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Arising from mostly de novo mutations, achondroplasia (ACH) is one of the most common, non-lethal forms of chondrodysplasia. The short stature indicative of ACH stems from a gain of function mutation within the complex FGFR3 signaling pathway—mutations mitigating the too-rapid ossification of cartilage to bone. Meclizine, an FDA-approved drug long prescribed for motion sickness, halts such a conversion and allows the reconstitution of chondrodysplasia cell lines in attempts at following a normal growth pattern. Evinced by various cell line rescues as well as increased long bone growth, it can be hypothesized that maternally administered meclizine can rescue the ACH phenotype enough to attenuate the largest danger to ACH infants, foramen magnum stenosis (FMS).

Glioblastoma (GBM) is an aggressive tumor of the brain, with an average post-diagnosis survival of 15 months. GBM stem cells (GBMSC) resist the standard-of-care therapy, temozolomide, and are considered a major contributor to tumor resistance. Mammalian target of rapamycin Complex 1 (mTORC1) regulates cell proliferation and has been shown by others to have reduced activity in GBMSC. We recently identified a novel chemical series of human-safe piperazine-based brain-penetrant mTORC1-specific inhibitors. We assayed the piperazine-mTOR binding strength by two biophysical measurements, biolayer interferometry and field-effect biosensing, and these confirmed each other and demonstrated a structure-activity relationship. As mTORC1 is altered in human GBMSC, and as mTORC1 inhibitors have been tested in previous GBM clinical trials, we tested the killing potency of the tightest-binding piperazines and observed that these were potent GBMSC killers. GBMSCs are resistant to the standard-of-care temozolomide therapy, but temozolomide supplemented with tight-binding piperazine meclizine and flunarizine greatly enhanced GBMSC death over temozolomide alone. Lastly, we investigated IDH1-mutated GBMSC mutations that are known to affect mitochondrial and mTORC1 metabolism, and the tight-binding meclizine provoked 'synthetic lethality' in IDH1-mutant GBMSCs. In other words, IDH1-mutated GBMSC showed greater sensitivity to the coadministration of temozolomide and meclizine. These data tend to support a novel clinical strategy for GBM, i.e., the co-administration of meclizine or flunarizine as adjuvant therapy in the treatment of GBM and IDH1-mutant GBM.

NAMRL evaluated antimotion sickness medications to help the USSOCOM Biomedical Initiatives Steering Committee explore alternatives to meclizine. This double-blind, placebo-controlled study compared five groups (n = 30 per condition): 1) oral + transdermal placebo (control); 2) 50 mg oral meclizine + transdermal placebo; 3) 25 mg oral promethazine + transdermal placebo; 4) 0.8 mg oral scopolamine + transdermal placebo; 5) oral placebo + transdermal scopolamine (1.5 mg). Each condition included oral caffeine (200 mg). Medication efficacy was defined as the number of tilts tolerated upon reaching sustained moderate nausea during a Coriolis, cross-coupling stimulus. A past motion susceptibility rating was employed as a covariate. Performance was evaluated with cognitive and psychomotor test batteries derived from USSOCOM?s Mission-Related Performance Measures. MANOVA detected no medication-related performance differences in either battery. Planned contrasts compared meclizine to promethazine and scopolamine (oral or transdermal), while controlling for past susceptibility. The only observed difference was between meclizine (M = 170 tilts, SE = 13) and oral scopolamine (M = 217, SE = 13), p = .04; however, a post-hoc comparison failed to distinguish oral scopolamine from placebo. Lack of observed medication performance differences implied that USSOCOM may consider alternatives to meclizine; however, efficacy findings were inconclusive.

A series of antimotion sickness drugs was evaluated on the human centrifuge at the Navy School of Aviation Medicine. The procedures used enabled the same stimulus to be applied to the individual subjects through the series of drug tests. A combination of hyoscine and d-amphetamine was found to be the most effective preparation. Hyoscine alone was the most effective single drug followed by d-amphetamine and meclizine Prochlorperazine was slightly effective, but chlorpromazine, thiethylperazine, and trimethobenzamide were ineffective. Hyoscine alone produced pronounced drowsiness. The combination with d-amphetamine relieved this side effect but not the vertigo and dry mouth. The advantages of the human centrifuge in the testing of antimotion sickness drugs are pointed out. (Author), Joint rept. with National Aeronautics and Space Administration, Washington, D. C.