Efficacy and Safety of a Fixed Combination of Cinnarizine 20 mg and Dimenhydrinate 40 mg vs Betahistine Dihydrochloride 16 mg in Patients with Peripheral Vestibular Vertigo: A Prospective, Multinational, Multicenter, Double-Blind, Randomized, Non-inferiority Clinical Trial

Scholtz, Arne W.; Hahn, Aleš; Stefflova, Bohdana; Medzhidieva, Daniela; Ryazantsev, S. V.; Paschinin, Alexander; Kunelskaya, N. L.; Schumacher, Kai; Weisshaar, Gerhard

doi:10.1007/s40261-019-00858-6

Cited by 25 publications

(17 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Because meclizine has a benign safety profile (one tradename is Dramamine) [26][27][28][29], we tested the idea of meclizine as adjuvant therapy, i.e., the ability of piperazine plus temozolomide to kill GBMSCs. As seen in Figure 5, there was a negligible decrease in GBMSC viability at all doses of temozolomide.…”

Section: Co-administration Of Temozolomide With Meclizine or Flunarizine Potentiates Gbmsc Killingmentioning

confidence: 99%

Novel mTORC1 Inhibitors Kill Glioblastoma Stem Cells

et al. 2020

View full text Add to dashboard Cite

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.

show abstract

Section: Co-administration Of Temozolomide With Meclizine or Flunarizine Potentiates Gbmsc Killingmentioning

confidence: 99%

Novel mTORC1 Inhibitors Kill Glioblastoma Stem Cells

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Because Meclizine (i.e. one tradename is Dramamine) has a benign safety profile (25)(26)(27)(28), we tested the idea of Meclizine as adjuvant therapy, i.e. the ability of piperazine plus temozolomide to kill GBMSCs.…”

Section: Comparison Of Gbm Cell Viability After Treatment With Meclizmentioning

confidence: 99%

Novel mTORC1 inhibitors kill Glioblastoma stem cells

Sandoval

Tomilov

Datta

et al. 2020

Preprint

View full text Add to dashboard Cite

Glioblastoma Multiforme (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. 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 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. Since mTORC1 is reduced 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 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, the tight-binding Meclizine provoked 'synthetic lethality' in IDH1-mutant GBMSCs. 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.

show abstract

“…[1][2][3] Furthermore, the antiemetic DMH is traditionally used in the treatment of motion sickness and peripheral vestibular vertigo. 4 Although DMH has several official impurities, 5 only toxicity assessment was available for benzophenone (BZP), (Fig. 1b) and benzhydrol ( Fig.…”

Section: Introductionmentioning

confidence: 99%