147 results on '"Meclizine"'
Search Results
2. Unraveling the Structure of Meclizine Dihydrochloride with MicroED.
- Author
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Lin, Jieye, Unge, Johan, and Gonen, Tamir
- Subjects
Meclizine (Antivert ,Bonine) ,Microcrystal electron diffraction (MicroED) ,Molecular docking ,Protein-drug interactions ,Racemic crystal ,Meclizine ,Molecular Docking Simulation ,Electrons ,Receptors ,Histamine H1 ,Proteins ,Histamine Antagonists - Abstract
Meclizine (Antivert, Bonine) is a first-generation H1 antihistamine used in the treatment of motion sickness and vertigo. Despite its wide medical use for over 70 years, its crystal structure and the details of protein-drug interactions remained unknown. Single-crystal X-ray diffraction (SC-XRD) is previously unsuccessful for meclizine. Today, microcrystal electron diffraction (MicroED) enables the analysis of nano- or micro-sized crystals that are merely a billionth the size needed for SC-XRD directly from seemingly amorphous powder. In this study, MicroED to determine the 3D crystal structure of meclizine dihydrochloride is used. Two racemic enantiomers (R/S) are found in the unit cell, which is packed as repetitive double layers in the crystal lattice. The packing is made of multiple strong N-H-Cl- hydrogen bonding interactions and weak interactions like C-H-Cl- and pi-stacking. Molecular docking reveals the binding mechanism of meclizine to the histamine H1 receptor. A comparison of the docking complexes between histamine H1 receptor and meclizine or levocetirizine (a second-generation antihistamine) shows the conserved binding sites. This research illustrates the combined use of MicroED and molecular docking in unraveling elusive drug structures and protein-drug interactions for precision drug design and optimization.
- Published
- 2024
3. Astaxanthin and meclizine extend lifespan in UM-HET3 male mice; fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate do not significantly affect lifespan in either sex at the doses and schedules used.
- Author
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Harrison, David, Strong, Randy, Reifsnyder, Peter, Rosenthal, Nadia, Korstanje, Ron, Fernandez, Elizabeth, Flurkey, Kevin, Ginsburg, Brett, Murrell, Meredith, Javors, Martin, Lopez-Cruzan, Marisa, Nelson, James, Willcox, Bradley, Allsopp, Richard, Watumull, David, Kirkland, James, Tchkonia, Tamar, Choi, Young, Yousefzadeh, Matthew, Robbins, Paul, Mitchell, James, Acar, Murat, Sarnoski, Ethan, Bene, Michael, Salmon, Adam, Kumar, Navasuja, Miller, Richard, and Cortopassi, Gino
- Subjects
4-Phenylbutyrate (PBA) ,Astaxanthin (Asta) ,Dimethyl Fumarate (DMF) ,Fisetin (Fis) ,Heterogeneous mice ,Lifespan ,Meclizine (Mec) ,Mycophenolic acid (MPA) ,SG1002 ,Female ,Mice ,Male ,Animals ,Longevity ,Meclizine ,Hydrogen Sulfide ,Dimethyl Fumarate ,Mycophenolic Acid ,Phenylbutyrates ,Xanthophylls ,Flavonols - Abstract
In genetically heterogeneous (UM-HET3) mice produced by the CByB6F1 × C3D2F1 cross, the Nrf2 activator astaxanthin (Asta) extended the median male lifespan by 12% (p = 0.003, log-rank test), while meclizine (Mec), an mTORC1 inhibitor, extended the male lifespan by 8% (p = 0.03). Asta was fed at 1840 ± 520 (9) ppm and Mec at 544 ± 48 (9) ppm, stated as mean ± SE (n) of independent diet preparations. Both were started at 12 months of age. The 90th percentile lifespan for both treatments was extended in absolute value by 6% in males, but neither was significant by the Wang-Allison test. Five other new agents were also tested as follows: fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate. None of these increased lifespan significantly at the dose and method of administration tested in either sex. Amounts of dimethyl fumarate in the diet averaged 35% of the target dose, which may explain the absence of lifespan effects. Body weight was not significantly affected in males by any of the test agents. Late life weights were lower in females fed Asta and Mec, but lifespan was not significantly affected in these females. The male-specific lifespan benefits from Asta and Mec may provide insights into sex-specific aspects of aging.
- Published
- 2024
4. Meclizine for Hepatocellular Carcinoma (OPTIM)
- Author
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Tannaz Armaghnay, Assistant Professor of Medicine - Hematology and Oncology
- Published
- 2024
5. Non Inferiority of Meclin® (Meclizine Chlorhydrate) Versus Dramin® (Dimenhydrinate) in Control of Acute Vertigo Symptoms From Peripheral Origin
- Published
- 2023
6. Novel mTORC1 Inhibitors Kill Glioblastoma Stem Cells
- Author
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Sandoval, Jose A, Tomilov, Alexey, Datta, Sandipan, Allen, Sonia, O’Donnell, Robert, Sears, Thomas, Woolard, Kevin, Kovalskyy, Dmytro, Angelastro, James M, and Cortopassi, Gino
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Rare Diseases ,Stem Cell Research - Nonembryonic - Human ,Clinical Research ,Brain Disorders ,Neurosciences ,Stem Cell Research ,Clinical Trials and Supportive Activities ,Brain Cancer ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,mTOR ,mTORC1 ,glioblastoma ,piperazine ,meclizine ,Pharmacology and Pharmaceutical Sciences ,Pharmacology and pharmaceutical sciences - Abstract
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.
- Published
- 2020
7. Evaluation of Meclizine Orodispersible Tablet Pharmacokinetic in Human Volunteers
- Published
- 2020
8. Meclizine Plasma Levels in Responders and Non-responders
- Author
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Yoni Gutkovich, deputy of the head of department for the human performance laboratory, the Israeli naval institute, Haifa.
- Published
- 2020
9. Meclizine, a piperazine-derivative antihistamine, binds to dimerized translationally controlled tumor protein and attenuates allergic reactions in a mouse model
- Author
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Eun-Hwa Jang, Hae-Duck Bae, Yejin Jeon, Dong Hae Shin, Soosung Kang, and Kyunglim Lee
- Subjects
TCTP ,HRF ,Meclizine ,Airway inflammation ,Antihistamine ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Translationally controlled tumor protein (TCTP), a highly conserved protein present in most eukaryotes, is involved in numerous biological processes. Only the dimeric form of TCTP (dTCTP) formed during inflammatory conditions exhibits cytokine-like activity. Therefore, dTCTP is considered as a therapeutic target for allergic diseases. Because monomeric TCTP (mTCTP) and dTCTP share a high topological similarity, we hypothesized that small molecules interacting with mTCTP would also bind to dTCTP and interfere with dTCTP-based cellular processes. In this study, nine compounds listed in the literature as interacting with mTCTP were investigated for their ability to suppress the activity of extracellular dTCTP in bronchial epithelial cells. It was found that one of the nine, meclizine, a piperazine-derivative antihistamine, significantly reduced IL-8 release and suppressed the NF-κB pathway. The direct interaction of meclizine with dTCTP was confirmed by surface plasmon resonance (SPR). Also, we found that meclizine can attenuate ovalbumin (OVA)-induced airway inflammation in mice. Therefore, meclizine might be a potential anti-allergic drug as an inhibitor for dTCTP.
- Published
- 2023
- Full Text
- View/download PDF
10. Formulation and in-silico study of meclizine ointment as anti-eczema.
- Author
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Al-Madhagi, Wafa M., Alzomor, Abdulkarim K. Y., Zamakshshari, Nor Hisam, and Mubarak, Maria A.
- Subjects
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MOTION sickness , *MOLECULAR docking , *CHEMICAL testing , *PILLS , *VOLUNTEERS , *VITAMIN B6 - Abstract
Meclizine is antihistamine and is used in combination with pyridoxine to treat motion sickness. The in-silico study of meclizine prediction studied showed that meclizine has anti-eczema activity with possible activity 95. This research aimed to explore the anti-eczema activity of meclizine. Therefore, five formulations of meclizine ointment have been prepared using different bases (white base, simple ointment base, hydrophilic petrolatum base, hydrophilic, and emulsifying ointment bases). The efficiency of meclizine ointment has been evaluated by testing the physical compatibility and stability, homogeneity and irritant effect, absorbance and spreadability, chemical identification, calibration curve, drug content (assay), and dissolution test. This is followed by evaluating the ointment's effectiveness on volunteers and molecular docking. Five creams trials have been prepared, and two formulas (F3, and F5) have been selected for further evaluation. The formulas three and five (F3, F5) have passed the physical and chemical tests and showed compatibility, homogenous, absorbed, non-irritant, and stable with calibration curve (R = 0.9999). Then, the F3 formula was selected by testing them on seven volunteers after evaluating the irritant test. Four of the volunteers showed excellent recovery, and three of the volunteers suffered from uncomforting feelings and the formation of new pills. Therefore, F5 has been tested by eight volunteers that contain high oleaginous activity; five showed an excellent recovery, while three of the volunteers showed no difference. According to that, F5 is more efficient for eczema patients than F3, and Meclizine showed promising activity as an anti-eczema that requires further evaluation in the future. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
11. Meclizine and Metabotropic Glutamate Receptor Agonists Attenuate Severe Pain and Ca2+ Activity of Primary Sensory Neurons in Chemotherapy-Induced Peripheral Neuropathy.
- Author
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Shannonhouse, John, Bernabucci, Matteo, Gomez, Ruben, Hyeonwi Son, Yan Zhang, Chih-Hsuan Ai, Hirotake Ishida, and Yu Shin Kim
- Subjects
- *
GLUTAMATE receptors , *SENSORY neurons , *PERIPHERAL neuropathy , *CHEMOTHERAPY complications , *ANTIHISTAMINES - Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) affects; 68% of patients undergoing chemotherapy, causing debilitating neuropathic pain and reducing quality of life. Cisplatin is a commonly used platinum-based chemotherapeutic drug known to cause CIPN, possibly by causing oxidative stress damage to primary sensory neurons. Metabotropic glutamate receptors (mGluRs) are widely hypothesized to be involved in pain processing and pain mitigation. Meclizine is an H1 histamine receptor antagonist known to have neuroprotective effects, including an anti-oxidative effect. Here, we used a mouse model of cisplatin-induced CIPN using male and female mice to test agonists of mGluR8 and Group II mGluR as well as meclizine as interventions to reduce cisplatin-induced pain. We performed behavioral pain tests, and we imaged Ca2+ activity of the large population of dorsal root ganglia (DRG) neurons in vivo. For the latter, we used a genetically-encoded Ca2+ indicator, Pirt-GCaMP3, which enabled us to monitor different drug interventions at the level of the intact DRG neuronal ensemble. We found that CIPN increased spontaneous Ca2+ activity in DRG neurons, increased number of Ca2+ transients, and increased hyper-responses to mechanical, thermal, and chemical stimuli. We found that mechanical and thermal pain caused by CIPN was significantly attenuated by the mGluR8 agonist, (S)23,4-DCPG, the Group II mGluR agonist, LY379268, and the H1 histamine receptor antagonist, meclizine. DRG neuronal Ca2+ activity elevated by CIPN was attenuated by LY379268 and meclizine, but not by (S)23,4-DCPG. Furthermore, meclizine and LY379268 attenuated cisplatin-induced weight loss. These results suggest that Group II mGluR agonist, mGluR8 agonist, and meclizine are promising candidates as new treatment options for CIPN, and studies of their mechanisms are warranted. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
12. Real-time Decision Support for Postoperative Nausea and Vomiting (PONV) Prophylaxis
- Author
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Jonathan Wanderer, Medical Director of Procedure Preparation Center
- Published
- 2019
13. Purchase Of Expendable Medical Stores For Echs -tab Complimina Retard 500 Mg, Tab Cyclobenzaprine 30 Mg, Tab Diazepam 5 Mg, Tab Ethambutol 800mg, Tab Etizolam 0.25 Mg, Tab Etizolam 1mg, Tab Glimipride 3 Mg + Metformin 850 Mg, Tab Meclizine 25 Mg, Tab Mefe
- Subjects
India. Indian Army ,Stores ,Ibuprofen ,Oxazepam ,Rasagiline ,Diazepam ,Metformin ,Meclizine ,Valsartan ,Business, international - Abstract
Tenders are invited for Purchase of Expendable Medical Stores for Echs -Tab Complimina retard 500 mg, Tab Cyclobenzaprine 30 mg, Tab Diazepam 5 mg, Tab Ethambutol 800mg, Tab Etizolam 0.25 [...]
- Published
- 2024
14. Antiemetic treatment of hyperemesis gravidarum in 1,064 Norwegian women and the impact of European warning on metoclopramide: a retrospective cohort study 2002-2019.
- Author
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Erdal, Hilde, Holst, Lone, Heitmann, Kristine, and Trovik, Jone
- Abstract
Background: Women suffering from severe nausea and vomiting during pregnancy, hyperemesis gravidarum, have poor quality of life and increased risk of potentially fatal maternal and fetal complications. There is increasing and reassuring knowledge about safety of antiemetics in pregnancy. In 2013, the European Medical Agency (EMA) issued a warning on metoclopramide limiting treatment to maximum five days. Metoclopramide was the most used antiemetic in pregnancy at the time the warning was implemented in the Norwegian hyperemesis guidelines (2014). We aimed at describing changes in the treatment of hyperemesis over time, including changes associated with the EMA warning.Methods: Retrospective chart review of all women hospitalized for hyperemesis gravidarum with metabolic disturbances between 01/Jan/2002 and 31/Dec/2019 at a university hospital serving nearly 10% of the pregnant population in Norway. Time-series analysis described changes over time and interrupted time series analysis quantified changes in treatment and clinical outcomes related to the EMA warning.Results: In total, 1,064 women (1.2% of the birthing population) were included. The use of meclizine, prochlorperazine, and ondansetron increased during 2002-2019. This led to a yearly increase in the percentage of women using any antiemetic of 1.5% (95%CI 0.6; 2.4) pre-hospital, 0.6% (95%CI 0.2; 1.1) during hospitalization, and 2.6% (95%CI 1.3; 3.8) at discharge. Overall, only 50% of the women received antiemetics pre-hospital. Following the EMA warning, prehospital use of metoclopramide dropped by 30% (95%CI 25; 36), while use of any antiemetic pre-hospital dropped by 20% (95%CI 5.7; 34). In timely association, we observed a decrease in gestational age (-3.8 days, 98.75%CI 0.6; 7.1) at first admission, as well as indication of increased rate of termination of pregnancy with an absolute increase of 4.8% (98.75%CI 0.9; 8.7) in 2014.Conclusion: During 2002-2019, the overall use of antiemetics in treatment of hyperemesis increased. The EMA-warning on metoclopramide in 2013 temporarily limited pre-hospital antiemetic provision associated with hospitalization at lower gestational length and indication of an increase in termination of pregnancy. [ABSTRACT FROM AUTHOR]- Published
- 2022
- Full Text
- View/download PDF
15. Treating Benign Paroxysmal Positional Vertigo (BPPV) in ED Patients
- Author
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David Burmeister, Chair, Department of Emergency Medicine
- Published
- 2018
16. Suggested Study as a Treatment Protocol for Coronavirus
- Author
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Shahin, M. I
- Subjects
coronavirus ,pyridoxine ,meclizine ,chloroquine ,corticosterone ,Mathematics ,QA1-939 ,Botany ,QK1-989 ,Zoology ,QL1-991 ,Geology ,QE1-996.5 - Abstract
Coronaviruses are a large family of RNA viruses without segment, positive-sense RNA genomes and single-stranded, which cause illnesses. The disease ranging from mild in most people to diseases that is more dangerous. It may progress to pneumonia, acute respiratory distress syndrome and finally failure in vital function. Many people did not show symptoms of the disease. Clinical laboratory finding are low white cell counts with high rate of C-reactive protein. Chloroquine has positive antiviral effects on virus infection of primitive cells. In addition, these inhibitory effects were seen when the drug was used before and after exposure to the virus, this is important for both the preventive and curative architecture as well as therapeutic advantage of chloroquine. Meclizine and pyridoxine hydrochloride are considered strong anti-inflammatory, which help in controlling cytokine storm. Treatment by mixture of chloroquine, corticosterone, meclizine and pyridoxine may be protecting against blood clotting, which limits the spread of the disease. Accordingly, chloroquine, corticosterone, meclizine and pyridoxine can be used as prevention and treatment against pathogenic viral infections.
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- 2020
- Full Text
- View/download PDF
17. Meclizine Inhibits Pseudorabies Virus Replication by Interfering With Virus Entry and Release.
- Author
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Liu, Panrao, Hu, Danhe, Yuan, Lili, Lian, Zhengmin, Yao, Xiaohui, Zhu, Zhenbang, Nowotny, Norbert, Shi, Yi, and Li, Xiangdong
- Subjects
AUJESZKY'S disease virus ,VIRAL replication ,VIRUS diseases ,SWINE industry ,ANTIVIRAL agents ,ACTINOBACILLUS ,VIRAL load ,PORCINE reproductive & respiratory syndrome - Abstract
Pseudorabies virus (PRV) is a pathogen that causes substantial economic losses to the swine industry. With the emergence and widespread of PRV variants since 2011 in China, current commercial vaccines cannot provide complete protection against PRV infection. Therefore, antiviral drugs may work as an alternative way to control and prevent PRV. In this study, the inhibitory effects and underlying molecular mechanisms of meclizine against PRV were studied. Meclizine displayed a significant inhibitory effect against PRV when it was added before, simultaneously with, or after virus infection. The inhibitory effect of meclizine occurred during viral entry and cell-to-cell spreading but not at viral attachment into PK-15 cells. Meclizine also inhibited viral particle release at the late stage of infection. The antiviral effect of meclizine was tested in mice, and the results showed that meclizine reduced the severity of clinical symptoms and the viral loads in tissues, and delayed the death, after PRV challenge. The above results indicated that meclizine had an inhibitory effect on PRV. Our findings will contribute to the development of potential therapeutic drugs against PRV infection. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
18. Meclizine Inhibits Pseudorabies Virus Replication by Interfering With Virus Entry and Release
- Author
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Panrao Liu, Danhe Hu, Lili Yuan, Zhengmin Lian, Xiaohui Yao, Zhenbang Zhu, Norbert Nowotny, Yi Shi, and Xiangdong Li
- Subjects
pseudorabies virus ,meclizine ,antiviral activity ,virus entry ,virus release ,Microbiology ,QR1-502 - Abstract
Pseudorabies virus (PRV) is a pathogen that causes substantial economic losses to the swine industry. With the emergence and widespread of PRV variants since 2011 in China, current commercial vaccines cannot provide complete protection against PRV infection. Therefore, antiviral drugs may work as an alternative way to control and prevent PRV. In this study, the inhibitory effects and underlying molecular mechanisms of meclizine against PRV were studied. Meclizine displayed a significant inhibitory effect against PRV when it was added before, simultaneously with, or after virus infection. The inhibitory effect of meclizine occurred during viral entry and cell-to-cell spreading but not at viral attachment into PK-15 cells. Meclizine also inhibited viral particle release at the late stage of infection. The antiviral effect of meclizine was tested in mice, and the results showed that meclizine reduced the severity of clinical symptoms and the viral loads in tissues, and delayed the death, after PRV challenge. The above results indicated that meclizine had an inhibitory effect on PRV. Our findings will contribute to the development of potential therapeutic drugs against PRV infection.
- Published
- 2021
- Full Text
- View/download PDF
19. Motion Sickness Medications and Vestibular Time Constant
- Author
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Dror Tal, Head of Motion Sickness and Human Performance Laboratory, Principal Investigator
- Published
- 2017
20. Meclizine as a Potential Smoking Cessation Treatment
- Author
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Philip Morris USA, Inc.
- Published
- 2014
21. The Effects of Antihistamines on Pre-Pulse Inhibition (PPI)
- Author
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Wallace H. Coulter Foundation
- Published
- 2013
22. Comparative Study of Augmented Classical Least Squares Models for UV Assay of Co-Formulated Antiemetics Together with Related Impurities.
- Author
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Al-Saleem MSM, Darwish HW, Naguib IA, and Draz ME
- Subjects
- Least-Squares Analysis, Meclizine, Calibration, Chromatography, High Pressure Liquid, Antiemetics
- Abstract
The classical least squares (CLS) model and three augmented CLS models are adopted and validated for the analysis of pyridoxine HCl (PYR), cyclizine HCl (CYC), and meclizine HCl (MEC) in a quinary mixture with two related impurities: the CYC main impurity, Benzhydrol (BEH), which has carcinogenic and hepatotoxic effects, and the MEC official impurity, 4-Chlorobenzophenone (BEP). The proposed augmented CLS models are orthogonal signal correction CLS (OSC-CLS), direct orthogonal signal correction CLS (DOSC-CLS), and net analyte processing CLS (NAP-CLS). These models were applied to quantify the three active constituents in their raw materials and their corresponding dosage forms using their UV spectra. To evaluate the CLS-based models sensibly, we design a comparative study involving two sets: the training set to construct models and the validation set to assess the prediction abilities of these models. A five-level, five-factor calibration design was established to produce 25 mixtures for the calibration set. In addition, 16 experiments were performed for a test set distributed equally between the in-space and out-space samples. The primary criterion for comparing the models' performance was the validation set's root mean square error of prediction (RMSEP) value. Finally, augmented CLS models showed acceptable results for assaying the three analytes. The results were compared statistically with the reported HPLC methods; however, the DOSC-CLS model proved the best for assaying the dosage forms.
- Published
- 2023
- Full Text
- View/download PDF
23. Supply Of Tab. Meclizine Hcl 25 Mg Tab. Meclizine Hcl 25 Mg Warranty Period: 18 Months After The Date Of Delivery
- Subjects
Central nervous system depressants ,Meclizine ,Business, international - Abstract
Tenders are invited for Supply of tab. meclizine hcl 25 mg tab. meclizine hcl 25 mg warranty period: 18 months after the date of delivery Tender Category : Goods OpeningDate [...]
- Published
- 2023
24. Genome-wide analyses reveal the detrimental impacts of SARS-CoV-2 viral gene Orf9c on human pluripotent stem cell-derived cardiomyocytes
- Author
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Juli Liu, Yucheng Zhang, Lei Han, Shuai Guo, Shiyong Wu, Emma Helen Doud, Cheng Wang, Hanying Chen, Michael Rubart-von der Lohe, Jun Wan, and Lei Yang
- Subjects
Pluripotent Stem Cells ,Ivermectin ,SARS-CoV-2 ,Action Potentials ,COVID-19 ,Down-Regulation ,Apoptosis ,Cell Biology ,Phosphoproteins ,Biochemistry ,Up-Regulation ,Meclizine ,Adenosine Triphosphate ,Genetics ,Coronavirus Nucleocapsid Proteins ,Humans ,Myocytes, Cardiac ,Protein Interaction Maps ,RNA, Messenger ,Transcriptome ,Genome-Wide Association Study ,Signal Transduction ,Developmental Biology - Abstract
Patients with coronavirus disease 2019 (COVID-19) commonly have manifestations of heart disease. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome encodes 27 proteins. Currently, SARS-CoV-2 gene-induced abnormalities of human heart muscle cells remain elusive. Here, we comprehensively characterized the detrimental effects of a SARS-CoV-2 gene, Orf9c, on human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) by preforming multi-omic analyses. Transcriptomic analyses of hPSC-CMs infected by SARS-CoV-2 with Orf9c overexpression (Orf9c
- Published
- 2022
25. Novel mTORC1 Inhibitors Kill Glioblastoma Stem Cells
- Author
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Jose A. Sandoval, Alexey Tomilov, Sandipan Datta, Sonia Allen, Robert O’Donnell, Thomas Sears, Kevin Woolard, Dmytro Kovalskyy, James M. Angelastro, and Gino Cortopassi
- Subjects
mTOR ,mTORC1 ,glioblastoma ,piperazine ,meclizine ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
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.
- Published
- 2020
- Full Text
- View/download PDF
26. Corrigendum: Meclizine Prevents Ovariectomy-Induced Bone Loss and Inhibits Osteoclastogenesis Partially by Upregulating PXR
- Author
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Jiachao Guo, Weijin Li, Yingxing Wu, Xingzhi Jing, Junming Huang, Jiaming Zhang, Wei Xiang, Ranyue Ren, Zhengtao Lv, Jun Xiao, and Fengjing Guo
- Subjects
meclizine ,PXR ,osteoclast ,RANKL ,osteoporosis ,Therapeutics. Pharmacology ,RM1-950 - Published
- 2018
- Full Text
- View/download PDF
27. Meclizine Prevents Ovariectomy-Induced Bone Loss and Inhibits Osteoclastogenesis Partially by Upregulating PXR
- Author
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Jiachao Guo, Weijin Li, Yingxing Wu, Xingzhi Jing, Junming Huang, Jiaming Zhang, Wei Xiang, Ranyue Ren, Zhengtao Lv, Jun Xiao, and Fengjing Guo
- Subjects
meclizine ,PXR ,osteoclast ,RANKL ,osteoporosis ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Pregnane X receptor (PXR) which belongs to the nuclear hormone receptor superfamily plays vital roles in several biological functions, especially in the inflammatory procedure. Besides that, PXR is revealed by recent studies to have essential effects on bone tissue. As an agonist of PXR, meclizine is a piperazine-derived histamine H1 antagonist, and has been frequently used for prevention and treatment of vomiting and nausea. Because osteoclastogenesis is characterized by the activation of inflammation-related signaling pathways, we speculated that meclizine may affect formation and function of osteoclast. In the present study, we explored the effect of meclizine on RANKL-induced osteoclastogenesis both in vivo and in vitro. In primary bone marrow-derived macrophages (BMMs), meclizine reduced osteoclast formation and bone resorption in a dose-dependent manner, while knockdown of PXR with siRNA partially abrogated the osteoclastogenesis inhibition of meclizine. On the one hand, at the molecular level, meclizine attenuated RANKL-induced activation of c-Fos, NFATc1, nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPKs), including ERK and p38, but not JNK. Meanwhile, meclizine reduced the expression of osteoclast-specific genes, including TRAP, MMP9, Cathepsin K and NFATc1. On the other hand, meclizine decreased OVX-induced bone loss by repressing osteoclast activity. In conclusion, our results indicated that meclizine inhibits osteoclastogenesis via regulation of several RANKL signaling pathways and PXR was involved in the processes. Therefore, meclizine may be considered as a novel therapeutic candidate for osteoclast-related diseases.
- Published
- 2017
- Full Text
- View/download PDF
28. Supply Of Tab. Meclizine Hcl 25 Mg Tab. Meclizine Hcl 25 Mg
- Subjects
Central nervous system depressants ,Meclizine ,Business, international - Abstract
Tenders are invited for Supply of tab. meclizine hcl 25 mg tab. meclizine hcl 25 mg Tender Category : Goods OpeningDate : Dec 26 2022 2:00AM Major organization : South [...]
- Published
- 2022
29. Phase 1b study on the repurposing of meclizine hydrochloride for children with achondroplasia.
- Author
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Matsushita M, Kitoh H, Mishima K, Kamiya Y, Kato D, Takemoto G, Sawamura K, Ueno S, Yasuhiro N, Nishida K, and Imagama S
- Subjects
- Mice, Animals, Drug Repositioning, Area Under Curve, Bone Development, Meclizine, Achondroplasia genetics
- Abstract
Achondroplasia (ACH) is a common skeletal dysplasia characterized by a disproportionately short stature. We found that meclizine, which is an over-the-counter drug for motion sickness, inhibited the fibroblast growth factor receptor 3 (FGFR3) gene using a drug repositioning strategy, and meclizine 1 and 2 mg/kg/day promoted bone growth in a mouse model of ACH. A previous phase 1a clinical trial for children with ACH demonstrated that a single dose of meclizine 25 and 50 mg was safe and that the simulated plasma concentration achieved steady state approximately 10 days after the first dose. The current study aimed to evaluate the safety and pharmacokinetics (PK) of meclizine in children with ACH after a 14-day-repeated dose of meclizine. Twelve patients with ACH aged 5-10 years were enrolled. Meclizine 12.5 (cohort 1) and 25 mg/day (cohort 2) were administered after meals for 14 days, and adverse events (AEs) and PK were evaluated. No patient experienced serious AEs in either group. The average (95% confidential interval [CI]) maximum drug concentration (Cmax), peak drug concentration (Tmax), area under the curve (AUC) from 0 to 24 h, and terminal elimination half-life (t1/2) after a 14-day-repeated administration of meclizine (12.5 mg) were 167 (83-250) ng/mL, 3.7 (3.1-4.2) h, 1170 (765-1570) ng·h/mL, and 7.4 (6.7-8.0) h, respectively. The AUC0-6h after the final administration was 1.5 times that after the initial dose. Cmax and AUC were higher in cohort 2 than in cohort 1 in a dose-dependent manner. Regarding the regimen of meclizine 12.5 and 25 mg in patients < 20 kg and ≥ 20 kg, respectively, the average (95% CI) AUC0-24h was 1270 (1100-1440) ng·h/mL. Compartment models demonstrated that the plasma concentration of meclizine achieved at a steady state after the 14th administration. Long-term administration of meclizine 12.5 or 25 mg/day is recommended for phase 2 clinical trials in children with ACH., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Matsushita et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2023
- Full Text
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30. Effects of Several Therapeutic Agents on Mammalian Vestibular Function: Meclizine, Diazepam, and JNJ7777120
- Author
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Timothy A. Jones and Choongheon Lee
- Subjects
Indoles ,Vestibular System ,01 natural sciences ,Piperazines ,Meclizine ,Mice ,03 medical and health sciences ,0302 clinical medicine ,0103 physical sciences ,otorhinolaryngologic diseases ,medicine ,Animals ,Vestibular dysfunction ,Short latency ,Prescribed medications ,010301 acoustics ,Vestibular system ,Diazepam ,business.industry ,Sensory Systems ,Peripheral ,Otorhinolaryngology ,Vestibule, Labyrinth ,sense organs ,business ,Neuroscience ,030217 neurology & neurosurgery ,Research Article ,medicine.drug - Abstract
Management of vestibular dysfunction may include treatment with medications that are thought to act to suppress vestibular function and reduce or eliminate abnormal sensitivity to head motions. The extent to which vestibular medications act centrally or peripherally is still debated. In this study, two commonly prescribed medications, meclizine and diazepam, and a candidate for future clinical use, JNJ7777120, were evaluated for their effects on short latency compound action potentials generated by the peripheral vestibular system and corresponding central neural relays (i.e., vestibular sensory-evoked potentials, VsEPs). The effects of the selected drugs developed slowly over the course of two hours in the mouse. Findings indicate that meclizine (600 mg/kg) and diazepam (> 60 mg/kg) can act on peripheral elements of the vestibular maculae whereas diazepam also acts most effectively on central gravity receptor circuits to exert its suppressive effects. The novel pharmacological agent JNJ7777120 (160 mg/kg) acts in the vestibular periphery to enhance macular responses to transient stimuli (VsEPs) while, hypothetically, suppressing macular responses to sustained or slowly changing stimuli.
- Published
- 2021
31. Meclizine, a piperazine-derivative antihistamine, binds to dimerized translationally controlled tumor protein and attenuates allergic reactions in a mouse model.
- Author
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Jang, Eun-Hwa, Bae, Hae-Duck, Jeon, Yejin, Shin, Dong Hae, Kang, Soosung, and Lee, Kyunglim
- Subjects
- *
TUMOR proteins , *ALLERGIES , *LABORATORY mice , *SURFACE plasmon resonance , *ANIMAL disease models - Abstract
Translationally controlled tumor protein (TCTP), a highly conserved protein present in most eukaryotes, is involved in numerous biological processes. Only the dimeric form of TCTP (dTCTP) formed during inflammatory conditions exhibits cytokine-like activity. Therefore, dTCTP is considered as a therapeutic target for allergic diseases. Because monomeric TCTP (mTCTP) and dTCTP share a high topological similarity, we hypothesized that small molecules interacting with mTCTP would also bind to dTCTP and interfere with dTCTP-based cellular processes. In this study, nine compounds listed in the literature as interacting with mTCTP were investigated for their ability to suppress the activity of extracellular dTCTP in bronchial epithelial cells. It was found that one of the nine, meclizine, a piperazine-derivative antihistamine, significantly reduced IL-8 release and suppressed the NF-κB pathway. The direct interaction of meclizine with dTCTP was confirmed by surface plasmon resonance (SPR). Also, we found that meclizine can attenuate ovalbumin (OVA)-induced airway inflammation in mice. Therefore, meclizine might be a potential anti-allergic drug as an inhibitor for dTCTP. [Display omitted] • Small molecules known to interact with mTCTP from literature were evaluated for their inhibitory effects on the dTCTP. • Meclizine, a piperazine-derivative antihistamine, showed a direct binding to dTCTP. • Meclizine reduced dTCTP-induced IL-8 secretion in bronchial epithelial cells, via the JNK and NFκB signaling pathways. • Meclizine inhibited dTCTP secretion and improved allergic reactions in mice with OVA-induced airway inflammation. • Meclizine may be useful in the treatment of dTCTP-related allergic diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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32. The phosphatidylethanolamine biosynthesis pathway provides a new target for cancer chemotherapy
- Author
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Yuan Guan, Ahmed Arslan, Gary Peltz, Saori Takeda, Ravindra Majeti, Xinyu Chen, Manhong Wu, Mindie H. Nguyen, Wan Zhu, Ming Zheng, and Daniel Thomas
- Subjects
Adult ,Male ,0301 basic medicine ,Carcinoma, Hepatocellular ,Combination therapy ,Cell Survival ,Pyridines ,Organogenesis ,Xenotransplantation ,medicine.medical_treatment ,Induced Pluripotent Stem Cells ,Biology ,Article ,Gene Knockout Techniques ,Meclizine ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Organoid ,medicine ,Animals ,Humans ,Induced pluripotent stem cell ,Aged ,Retrospective Studies ,Hepatology ,Phosphatidylethanolamines ,Liver Neoplasms ,Myeloid leukemia ,Cancer ,RNA Nucleotidyltransferases ,Hep G2 Cells ,Middle Aged ,medicine.disease ,Xenograft Model Antitumor Assays ,Embryonic stem cell ,Organoids ,Leukemia, Myeloid, Acute ,Treatment Outcome ,030104 developmental biology ,Liver ,Cancer cell ,Quinolines ,Cancer research ,Drug Therapy, Combination ,Female ,030211 gastroenterology & hepatology ,Glycolysis - Abstract
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.
- Published
- 2020
33. The effects of meclizine on motion sickness revisited
- Author
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Tony Pansell, Luca Verrecchia, Tobias Wibble, and Johanna Engström
- Subjects
medicine.medical_specialty ,Eye Movements ,Motion Sickness ,Nystagmus ,Audiology ,Placebo ,030226 pharmacology & pharmacy ,law.invention ,Meclizine ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,medicine ,Humans ,Pharmacology (medical) ,030212 general & internal medicine ,Pharmacology ,Vestibular system ,neuroscience < neuropharmacology ,business.industry ,Eye movement ,Original Articles ,medicine.disease ,ophthalmology ,Motion sickness ,Reflex ,Original Article ,Analysis of variance ,medicine.symptom ,business ,therapeutics < clinical pharmacology - Abstract
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°/s2 . 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.
- Published
- 2020
34. The Theory of Maternal Administration of Meclizine: An Achondroplasic Review and the Proposed Treatment of Foramen Magnum Stenosis within a Murine Model
- Abstract
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).
- Published
- 2021
35. The theory of maternal administration of meclizine : an achondroplasic review and the proposed treatment of Foramen Magnum Stenosis within a Murine model
- Author
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Perez Erickson, Ava and Perez Erickson, Ava
- Subjects
- Achondroplasia., Achondroplasia, Achondroplasie., Achondroplasia
- Abstract
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).
- Published
- 2021
36. Adoption of Advanced Chemometric Methods for Determination of Pyridoxine HCl, Cyclizine HCl, and Meclizine HCl in the Presence of Related Impurities: A Comparative Study
- Author
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Mohammed E. Draz, Ahmed S. Saad, Fatma F. Abdallah, Adel S Lashien, Ibrahim A. Naguib, and Hala E. Zaazaa
- Subjects
Pharmacology ,Training set ,Chromatography ,OPLS ,Cyclizine HCl ,Pyridoxine ,Meclizine HCl ,PYRIDOXINE HCL ,Analytical Chemistry ,Meclizine ,Test set ,Partial least squares regression ,Environmental Chemistry ,Cyclizine ,Chemometrics ,Least-Squares Analysis ,Related impurities ,Agronomy and Crop Science ,Food Science ,Mathematics - Abstract
Background Noising is an undesirable phenomenon accompanying the development of widely used chemometric models such as partial least square regression (PLSR) and support vector regression (SVR). Objective Optimizations of these chemometric models by applying orthogonal projection to latent structures (OPLS) as a preprocessing step which is characterized by canceling noise is the purpose of this research study. Additionally, a comprehensive comparative study between the developed methods was undertaken highlighting pros and cons. Methods OPLS was conducted with PLSR and SVR for quantitative determination of pyridoxine HCl, cyclizine HCl, and meclizine HCl in the presence of their related impurities. The training set was formed from 25 mixtures as there were five mixtures for each compound at each concentration level. Additionally, to check the validity and predictive ability of the developed chemometric models, independent test set mixtures were prepared by repeating the preparation of four mixtures of the training set plus preparation of another four independent mixtures. Results Upon application of the OPLS processing method, an upswing of the predictive abilities of PLSR and SVR was found. The root-mean-square error of prediction of the test set was the basic benchmark for comparison. Conclusion The major finding from the conducted research is that processing with OPLS reinforces the ability of models to anticipate the future samples. Highlights Novel optimizations of the widely used chemometric models; application of a comparative study between the suggested methods; application of OPLS preprocessing methods; quantitative determination of pyridoxine HCl, cyclizine HCl and meclizine HCl; checking the predictive power of developed chemometric models; analysis of active ingredients in their pharmaceutical dosage forms.
- Published
- 2021
37. Novel mTORC1 Inhibitors Kill Glioblastoma Stem Cells
- Author
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Sandipan Datta, Gino A Cortopassi, Kevin D. Woolard, Dmytro Kovalskyy, Alexey Tomilov, Sonia A. Allen, Thomas K. Sears, James M. Angelastro, Robert T. O'Donnell, and Jose Sandoval
- Subjects
0301 basic medicine ,Clinical Trials and Supportive Activities ,meclizine ,Pharmaceutical Science ,lcsh:Medicine ,lcsh:RS1-441 ,Synthetic lethality ,mTORC1 ,Article ,lcsh:Pharmacy and materia medica ,03 medical and health sciences ,Rare Diseases ,0302 clinical medicine ,Stem Cell Research - Nonembryonic - Human ,Clinical Research ,Drug Discovery ,Adjuvant therapy ,Medicine ,Flunarizine ,PI3K/AKT/mTOR pathway ,Cancer ,Temozolomide ,business.industry ,Cell growth ,lcsh:R ,Neurosciences ,glioblastoma ,Pharmacology and Pharmaceutical Sciences ,Stem Cell Research ,piperazine ,Brain Disorders ,Brain Cancer ,030104 developmental biology ,5.1 Pharmaceuticals ,030220 oncology & carcinogenesis ,Cancer research ,mTOR ,Molecular Medicine ,Development of treatments and therapeutic interventions ,Stem cell ,business ,medicine.drug - Abstract
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&ndash, 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 &lsquo, synthetic lethality&rsquo, 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.
- Published
- 2020
38. 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase Suppresses Neuronal Apoptosis by Increasing Glycolysis and 'cyclin-dependent kinase 1-Mediated Phosphorylation of p27 After Traumatic Spinal Cord Injury in Rats
- Author
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Weilin Xu, Tengfei Zhao, Jianru Li, Guangyu Ying, Bing Qin, Tao Li, Chun Wang, Liansheng Gao, Yongjian Zhu, Cameron Lenahan, and Gao Chen
- Subjects
Agonist ,neuronal apoptosis ,Male ,Time Factors ,medicine.drug_class ,Phosphofructokinase-2 ,Biomedical Engineering ,meclizine ,lcsh:Medicine ,Apoptosis ,Pharmacology ,Motor Activity ,Neuroprotection ,Models, Biological ,Rats, Sprague-Dawley ,PFKFB3 ,CDC2 Protein Kinase ,medicine ,Fructosediphosphates ,Animals ,Glycolysis ,traumatic spinal cord injury ,Lactic Acid ,Phosphorylation ,Spinal cord injury ,Spinal Cord Injuries ,Neurons ,Transplantation ,Cyclin-dependent kinase 1 ,Kinase ,Chemistry ,lcsh:R ,Cell Biology ,glycolysis ,medicine.disease ,White Matter ,Mitochondria ,Up-Regulation ,Thiazoles ,Spinal Cord ,Gene Knockdown Techniques ,Quinolines ,Original Article ,Cyclin-Dependent Kinase Inhibitor p27 - Abstract
Apoptosis is a vital pathological factor that accounts for the poor prognosis of traumatic spinal cord injury (t-SCI). The 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3) is a critical regulator for energy metabolism and proven to have antiapoptotic effects. This study aimed to investigate the neuroprotective role of PFKFB3 in t-SCI. A compressive clip was introduced to establish the t-SCI model. Herein, we identified that PFKFB3 was extensively distributed in neurons, and PFKFB3 levels significantly increased and peaked 24 h after t-SCI. Additionally, knockdown of PFKFB3 inhibited glycolysis, accompanied by aggravated neuronal apoptosis and white matter injury, while pharmacological activation of PFKFB3 with meclizine significantly enhanced glycolysis, attenuated t-SCI-induced spinal cord injury, and alleviated neurological impairment. The PFKFB3 agonist, meclizine, activated cyclin-dependent kinase 1 (CDK1) and promoted the phosphorylation of p27, ultimately suppressing neuronal apoptosis. However, the neuroprotective effects of meclizine against t-SCI were abolished by the CDK1 antagonist, RO3306. In summary, our data demonstrated that PFKFB3 contributes robust neuroprotection against t-SCI by enhancing glycolysis and modulating CDK1-related antiapoptotic signals. Moreover, targeting PFKFB3 may be a novel and promising therapeutic strategy for t-SCI.
- Published
- 2020
39. QbD based Eudragit coated Meclizine HCl immediate and extended release multiparticulates: formulation, characterization and pharmacokinetic evaluation using HPLC-Fluorescence detection method
- Author
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Kamran Ahmed, Fahad Siddiqui, Farrukh Rafiq Ahmed, Faaiza Qazi, Rabia Ismail Yousuf, Muhammad Shoaib, Iyad Naeem Muhammad, and Muhammad Iqbal Nasiri
- Subjects
Adult ,Male ,Chemistry, Pharmaceutical ,Pellets ,Cmax ,lcsh:Medicine ,Meclizine HCl ,Talc ,030226 pharmacology & pharmacy ,01 natural sciences ,Article ,Fluorescence ,03 medical and health sciences ,chemistry.chemical_compound ,Meclizine ,Young Adult ,0302 clinical medicine ,Medical research ,Hplc fluorescence ,Pharmacokinetics ,Polymethacrylic Acids ,Anti-Allergic Agents ,medicine ,Humans ,Lactose ,lcsh:Science ,Chromatography, High Pressure Liquid ,Multidisciplinary ,Chromatography ,Chemistry ,010401 analytical chemistry ,Biological techniques ,digestive, oral, and skin physiology ,lcsh:R ,Health care ,Materials science ,0104 chemical sciences ,Delayed-Action Preparations ,lcsh:Q ,Female ,Extended release ,medicine.drug - Abstract
This study is based on the QbD development of extended-release (ER) extruded-spheronized pellets of Meclizine HCl and its comparative pharmacokinetic evaluation with immediate-release (IR) pellets. HPLC-fluorescence method was developed and validated for plasma drug analysis. IR drug cores were prepared from lactose, MCC, and PVP using water as granulating fluid. Three-level, three-factor CCRD was applied for modeling and optimization to study the influence of Eudragit (RL100-RS100), TEC, and talc on drug release and sphericity of coated pellets. HPLC-fluorescence method was sensitive with LLOQ 1 ng/ml and linearity between 10 and 200 ng/ml with R2 > 0.999. Pharmacokinetic parameters were obtained by non-compartmental analysis and results were statistically compared using logarithmically transformed data, where p > 0.05 was considered as non-significant with a 90% CI limit of 0.8–1.25. The AUC0–t and AUC0–∞ of ER pellets were not significantly different with geometric mean ratio 1.0096 and 1.0093, respectively. The Cmax of IR pellets (98.051 ng/ml) was higher than the ER pellets (84.052 ng/ml) and the Tmax of ER pellets (5.116 h) was higher than the IR pellets (3.029 h). No significant food effect was observed on key pharmacokinetic parameters of ER pellets. Eudragit RL100 (6%) coated Meclizine HCl pellets have a potential therapeutic effect for an extended time period.
- Published
- 2020
40. Meclizine and Metabotropic Glutamate Receptor Agonists Attenuate Severe Pain and Ca 2+ Activity of Primary Sensory Neurons in Chemotherapy-Induced Peripheral Neuropathy.
- Author
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Shannonhouse J, Bernabucci M, Gomez R, Son H, Zhang Y, Ai CH, Ishida H, and Kim YS
- Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) affects ∼68% of patients undergoing chemotherapy, causing debilitating neuropathic pain and reducing quality of life. Cisplatin is a commonly used platinum-based chemotherapeutic drug known to cause CIPN, possibly by causing oxidative stress damage to primary sensory neurons. Metabotropic glutamate receptors (mGluRs) are widely hypothesized to be involved in pain processing and pain mitigation. Meclizine is an H1 histamine receptor antagonist known to have neuroprotective effects, including an anti-oxidative effect. Here, we used a mouse model of cisplatin-induced CIPN using male and female mice to test agonists of mGluR8 and Group II mGluR as well as meclizine as interventions to reduce cisplatin-induced pain. We performed behavioral pain tests, and we imaged Ca
2+ activity of the large population of dorsal root ganglia (DRG) neurons in vivo For the latter, we used a genetically-encoded Ca2+ indicator, Pirt-GCaMP3, which enabled us to monitor different drug interventions at the level of the intact DRG neuronal ensemble. We found that CIPN increased spontaneous Ca2+ activity in DRG neurons, increased number of Ca2+ transients, and increased hyper-responses to mechanical, thermal, and chemical stimuli. We found that mechanical and thermal pain caused by CIPN was significantly attenuated by the mGluR8 agonist, (S)-3,4-DCPG, the Group II mGluR agonist, LY379268, and the H1 histamine receptor antagonist, meclizine. DRG neuronal Ca2+ activity elevated by CIPN was attenuated by LY379268 and meclizine, but not by (S)-3,4-DCPG. Furthermore, meclizine and LY379268 attenuated cisplatin-induced weight loss. These results suggest that Group II mGluR agonist, mGluR8 agonist, and meclizine are promising candidates as new treatment options for CIPN, and studies of their mechanisms are warranted. SIGNIFICANCE STATEMENT Chemotherapy-induced peripheral neuropathy (CIPN) is a painful condition that affects most chemotherapy patients and persists several months or longer after treatment ends. Research on CIPN mechanism is extensive but has produced only few clinically useful treatments. Using in vivo GCaMP Ca2+ imaging in live animals over 1800 neurons/dorsal root ganglia (DRG) at once, we have characterized the effects of the chemotherapeutic drug, cisplatin and three treatments that decrease CIPN pain. Cisplatin increases sensory neuronal Ca2+ activity and develops various sensitization. Metabotropic glutamate receptor (mGluR) agonist, LY379268 or the H1 histamine receptor antagonist, meclizine decreases cisplatin's effects on neuronal Ca2+ activity and reduces pain hypersensitivity. Our results and experiments provide insights into cellular effects of cisplatin and drugs preventing CIPN pain., (Copyright © 2022 the authors.)- Published
- 2022
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41. Validated Analytical Methods for the Determination of Drugs Used in the Treatment of Hyperemesis Gravidarum in Multiple Formulations
- Author
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Mohammed E. Draz, Ibrahim A. Naguib, Ahmed S. Saad, Adel S Lashien, and Hala E. Zaazaa
- Subjects
Drug Compounding ,01 natural sciences ,High-performance liquid chromatography ,Analytical Chemistry ,Meclizine ,chemistry.chemical_compound ,Cyclizine ,medicine ,Environmental Chemistry ,Dual wavelength ,Least-Squares Analysis ,Routine analysis ,Phosphoric acid ,Chromatography, High Pressure Liquid ,Pharmacology ,Chromatography ,010405 organic chemistry ,Chemistry ,010401 analytical chemistry ,Pyridoxine ,0104 chemical sciences ,Solvent ,Drug Combinations ,Calibration ,Antiemetics ,Regression Analysis ,Spectrophotometry, Ultraviolet ,Methanol ,Ternary operation ,Agronomy and Crop Science ,Food Science ,medicine.drug - Abstract
Quantitative multicomponent analysis is considered an analytical goal to save time and cost in analysis. Hence, this work aimed to provide sensitive and selective UV-spectrophotometric, chemometric manipulation, and ultra-performance LC (UPLC) methods for the determination of well-known coformulated antiemetics used in pregnancy, namely pyridoxine HCl (PYR), meclozine HCl, and cyclizine. The developed UV-spectrophotometric methods are dual wavelength in ratio spectra and first derivative of the ratio spectra with which PYR was determined selectively at 290.8 nm, whereas the other drugs in a ternary mixture were determined from their ratio spectra using a spectrum of PYR as a divisor in 0.1 M HCl. An ecofriendly partial least-squares regression chemometric method was applied to raw UV absorbance data for the determination of the ternary mixture in a 218–355 nm range using a three-factor, three-level design with water as the green solvent. A gradient UPLC method was developed and successfully resolved the ternary mixture within 5 min. Different ratios of water (adjusted to pH 3 with phosphoric acid) and methanol were delivered at 0.5 mL/min as the mobile phase into a Hypersil Gold C18 column (50 × 2.1 mm, 1.9 µm). The developed methods were successfully applied to different pharmaceutical formulations containing the aforementioned drugs and validated according to the International Conference on Harmonization guidelines. The results obtained were reproducible and reliable and can be applied for routine analysis and QC in laboratories.
- Published
- 2018
42. Meclizine: Safety and Efficacy in the Treatment and Prevention of Motion Sickness.
- Author
-
Patel, Priti N. and Ambizas, Emily M.
- Abstract
Motion sickness is a self-limiting but uncomfortable phenomenon experienced by many people. It is common during civilian travel and also among professionals during travel or military manoeuvres. Meclizine is a piperzine antihistamine that is effective for the prevention and treatment of motion sickness, particularly during mild civilian travel. It is well tolerated with few adverse effects and its oral dosage form is convenient for patients to take prior to exposure to motion as a preventative measure. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
43. Maltodextrin: A Novel Excipient Used in Sugar-Based Orally Disintegrating Tablets and Phase Transition Process.
- Author
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Elnaggar, Yosra, El-Massik, Magda, Abdallah, Ossama, and Ebian, Abd
- Abstract
The recent challenge in orally disintegrating tablets (ODT) manufacturing encompasses the compromise between instantaneous disintegration, sufficient hardness, and standard processing equipment. The current investigation constitutes one attempt to fulfill this challenge. Maltodextrin, in the present work, was utilized as a novel excipient to prepare ODT of meclizine. Tablets were prepared by both direct compression and wet granulation techniques. The effect of maltodextrin concentrations on ODT characteristics—manifested as hardness and disintegration time—was studied. The effect of conditioning (40°C and 75% relative humidity) as a post-compression treatment on ODT characteristics was also assessed. Furthermore, maltodextrin-pronounced hardening effect was investigated using differential scanning calorimetry (DSC) and X-ray analysis. Results revealed that in both techniques, rapid disintegration (30–40 s) would be achieved on the cost of tablet hardness (about 1 kg). Post-compression conditioning of tablets resulted in an increase in hardness (3 kg), while keeping rapid disintegration (30–40 s) according to guidance of the FDA for ODT. However, direct compression-conditioning technique exhibited drawbacks of long conditioning time and appearance of the so-called patch effect. These problems were, yet, absent in wet granulation-conditioning technique. DSC and X-ray analysis suggested involvement of glass-elastic deformation in maltodextrin hardening effect. High-performance liquid chromatography analysis of meclizine ODT suggested no degradation of the drug by the applied conditions of temperature and humidity. Overall results proposed that maltodextrin is a promising saccharide for production of ODT with accepted hardness-disintegration time compromise, utilizing standard processing equipment and phenomena of phase transition. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
44. Induction of apoptosis and cell-cycle arrest in human colon cancer cells by meclizine
- Author
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Lin, Jiunn-Chang, Ho, Yuan-Soon, Lee, Jie-Jen, Liu, Chien-Liang, Yang, Tsen-Long, and Wu, Chih-Hsiung
- Subjects
- *
ANTIHISTAMINES , *MOTION sickness treatment , *VERTIGO treatment , *APOPTOSIS , *COLON cancer , *CELL lines - Abstract
Abstract: Meclizine (MEC), a histamine H1 antagonist, is used for the treatment of motion sickness and vertigo. In this study, we demonstrate that MEC dose-dependently induced apoptosis in human colon cancer cell lines (COLO 205 and HT 29 cells). Results of a DNA ladder assay revealed that DNA ladders appeared with MEC treatment in COLO 205 cells at dosage of >50μM. In addition, the total cell number decreased dose-dependently after treatment with MEC in COLO 205 and HT 29 cells. Using flow cytometry, the percentage of COLO 205 cells arrested at G0/G1 phase increased dose-dependently. Analysis of changes in cell-cycle arrest-associated proteins with Western blotting showed that p53 and p21 were upregulated after treatment with MEC. The kinase activities of cyclin-dependent kinase 2 (CDK2) and CDK4 were suppressed in MEC-treated cells. As for apoptosis, MEC may induce upregulation of p53 and downregulation of Bcl-2, thus causing the release of cytochrome C from mitochondria and the translocation of apoptosis-inducing factor (AIF) to the nucleus. This resulted in the activation of caspase 3, 8, and 9. Our results provide the molecular basis of MEC-induced apoptosis and cell-cycle arrest in human colon cancer cells. [Copyright &y& Elsevier]
- Published
- 2007
- Full Text
- View/download PDF
45. Lipids bearing extruded-spheronized pellets for extended release of poorly soluble antiemetic agent—Meclizine HCl
- Author
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Rabia Ismail Yousuf, Kamran Ahmed, Muhammad Iqbal Nasiri, Faaiza Qazi, Muhammad Shoaib, and Mansoor Ahmad
- Subjects
Pellets ,Endocrinology, Diabetes and Metabolism ,Drug Compounding ,Drug Storage ,Clinical Biochemistry ,Administration, Oral ,02 engineering and technology ,Meclizine HCl ,Pharmacology ,030226 pharmacology & pharmacy ,Dosage form ,Glycerides ,Diglycerides ,03 medical and health sciences ,chemistry.chemical_compound ,Meclizine ,0302 clinical medicine ,Endocrinology ,Drug Stability ,Spectroscopy, Fourier Transform Infrared ,Humans ,Fourier transform infrared spectroscopy ,Dissolution ,lcsh:RC620-627 ,Chromatography ,Research ,Biochemistry (medical) ,Fatty Acids ,Water ,Hydrogen-Ion Concentration ,021001 nanoscience & nanotechnology ,Lipids ,Drug Liberation ,Extended release ,lcsh:Nutritional diseases. Deficiency diseases ,chemistry ,Solubility ,Delayed-Action Preparations ,Waxes ,Microscopy, Electron, Scanning ,Antiemetics ,Extrusion spheronization ,Glyceryl behenate ,Carnauba wax ,Pharmaceutical Vehicles ,0210 nano-technology - Abstract
Background Antiemetic agent Meclizine HCl, widely prescribed in vertigo, is available only in immediate release dosage forms. The approved therapeutic dose and shorter elimination half-life make Meclizine HCl a potential candidate to be formulated in extended release dosage form. This study was aimed to develop extended release Meclizine HCl pellets by extrusion spheronization using natural and synthetic lipids. Influence of lipid type, drug/lipid ratio and combinations of different lipids on drug release and sphericity of pellets were evaluated. Methods Thirty two formulations were prepared with four different lipids, Glyceryl monostearate (Geleol®), Glyceryl palmitostearate (Precirol®), Glyceryl behenate (Compritol®) and Carnauba wax, utilized either alone or in combinations of drug/lipid ratio of 1:0.5–1:3. Dissolution studies were performed at variable pH and release kinetics were analyzed. Fourier transform infrared spectroscopy was conducted and no drug lipid interaction was found. Results Sphericity indicated by shape factor (eR) varied with type and concentration of lipids: Geleol® (eR = 0.891–0.997), Precirol® (eR = 0.611–0.743), Compritol® (eR = 0.665–0.729) and Carnauba wax (eR = 0.499-0.551). Highly spherical pellets were obtained with Geleol® (Aspect ratio = 1.005–1.052) whereas irregularly shaped pellets were formed using Carnauba wax (Aspect ratio = 1.153–1.309). Drug release was effectively controlled by three different combinations of lipids: (i) Geleol® and Compritol®, (ii) Geleol® and Carnauba wax and (iii) Geleol®, Compritol® and Carnauba wax. Scanning electron microscopy of Compritol® pellets showed smooth surface with pores, whereas, irregular rough surface with hollow depressions was observed in Carnauba wax pellets. Energy dispersive spectroscopy indicated elemental composition of lipid matrix pellets. Kinetics of (i) Geleol® and Compritol® pellets, explained by Korsmeyer-Peppas (R2 = 0.978–0.993) indicated non-Fickian diffusion (n = 0.519-0.597). Combinations of (ii) Geleol® and Carnauba wax and (iii) Geleol®, Compritol® and Carnauba wax pellets followed Zero-order (R2 = 0.991–0.995). Similarity test was performed using combination of Geleol® and Compritol® (i) as a reference. Conclusions Matrices for the extended release of Meclizine HCl from extruded-spheronized pellets were successfully formed by using three lipids (Geleol®, Compritol® and Carnauba wax) in different combinations. The encapsulated pellets of Meclizine HCl can be effectively used for treatment of motion sickness, nausea and vertigo for extended period of time.
- Published
- 2017
46. Quantitative enantiomeric analysis of chlorcyclizine, hydroxyzine, and meclizine by capillary electrophoresis.
- Author
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Yu- Hsiang Ho, Hsin- Lung Wu, Shou- Mei Wu, Su- Hwei Chen, and Hwang- Shang Kou
- Subjects
- *
CAPILLARY electrophoresis , *ANTIHISTAMINES , *GLYCINE , *CYCLODEXTRINS , *ENANTIOMERS , *ULTRAVIOLET spectra - Abstract
A simple capillary zone electrophoresis method was developed for the quantitative enantiomeric analysis of piperazine antihistamines with teratogenic suspicion in animals. Enantioseparation of chlorcyclizine, hydroxyzine, and meclizine was performed in glycine buffer (0.6 mol L-1; pH 3.00) with sulfated β-cyclodextrin (5 mg mL-1) as a chiral selector; and the separated drugs were monitored by ultra-violet detector. The lower quantitation of the individual enantiomer is attainable at 10 µmol L-1, using an achiral piperazine drug (cyclizine) as internal standard. The method is simple and rapid with a short run time (<5 min) for the analysis of chlorcyclizine, hydroxyzine or meclizine enantiomers. [ABSTRACT FROM AUTHOR]
- Published
- 2003
- Full Text
- View/download PDF
47. Augmentation of glycolytic metabolism by meclizine is indispensable for protection of dorsal root ganglion neurons from hypoxia-induced mitochondrial compromise
- Author
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Murat F. Gorgun, Ella W. Englander, and Ming Zhuo
- Subjects
Male ,0301 basic medicine ,Neurite ,Primary Cell Culture ,Oxidative phosphorylation ,Mitochondrion ,Biology ,Protective Agents ,Biochemistry ,Neuroprotection ,Article ,Energy homeostasis ,Meclizine ,Mice ,03 medical and health sciences ,Adenosine Triphosphate ,Oxygen Consumption ,Dorsal root ganglion ,Stress, Physiological ,Ganglia, Spinal ,Physiology (medical) ,medicine ,Animals ,Glycolysis ,Lactic Acid ,Neurons ,Hydrogen-Ion Concentration ,Hypoxia (medical) ,Cell Hypoxia ,Mitochondria ,Cell biology ,Mice, Inbred C57BL ,Glucose ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,Astrocytes ,Histamine H1 Antagonists ,medicine.symptom - Abstract
To meet energy demands, dorsal root ganglion (DRG) neurons harbor high mitochondrial content, which renders them acutely vulnerable to disruptions of energy homeostasis. While neurons typically rely on mitochondrial energy production and have not been associated with metabolic plasticity, new studies reveal that meclizine, a drug, recently linked to modulations of energy metabolism, protects neurons from insults that disrupt energy homeostasis. We show that meclizine rapidly enhances glycolysis in DRG neurons and that glycolytic metabolism is indispensable for meclizine-exerted protection of DRG neurons from hypoxic stress. We report that supplementation of meclizine during hypoxic exposure prevents ATP depletion, preserves NADPH and glutathione stores, curbs reactive oxygen species (ROS) and attenuates mitochondrial clustering in DRG neurites. Using extracellular flux analyzer, we show that in cultured DRG neurons meclizine mitigates hypoxia-induced loss of mitochondrial respiratory capacity. Respiratory capacity is a measure of mitochondrial fitness and cell ability to meet fluctuating energy demands and therefore, a key determinant of cellular fate. While meclizine is an ‘old’ drug with long record of clinical use, its ability to modulate energy metabolism has been uncovered only recently. Our findings documenting neuroprotection by meclizine in a setting of hypoxic stress reveal previously unappreciated metabolic plasticity of DRG neurons as well as potential for pharmacological harnessing of the newly discovered metabolic plasticity for protection of peripheral nervous system under mitochondria compromising conditions.
- Published
- 2016
48. Correction
- Subjects
Adult ,Metoclopramide ,Emotions ,Severity of Illness Index ,patient perspectives ,Meclizine ,Pregnancy ,Hyperemesis Gravidarum ,Surveys and Questionnaires ,Activities of Daily Living ,Weight Loss ,Humans ,Dehydration ,Norway ,Nausea and vomiting in pregnancy (NVP) ,Correction ,Abortion, Induced ,Nausea ,Ketosis ,Hospitalization ,HG management ,Cross-Sectional Studies ,Attitude ,Hyperemesis gravidarum (HG) ,Patient Satisfaction ,Quality of Life ,Antiemetics ,Original Article ,Female ,Pregnant Women - Abstract
Objective: Hyperemesis gravidarum (HG) affects 0.3–3% of pregnant women and is a leading cause of hospitalization in early pregnancy. The aim of the study was to investigate women’s treatment and management of HG, as well as the consequences of HG on women’s daily life. Design and setting: A cross-sectional study based on a structured telephone interview and an online questionnaire. Participants were recruited by social media and by the Norwegian patient’s organization for HG. Subjects: Norwegian women that experienced HG. Main outcome measure: Women’s perspectives on management and consequences of HG. Results: The study included 107 women. Maternal morbidity was profound; about 3/4 of participants were hospitalized due to HG, and the majority showed clinical signs of dehydration (79%), ketonuria (75%), and >5% weight loss (84%). Antiemetics were used by >90% and frequently prescribed “as needed”. Metoclopramide (71%) and meclozine (51%) were most commonly used. Participants described HG as having severe psychosocial consequences and profound impact on daily activities. Almost two out of five reported thoughts of elective abortion, and 8 women had at least one elective pregnancy termination due to HG. Overall, 20 women (19%) changed GPs due to dissatisfaction with HG management. Conclusion: Despite the high psychosocial burden and major impact on daily activities, many women with HG reported a lack of support from healthcare professionals and suboptimal management. Greater awareness and knowledge among healthcare professionals is needed to improve care for women with HG.Key PointsThere is a paucity of studies on management and the consequences of HG on women’s daily lives and psychosocial burden. We found that:• Many women described HG as one of their worst life experiences with profound morbidity.• Many women reported suboptimal management of HG and lack of support from healthcare professionals.• Greater understanding of patient perspectives among healthcare professionals is important to improve care and management for HG patients.
- Published
- 2019
49. Genome-wide analyses reveal the detrimental impacts of SARS-CoV-2 viral gene Orf9c on human pluripotent stem cell-derived cardiomyocytes.
- Author
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Liu J, Zhang Y, Han L, Guo S, Wu S, Doud EH, Wang C, Chen H, Rubart-von der Lohe M, Wan J, and Yang L
- Subjects
- Action Potentials drug effects, Adenosine Triphosphate metabolism, Apoptosis drug effects, Apoptosis genetics, COVID-19 virology, Down-Regulation, Humans, Ivermectin pharmacology, Meclizine pharmacology, Myocytes, Cardiac cytology, Myocytes, Cardiac metabolism, Phosphoproteins genetics, Pluripotent Stem Cells cytology, Pluripotent Stem Cells metabolism, Protein Interaction Maps genetics, RNA, Messenger chemistry, RNA, Messenger metabolism, SARS-CoV-2 isolation & purification, Signal Transduction genetics, Transcriptome drug effects, Up-Regulation, COVID-19 pathology, Coronavirus Nucleocapsid Proteins genetics, Genome-Wide Association Study methods, SARS-CoV-2 genetics
- Abstract
Patients with coronavirus disease 2019 (COVID-19) commonly have manifestations of heart disease. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome encodes 27 proteins. Currently, SARS-CoV-2 gene-induced abnormalities of human heart muscle cells remain elusive. Here, we comprehensively characterized the detrimental effects of a SARS-CoV-2 gene, Orf9c, on human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) by preforming multi-omic analyses. Transcriptomic analyses of hPSC-CMs infected by SARS-CoV-2 with Orf9c overexpression (Orf9c
OE ) identified concordantly up-regulated genes enriched into stress-related apoptosis and inflammation signaling pathways, and down-regulated CM functional genes. Proteomic analysis revealed enhanced expressions of apoptotic factors, whereas reduced protein factors for ATP synthesis by Orf9cOE . Orf9cOE significantly reduced cellular ATP level, induced apoptosis, and caused electrical dysfunctions of hPSC-CMs. Finally, drugs approved by the U.S. Food and Drug Administration, namely, ivermectin and meclizine, restored ATP levels and ameliorated CM death and functional abnormalities of Orf9cOE hPSC-CMs. Overall, we defined the molecular mechanisms underlying the detrimental impacts of Orf9c on hPSC-CMs and explored potentially therapeutic approaches to ameliorate Orf9c-induced cardiac injury and abnormalities., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2022
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- View/download PDF
50. シンキ サイボウ エネルギー タイシャ スクリーニング ニ モトズイタ キュウセイ ジンショウガイ ヨボウヤク チリョウヤク ノ タンサク ト カイハツ
- Subjects
Meclizine ,urogenital system ,Kennedy Pathway ,AKI(Acute Kidney Injury) - Abstract
Acute kidney injury(AKI)is a big clinical problem. In addition to high mortality rate, AKI is a potent risk factor of end-stage kidney disease. Ischemia reperfusion injury(IRI)is the leading cause of AKI and we have no specific treatment options to treat AKI. Shifting energy metabolism from mitochondrial respiration to glycolysis may offer a novel therapy against ischemic organ injury. Based on this theory, Meclizine, first-generation antihistamine used for motion sickness and vertigo, was identified in a novel chemical screen. Kidney tubular injury after ischemia reperfusion was significantly decreased in meclizine treated mice compared with the vehicle treated mice(100mg/kg of meclizine, 17 hours prior to ischemia). Meclizine treated kidney showed reduced inflammation, oxidative stress and mitochondrial fragmentation after IRI. Meclizine pretreatment reduced mitochondrial oxygen consumption. Reduced cell death and cytochrome c release was found in kidney tubular epithelial cells. Metabolic profiling revealed that Meclizine caused rapid accumulation of cellular phosphoethanolamine(PEtn). PEtn inhibits mitochondrial respiration and is an intermediate in phosphatidylethanolamine biosynthesis pathway(Kennedy pathway). In conclusion, Meclizine, or a derivative, is a candidate drug to minimize AKI risk and Kennedy pathway can be a novel therapeutic target for ischiemic kidney injury.
- Published
- 2016
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