Identification of SOD1 as the mutated protein in a significant subset of familial amyotrophic lateral sclerosis (FALS) cases has led to the generation of transgenic rodent models of autosomal dominant SOD1 FALS. Mice carrying 23 copies of the human SOD1(G93A) transgene are considered the standard model for FALS and ALS therapeutic studies. To date, there have been at least 50 publications describing therapeutic agents that extend the lifespan of this mouse. However, no therapeutic agent besides riluzole has shown corresponding clinical efficacy. We used computer modeling and statistical analysis of 5429 SOD1(G93A) mice from our efficacy studies to quantify the impact of several critical confounding biological variables that must be appreciated and should be controlled for when designing and interpreting efficacy studies. Having identified the most critical of these biological variables, we subsequently instituted parameters for optimal study design in the SOD1(G93A) mouse model. We retested several compounds reported in major animal studies (minocycline, creatine, celecoxib, sodium phenylbutyrate, ceftriaxone, WHI-P131, thalidomide, and riluzole) using this optimal study design and found no survival benefit in the SOD1(G93A) mouse for any compounds (including riluzole) administered by their previously reported routes and doses. The presence of these uncontrolled confounding variables in the screening system, and the failure of these several drugs to demonstrate efficacy in adequately designed and powered repeat studies, leads us to conclude that the majority of published effects are most likely measurements of noise in the distribution of survival means as opposed to actual drug effect. We recommend a minimum study design for this mouse model to best address and manage this inherent noise and to facilitate more significant and reproducible results among all laboratories employing the SOD1(G93A) mouse.

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The physico-chemical properties of biodegradable polylactide-co-glycolide (PLGA) microspheres containing the peptide salmon calcitonin (sCT) were affected by the processing parameters. The microsphere size increased with an increase in the viscosity of the polymer solution. Concentration of methanol and peptide in the dispersed phase had the most discernible effects with the combination causing external and internal porosity. Increasing sCT in the presence of methanol increased the surface area and porosity. The surface area also increased as the molecular weight of the polymer was decreased. At higher ratios of the dispersed phase volume to the continuous phase volume, the surface area and surface porosity were higher and the particle size was lower. Thus, the physico-chemical properties of the microspheres can be easily altered by varying the processing parameters allowing formation of microspheres with a range of properties. The microspheres may be used to evaluate the relationship between the properties and ultimate in-vivo performance.

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