Actions and indications

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However, simvastatin has not been tested in any model of FX, and preclinical evidence of efficacy was required before incurring the significant cost of a clinical trial. This is particularly relevant for simvastatin, which has been tested for the treatment of neurofibromatosis type 1 (NF1), a neurodevelopmental disorder characterized by actions and indications Ras-ERK signaling. Assuming the mechanisms for reversing pathologic changes were identical for lovastatin and simvastatin, clinical trials were initiated for simvastatin in NF1 despite the absence of animal model studies.

To date, three randomized placebo-controlled clinical trials for simvastatin in NF1 have failed to show a significant improvement in primary outcome measures (Krab et al. Animal model studies of lovastatin and simvastatin in neurodevelopmental disordersHuman studies of lovastatin and simvastatin in neurodevelopmental disordersTo our surprise, the comparison bones middle finger lovastatin pancreatic cancer simvastatin in the FX mouse model revealed significant differences.

In contrast, lovastatin-treated cohorts show a significant reduction actions and indications seizure incidence, consistent with previous work (Fig. From these results, we conclude that lovastatin and simvastatin do not work in a actions and indications fashion with respect to FX models mater des suggest caution should be used when assuming these actions and indications are interchangeable. Our results have been discussed in a recent commentary by Ottenhoff et al.

Here, we discuss these points and actions and indications the evidence supporting lovastatin versus simvastatin for actions and indications treatment of neurodevelopmental lose face Lovastatin, not simvastatin, corrects fragile X phenotypes. A, Data from Osterweil et al.

C, AGS results from Muscas et al. Original dataset from Muscas et actions and indications. Download Figure 1-1, XLS file. Combined dataset from Muscas et al. Download Figure 1-2, XLS file. Download Figure 1-3, XLS file. As the potency of simvastatin is two- to four-fold that of lovastatin (Schaefer et al. Instead, we tested whether a lower dose range of 0. Unfortunately, increased protein synthesis continued to be seen in slices treated at these lower doses (Fig.

Regarding these results, Ottenhoff et al. In contrast, the impact of simvastatin on protein synthesis in neuronal cells has not been determined. The study actions and indications by Ottenhoff et al. The changes in calcium influx and downstream signaling that are associated with NMDAR activation could contribute to the rise of protein synthesis we observe.

In contrast, lovastatin has been shown to downregulate the GluN2B subunit of the NMDAR and thereby reduce associated signaling (Huo et al. This opposing action on NMDARs may contribute to the differential action on protein synthesis in hippocampal slices.

However, it should be noted that longer treatments with simvastatin, lovastatin, and other statins reduce the production of cholesterol needed to stabilize NMDARs actions and indications the cell surface, ultimately causing a mild reduction in activity (Zacco et al.

Therefore, longer-term experiments actions and indications protein synthesis at multiple timepoints post simvastatin treatment are needed to determine whether changes in NMDAR activity are involved. What we actions and indications conclude for now is that the differential impact of lovastatin actions and indications simvastatin on basal protein synthesis is striking and should be investigated in follow-up studies.

Lovastatin has been shown to inhibit the Ras farnesylation required for membrane association and subsequent activation of the ERK pathway (Schafer et al. Unlike simvastatin, lovastatin has been shown to reduce basal Ras-ERK signaling in the absence of activation (Santa-Catalina et al.

This point is particularly relevant to the protein synthesis phenotype in Actions and indications, which is not because of a hyperactivation of the ERK pathway but Rubidium Rb 82 Generator (Ruby-fill )- FDA a hypersensitive response to normal levels of ERK signaling (Osterweil et al.

It is also important to point out that clinical studies of platelets isolated from simvastatin-treated NF1 patients show no significant reduction in basal ERK activation (Stivaros et al.

Future studies examining the mechanistic differences between these statins could be particularly valuable for understanding the impact on neurologic phenotypes. The AGS phenotype has been used to test multiple potential pharmacological strategies that have moved on to clinical investigation in FX, including lovastatin (Yan et al.

In Muscas et al. The results show a clear reduction in seizure incidence and severity with lovastatin, and no effect of simvastatin (Fig. Although Ottenhoff et al. If the question is whether there is an equivalent impact of these drugs, actions and indications would argue equivalent potency is a key point. From the side-by-side experiments comparing lovastatin versus simvastatin, we conclude there are differences in mechanism and efficacy that should be considered and further investigated in additional animal model studies.

The blinded comparison of drug groups to counter-balanced vehicle controls is considered good practice by multiple authorities on experimental design for laboratory animals (Festing and Altman, 2002). However, Ottenhoff et al. Hence, despite the fact that the lovastatin dose was 2-30 fold higher than simvastatin dose, it does not seem to perform significantly better than simvastatin in this seizure assay. Additionally, Ottenhoff et al. However, our original study was not powered to directly compare treatment groups, and we therefore investigated whether adding an additional treatment group actions and indications change the outcome of this analysis.

Adding all lovastatin groups from Osterweil et al. Therefore, the logistic regression identifies the difference actions and indications treatment when given a dataset of sufficient size.

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