characterise Rimeporide's anti-fibrotic and anti-inflammatory properties and there is evidence that NHE-1 inhibitors could play a significant role in modifying DMD cardiac and also skeletal pathologies, as the NHE-1 isoform is ubiquitous. We report here the first study with Rimeporide in DMD patients. This 4-week treatment, open label phase Ib, multiple oral ascending dose study, enrolled 20 ambulant boys with DMD (6-11 years), with outcomes including safety, pharmacokinetic (PK) and pharmacodynamic (PD) biomarkers. Rimeporide was safe and well-tolerated at all doses. PK evaluations showed that Rimeporide was well absorbed orally reaching pharmacological concentrations from the lowest dose, with exposure increasing linearly with dose and with no evidence of accumulation upon repeated dosing. Exploratory PD biomarkers showed positive effect upon a 4-week treatment, supporting its therapeutic potential in patients with DMD, primarily as a cardioprotective treatment, and provide rationale for further efficacy studies

Scope for further analytical solutions for constant flux infiltration into a semi-infinite soil profile or redistribution in a finite soil profile.

We attempt to generate new solutions for the moisture content form of the one-dimensional Richards\u27 [1931] equation using the Lisle [1992] equivalence mapping. This mapping is used as no more general set of transformations exists for mapping the one-dimensional Richards\u27 equation into itself. Starting from a given solution, the mapping has the potential to generate an infinite number of new solutions for a series of nonlinear diffusivity and hydraulic conductivity functions. We first seek new analytical solutions satisfying Richards\u27 equation subject to a constant flux surface boundary condition for a semi-infinite dry soil, starting with the Burgers model. The first iteration produces an existing solution, while subsequent iterations are shown to endlessly reproduce this same solution. Next, we briefly consider the problem of redistribution in a finite-length soil. In this case, Lisle\u27s equivalence mapping is generalized to account for arbitrary initial conditions. As was the case for infiltration, however, it is found that new analytical solutions are not generated using the equivalence mapping, although existing solutions are recovered.<br /