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Chirality Aug 2020Enantiomeric resolution and molecular docking studies of meclizine hydrochloride on polysaccharide-based chiral stationary phase comprising cellulose...
Bioanalytical chiral chromatographic technique and docking studies for enantioselective separation of meclizine hydrochloride: Application to pharmacokinetic study in rabbits.
Enantiomeric resolution and molecular docking studies of meclizine hydrochloride on polysaccharide-based chiral stationary phase comprising cellulose tris(4-methylbenzoate) chiral selector (150 × 4.6 mm, 3.0 μm) were presented. The mobile phase used was acetonitrile:10mM ammonium bicarbonate (95:05, v/v). The developed technique was used to perform the enantioselective assay of meclizine hydrochloride in its marketed formulation. The elution order of meclizine hydrochloride enantiomers was determined by docking studies. Target compound was extracted from rabbit plasma using protein precipitation technique, followed by development of bioanalytical chiral separation method using the same matrix. Application of the method to determine pharmacokinetic parameters of meclizine hydrochloride enantiomers was performed using Phoenix WinNonlin 8.1 software. The results demonstrated stereoselective disposition of meclizine hydrochloride enantiomers in rabbits.
Topics: Animals; Drug Compounding; Meclizine; Molecular Docking Simulation; Rabbits; Stereoisomerism; Tissue Distribution
PubMed: 32567097
DOI: 10.1002/chir.23241 -
International Journal of Pharmaceutics Jun 2020The aim of this study was to formulate an easily-administered, safe and effective dosage form loaded with meclizine for treatment of chemotherapy-induced nausea and...
Nanotechnology based blended chitosan-pectin hybrid for safe and efficient consolidative antiemetic and neuro-protective effect of meclizine hydrochloride in chemotherapy induced emesis.
The aim of this study was to formulate an easily-administered, safe and effective dosage form loaded with meclizine for treatment of chemotherapy-induced nausea and vomiting (CINV) through the buccal route. CINV comprises bothersome side effects accompanying cytotoxic drugs administration in cancer patients. Meclizine was loaded in chitosan-pectin nanoparticles which were further incorporated within a buccal film. Different formulations were prepared based on a 2.3 full factorial study using Design Expert®8. The optimum formulation possessed favorable characters regarding its particle size (129 nm), entrapment efficiency (90%) and release profile. Moreover, its permeation efficiency through sheep buccal mucosa was assessed via Franz cell diffusion and confocal laser microscopy methods. Enhanced permeation was achieved compared with the free drug form. In-vivo performance was assessed using cyclophosphamide induced emesis. The proposed formulation exerted significant relief of the measured responses (reduced body weight and motor coordination, elevated emesis, anorexia, proinflammatory mediators and neurotransmitters that were also associated with scattered degenerated neurons and glial cells). The developed formulation ameliorated all behavioral, biochemical and histopathological changes induced by cyclophosphamide. The obtained data were promising suggesting that our bioadhesive formulation can offer an auspicious medication for treating distressing symptoms associated with chemotherapy for cancer patients.
Topics: Administration, Buccal; Animals; Antiemetics; Antineoplastic Agents; Chemistry, Pharmaceutical; Chitosan; Cyclophosphamide; Cytokines; Delayed-Action Preparations; Drug Carriers; Drug Liberation; Humans; Hydrogen-Ion Concentration; Inflammation Mediators; Male; Meclizine; Microscopy, Electron, Transmission; Nanoparticles; Neurotransmitter Agents; Oral Mucosal Absorption; Pectins; Rats; Rats, Wistar; Sheep; Spectroscopy, Fourier Transform Infrared; Tensile Strength; Vomiting
PubMed: 32423876
DOI: 10.1016/j.ijpharm.2020.119411 -
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 -
Canadian Journal of Physiology and... Jun 2020Pregnane X receptors (PXRs) regulate the expression of ATP-binding cassette proteins transporters and organic anion transporting polypeptides responsible for...
Pregnane X receptors (PXRs) regulate the expression of ATP-binding cassette proteins transporters and organic anion transporting polypeptides responsible for influx/efflux of xenobiotics across the brain. Ligand activation of PXR augments the expression of P-gp and promotes amyloid-β clearance across the blood-brain barrier. Dementia was induced in mice by intacerebroventricular administration of streptozotocin (STZ) followed by treatment with meclizine, a PXR agonist, and subsequently exposed to the Morris water maze test and biochemical and histopathological analysis to evaluate the effect on cognition. STZ-treated mice exhibited significant enhancement in brain thiobarbituric acid reactive species, interleukin-1β, tumour necrosis factor-α, myeloperoxidase, and acetylcholinestrase activity in addition to diminution in glutathione levels and superoxide dismutase activity in comparison to untreated mice. Administration of meclizine to STZ mice recuperated cognition and biochemical alterations. Concomitant administration of ketoconazole, a PXR antagonist, with meclizine prevented the protective effects. The upshots of our study proclaim that meclizine protects cognitive deficits by virtue of its antioxidant, anticholinesterase, and antiinflammatory properties. Results also signify the potential of PXR in neuroprotective actions of meclizine in dementia.
Topics: Animals; Brain; Dementia; Disease Models, Animal; Female; Glutathione; Interleukin-1beta; Male; Meclizine; Memory Disorders; Mice; Neuroprotective Agents; Pregnane X Receptor; Streptozocin; Superoxide Dismutase; Tumor Necrosis Factor-alpha
PubMed: 31935134
DOI: 10.1139/cjpp-2019-0421 -
Seminars in Neurology Feb 2020Treatment of vestibular migraine currently lacks a firm scientific basis, as high quality randomized controlled trials are not available. Therefore, recommendations are... (Review)
Review
Treatment of vestibular migraine currently lacks a firm scientific basis, as high quality randomized controlled trials are not available. Therefore, recommendations are largely borrowed from the migraine sphere. The first therapeutic step is explanation and reassurance. Many patients do not need pharmacological treatment, as attacks may be infrequent and tolerable. Acute attacks can be ameliorated in some patients with antiemetic drugs such as diphenhydramine, meclizine, and metoclopramide. Frequent attacks may warrant pharmacological prophylaxis with metoprolol, amitriptyline, topiramate, valproic acid, or flunarizine. Nonpharmacological measures including regular exercise, relaxation techniques, stress management, and biofeedback may be similarly effective and can be combined with a pharmacological approach. Limited data indicate that the prognosis appears to be less favorable for vestibular migraine than for migraine headaches.
Topics: Humans; Migraine Disorders; Prognosis; Vertigo
PubMed: 31887753
DOI: 10.1055/s-0039-3402067 -
Current Drug Research Reviews 2020A basic, powerful and isocratic chiral fluid chromatographic technique was created and approved for the enantiomeric partition of meclizine hydrochloride in...
OBJECTIVE
A basic, powerful and isocratic chiral fluid chromatographic technique was created and approved for the enantiomeric partition of meclizine hydrochloride in pharmaceutical dose structure.
METHODS
The chromatographic partition was accomplished on Phenomenex® Lux Cellulose 1 (250 mm x 4.6 mm i.d, 5 μm molecule size) section utilizing portable stage framework containing acetonitrile: 25mM ammonium bicarbonate (75:25%v /v). The versatile stage was siphoned on the segment at the stream pace of 1.0 mL/min, and UV recognition was done at 230 nm.
RESULT
The breaking points of recognition and measurement were observed to be 0.25 μg/mL and 1.00 μg/mL individually, for 20μL infusion volume. The alignment bend demonstrated phenomenal linearity over the focus scope of 1-5 μg/mL for (±) meclizine enantiomers with a relationship coefficient (r2 = 0.999). The recuperation investigation of meclizine from tablet plan was observed to be 97.33% and 98.81% separately. Meclizine standard arrangement and versatile stage were observed to be steady for in any event 32h. The meclizine enantiomers were very much settled with mean maintenance times of about (+) Meclizine at 13.14 min and (-) Meclizine at 14.33 min individually.
CONCLUSION
The created technique was broadly approved and demonstrated to be hearty, exact, exact and appropriate for the examination of meclizine enantiomers in tablet measurement structure and security investigations of meclizine.
Topics: Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Histamine H1 Antagonists; Meclizine; Stereoisomerism; Tablets; Time Factors
PubMed: 31823710
DOI: 10.2174/2589977511666191211123337 -
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