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PloS One 2020Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia caused by activating mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. We...
Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia caused by activating mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. We identified that meclizine hydrochloride inhibited FGFR3 signaling in various chondrocytic cells and promoted longitudinal bone growth in mouse model of ACH. Meclizine has safely been used for more than 50 years, but it lacks the safety data for repeated administration and pharmacokinetics (PK) when administered to children. We performed a phase Ia study to evaluate the PK and safety of meclizine administered orally to ACH children. Twelve ACH children aged from 5 to younger than 11 years were recruited, and the first 6 subjects received once a day of meclizine in the fasted condition, subsequent 6 subjects received twice a day of meclizine in the fed condition. Meclizine was well tolerated in ACH children with no serious adverse events. The mean Cmax, Tmax, AUC0-24h, t1/2 during 24 hours in the fasted condition were 130 ng/mL, 1.7 hours, 761 ng·h/mL, and 8.5 hours respectively. The simulation of repeated administration of meclizine for 14 days demonstrated that plasma concentration apparently reached steady state around 10 days after the first dose both at once a day and twice a day administration. The AUC0-10h of the fasting and fed condition were 504 ng·h/mL and 813 ng·h/mL, respectively, indicating exposure of meclizine increased with the diet. Although higher drug exposure was confirmed in ACH children compared to adults, a single administration of meclizine seemed to be well tolerated.
Topics: Achondroplasia; Administration, Oral; Animals; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Meclizine; Mice; Pharmacokinetics
PubMed: 32282831
DOI: 10.1371/journal.pone.0229639 -
Neuroscience Bulletin Jul 2020Neurons, especially axons, are metabolically demanding and energetically vulnerable during injury. However, the exact energy budget alterations that occur early after...
Neurons, especially axons, are metabolically demanding and energetically vulnerable during injury. However, the exact energy budget alterations that occur early after axon injury and the effects of these changes on neuronal survival remain unknown. Using a classic mouse model of optic nerve-crush injury, we found that traumatized optic nerves and retinas harbor the potential to mobilize two primary energetic machineries, glycolysis and oxidative phosphorylation, to satisfy the robustly increased adenosine triphosphate (ATP) demand. Further exploration of metabolic activation showed that mitochondrial oxidative phosphorylation was amplified over other pathways, which may lead to decreased retinal ganglion cell (RGC) survival despite its supplement to ATP production. Gene set enrichment analysis of a microarray (GSE32309) identified significant activation of oxidative phosphorylation in injured retinas from wild-type mice compared to those from mice with deletion of phosphatase and tensin homolog (PTEN), while PTEN-/- mice had more robust RGC survival. Therefore, we speculated that the oxidation-favoring metabolic pattern after optic nerve-crush injury could be adverse for RGC survival. After redirecting metabolic flux toward glycolysis (magnifying the Warburg effect) using the drug meclizine, we successfully increased RGC survival. Thus, we provide novel insights into a potential bioenergetics-based strategy for neuroprotection.
Topics: Animals; Axons; Cell Survival; Crush Injuries; Disease Models, Animal; Energy Metabolism; Glycolysis; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Optic Nerve; Optic Nerve Injuries; Retinal Ganglion Cells
PubMed: 32277382
DOI: 10.1007/s12264-020-00490-x -
British Journal of Clinical Pharmacology Aug 2020Antihistamines make up the first line of treatments against motion-sickness. Still, their efficacy and specific mechanism have come into question. The aim of this study... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
Antihistamines make up the first line of treatments against motion-sickness. Still, their efficacy and specific mechanism have come into question. The aim of this study was to investigate the effect of meclizine on motion-sensitivity.
METHODS
This study was carried out as a triple-blinded randomized trial involving 12 healthy subjects who were exposed to (i) vestibular (VES), (ii) visual (VIS) and (iii) visual-vestibular (VIS+VES) stimulations in the roll plane. Subjects were divided into 2 groups by stratified randomization, receiving either meclizine or a placebo. Stimulations were carried out before, and after, drug administration, presented at 2 intensity levels of 14 and 28°/s . Eye movements were tracked, and torsional slow-phase velocities, amplitudes and nystagmus beats were retrieved. Subjects initially graded for their motion-sickness susceptibility.
RESULTS
Susceptibility had no effect on intervention outcome. Despite large variations, repeated ANOVAS showed that meclizine led to a relative increase in torsional velocity compared to placebo during vestibular stimulation for both intensities: 2.36 (7.65) from -0.01 (4.17) during low intensities, and 2.61 (6.67) from -3.49 (4.76) during high. The visual-vestibular stimuli yielded a decrease during low acceleration, -0.40 (3.87) from 3.75 (5.62), but increased during high, 3.88 (6.51) from -3.88 (8.55).
CONCLUSIONS
Meclizine had an inhibitory effect on eye movement reflexes for low accelerations during VIS+VES trials. This indicates that meclizine may not primarily work through sensory-specific mechanisms, but rather on a more central level. Practically, meclizine shows promise in targeting motion-sickness evoked by everyday activities, but its use may be counterproductive in high-acceleration environments.
Topics: Eye Movements; Humans; Meclizine; Motion Sickness
PubMed: 32077140
DOI: 10.1111/bcp.14257 -
American Journal of Cancer Research 2020Increased activity of amino acid transporters has been observed in a wide variety of cancers. However, whether amino acid metabolism is related to estrogen...
Increased activity of amino acid transporters has been observed in a wide variety of cancers. However, whether amino acid metabolism is related to estrogen receptor-positive (ER) breast cancer has been less well studied. We identified the rate-limiting enzyme involved in amino acid metabolism associated with ER breast cancer by integrating numerous bioinformatics tools and laboratory studies. The bioinformatics analysis revealed that highly expressed genes in ER breast cancer patients were correlated with breast cancer-related pathways, including ESR1 and PI3K signaling. The metabolic signaling and the amino acid metabolism were significantly regulated in breast neoplasms. We used the ER breast cancer cell line MCF-7 and breast cancer tissue from National Cheng Kung University Hospital to validate our findings in bioinformatics. In estradiol-treated MCF-7 cells, genes associated with anabolic metabolism of serine and methionine and genes associated with catabolic metabolism of tyrosine, phenylalanine and arginine were upregulated. Furthermore, the expression levels of ARG2, PSAT1, PSPH, TH, PAH, and MAT1A mRNA were increased in breast cancer patients relative to controls. The aforementioned genes were also found to be highly correlated with distant metastasis-free survival in breast cancer patients. High expression levels of ARG2, CBS, PHGDH, AHCY, HAL, TDO2, SHMT2, MAT1A, MAT2A, GLDC, GLS2, BCAT2, GLUD1, PAH and MTR contributed to poor prognoses, whereas high mRNA expression levels of HECA, CTH, PRODH, TAT, and MAT2B were correlated with good prognoses. FDA-approved drugs, including piperlongumine, ellipticine, etidronic acid, harmine, and meclozine, may have novel therapeutic effects in ER patients based on connectivity map (CMap) analyses. Collectively, our present study demonstrated that amino acid metabolism genes play crucial roles in tumor development and may serve as prospective drug targets or biomarkers for ER breast cancer.
PubMed: 32064155
DOI: No ID Found -
Journal of Hepatology Apr 2020Since human induced pluripotent stem cells (iPSCs) develop into hepatic organoids through stages that resemble human embryonic liver development, they can be used to...
BACKGROUND & AIMS
Since human induced pluripotent stem cells (iPSCs) develop into hepatic organoids through stages that resemble human embryonic liver development, they can be used to study developmental processes and disease pathology. Therefore, we examined the early stages of hepatic organoid formation to identify key pathways affecting early liver development.
METHODS
Single-cell RNA-sequencing and metabolomic analysis was performed on developing organoid cultures at the iPSC, hepatoblast (day 9) and mature organoid stage. The importance of the phosphatidylethanolamine biosynthesis pathway to early liver development was examined in developing organoid cultures using iPSC with a CRISPR-mediated gene knockout and an over the counter medication (meclizine) that inhibits the rate-limiting enzyme in this pathway. Meclizine's effect on the growth of a human hepatocarcinoma cell line in a xenotransplantation model and on the growth of acute myeloid leukemia cells in vitro was also examined.
RESULTS
Transcriptomic and metabolomic analysis of organoid development indicated that the phosphatidylethanolamine biosynthesis pathway is essential for early liver development. Unexpectedly, early hepatoblasts were selectively sensitive to the cytotoxic effect of meclizine. We demonstrate that meclizine could be repurposed for use in a new synergistic combination therapy for primary liver cancer: a glycolysis inhibitor reprograms cancer cell metabolism to make it susceptible to the cytotoxic effect of meclizine. This combination inhibited the growth of a human liver carcinoma cell line in vitro and in a xenotransplantation model, without causing significant side effects. This drug combination was also highly active against acute myeloid leukemia cells.
CONCLUSION
Our data indicate that phosphatidylethanolamine biosynthesis is a targetable pathway for cancer; meclizine may have clinical efficacy as a repurposed anti-cancer drug when used as part of a new combination therapy.
LAY SUMMARY
The early stages of human liver development were modeled using human hepatic organoids. We identified a pathway that was essential for early liver development. Based upon this finding, a novel combination drug therapy was identified that could be used to treat primary liver cancer and possibly other types of cancer.
Topics: Adult; Aged; Animals; Carcinoma, Hepatocellular; Cell Survival; Drug Therapy, Combination; Female; Gene Knockout Techniques; Glycolysis; Hep G2 Cells; Humans; Induced Pluripotent Stem Cells; Leukemia, Myeloid, Acute; Liver; Liver Neoplasms; Male; Meclizine; Mice; Middle Aged; Organogenesis; Organoids; Phosphatidylethanolamines; Pyridines; Quinolines; RNA Nucleotidyltransferases; Retrospective Studies; Treatment Outcome; Xenograft Model Antitumor Assays
PubMed: 31760071
DOI: 10.1016/j.jhep.2019.11.007 -
British Journal of Pharmacology Feb 2020Histamine H receptors are expressed in the peripheral vestibular system, and their selective inhibition improves vertigo symptoms in rats with unilateral vestibular...
BACKGROUND AND PURPOSE
Histamine H receptors are expressed in the peripheral vestibular system, and their selective inhibition improves vertigo symptoms in rats with unilateral vestibular lesions. The effects of SENS-111, a selective oral H receptor antagonist with high affinity to both animal and human receptors, on vertigo symptoms was evaluated in a translational in vivo model of unilateral vestibular loss.
EXPERIMENTAL APPROACH
Pharmacokinetics of SENS-111 in rats was determined to aid dose selection for efficacy testing. Vestibular lesions were induced in rats by unilateral transtympanic injection of kainic acid. The effect of SENS-111 (10 or 20 mg·kg ) on spontaneous nystagmus was evaluated compared with placebo vehicle using video-nystagmography, and the effective dose was compared with those of similar drugs used clinically, as single agents or combined with SENS-111.
KEY RESULTS
Doses were selected for plasma exposure were consistent with published phase 1 results from healthy volunteers. SENS-111 of 10 mg·kg gave a 21-22% reduction in nystagmus at 1 hr post-administration, whereas a loss of efficacy was seen with 20 mg·kg . Compared with SENS-111, meclizine and methylprednisolone had minimal effects on nystagmus as single agents, and meclizine abolished the effect of SENS-111 when combined with SENS-111. All evaluated drugs were well tolerated.
CONCLUSIONS AND IMPLICATIONS
The exposure-efficacy relationship for improved spontaneous nystagmus seen with SENS-111 in this in vivo model is consistent with phase 1 clinical results and provides preclinical support for pharmacokinetic/pharmacodynamic modelling and selection of effective clinical drug concentrations.
LINKED ARTICLES
This article is part of a themed section on New Uses for 21st Century. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.3/issuetoc.
Topics: Animals; Azetidines; Histamine; Histamine Antagonists; Pyrimidines; Rats
PubMed: 31347148
DOI: 10.1111/bph.14803