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The Journal of Neuroscience : the... Apr 2024
Erratum: Shannonhouse et al., "Meclizine and Metabotropic Glutamate Receptor Agonists Attenuate Severe Pain and Ca Activity of Primary Sensory Neurons in Chemotherapy-Induced Peripheral Neuropathy".
PubMed: 38594070
DOI: 10.1523/JNEUROSCI.0541-24.2024 -
Endocrine Journal Apr 2024Achondroplasia (ACH) is a representative skeletal disorder characterized by rhizomelic shortened limbs and short stature. ACH is classified as belonging to the...
Achondroplasia (ACH) is a representative skeletal disorder characterized by rhizomelic shortened limbs and short stature. ACH is classified as belonging to the fibroblast growth factor receptor 3 (FGFR3) group. The downstream signal transduction of FGFR3 consists of STAT1 and RAS/RAF/MEK/ERK pathways. The mutant FGFR3 found in ACH is continuously phosphorylated and activates downstream signals, resulting in abnormal proliferation and differentiation of chondrocytes in the growth plate and cranial base synchondrosis. A patient registry has been developed and has contributed to revealing the natural history of ACH patients. Concerning the short stature, the adult height of ACH patients ranges between 126.7-135.2 cm for men and 119.9-125.5 cm for women in many countries. Along with severe short stature, foramen magnum stenosis and spinal canal stenosis are major complications: the former leads to sleep apnea, breathing disorders, myelopathy, hydrocephalus, and sudden death, and the latter causes pain in the extremities, numbness, muscle weakness, movement disorders, intermittent claudication, and bladder-rectal disorders. Growth hormone treatment is available for ACH only in Japan. However, the effect of the treatment on adult height is not satisfactory. Recently, the neutral endopeptidase-resistant CNP analogue vosoritide has been approved as a new drug for ACH. Additionally in development are a tyrosine kinase inhibitor, a soluble FGFR3, an antibody against FGFR3, meclizine, and the FGF2-aptamer. New drugs will bring a brighter future for patients with ACH.
PubMed: 38569854
DOI: 10.1507/endocrj.EJ24-0109 -
JBMR Plus Apr 2024Achondroplasia (ACH) is a skeletal dysplasia characterized by short-limbed short stature caused by the gain-of-function mutations in the fibroblast growth factor...
Achondroplasia (ACH) is a skeletal dysplasia characterized by short-limbed short stature caused by the gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Activated FGFR3, which is a negative regulator of bone elongation, impairs the growth of long bones and the spinal arch by inhibiting chondrocyte proliferation and differentiation. Most patients with ACH have spinal canal stenosis in addition to short stature. Meclozine has been found to inhibit FGFR3 via drug repurposing. A 10-d treatment with meclozine promoted long-bone growth in a mouse model of ACH ( mice). This study aimed to evaluate the effects of long-term meclozine administration on promoting bone growth and the spinal canal in mice. Meclozine (2 mg/kg/d) was orally administered to mice for 5 d per wk from the age of 7 d to 56 d. Meclozine (2 mg/kg/d) significantly reduced the rate of death or paralysis and improved the length of the body, cranium, and long bones in male and female mice. Micro-computed tomography analysis revealed that meclozine ameliorated kyphotic deformities and trabecular parameters, including BMD, bone volume/tissue volume, trabecular thickness, and trabecular number at distal femur of mice in both sexes. Histological analyses revealed that the hypertrophic zone in the growth plate was restored in mice following meclozine treatment, suggesting upregulation of endochondral ossification. Skeletal preparations demonstrated that meclozine restored the spinal canal diameter in mice in addition to improving the length of each bone. The 2 mg/kg/d dose of meclozine reduced the rate of spinal paralysis caused by spinal canal stenosis, maintained the growth plate structure, and recovered the bone quality and growth of axial and appendicular skeletons of mice in both sexes. Long-term meclozine administration has the potential to ameliorate spinal paralysis and bone growth in patients with ACH.
PubMed: 38544920
DOI: 10.1093/jbmrpl/ziae018 -
ACS Omega Jan 2024In this work, we demonstrate a sensitive high-performance liquid chromatography (HPLC) method for the determination of piperazine antihistamine drugs employing...
In this work, we demonstrate a sensitive high-performance liquid chromatography (HPLC) method for the determination of piperazine antihistamine drugs employing innovative electrochemical detection based on a spark-generated nickel oxide nanoparticle-modified carbon fiber microelectrode built into a miniaturized electrochemical detector. The direct carbon fiber-to-nickel plate electrode spark discharge, carried at 0.8 kV DC, with the nickel electrode connected to the negative pole of the high-voltage power supply, provides extremely fast (1 s) in situ tailoring of the carbon fiber microelectrode surface by nickel oxide nanoparticles. It has been found that nickel oxide nanoparticles exhibit an electrocatalytic effect toward the piperazine moiety electrooxidation process, as confirmed by voltammetric experiments, revealing the shift in the peak potential from 1.25 to 1.09 V versus Ag/AgCl. Cetirizine, cyclizine, chlorcyclizine, flunarizine, meclizine, and buclizine were selected as sample piperazine antihistamine drugs, while diclofenac served as an internal standard. The isocratic reversed-phase separation of the above set was achieved within 15 min using an ARION-CN 3 μm column with a binary mobile phase consisting of 50 mM phosphate buffer (pH 3) and methanol (45/55, v/v). The limits of detection (LOD) were within the range of 3.8-120 nM (for cyclizine and buclizine) at = +1500 mV (vs Ag/AgCl), while the response was linear within the concentration range measured up to 5 μmol L. The method was successfully applied to the determination of piperazine antihistamine drugs in spiked plasma samples.
PubMed: 38313503
DOI: 10.1021/acsomega.3c09474 -
Frontiers in Pharmacology 2023The medicines information service, SafeMotherMedicine, regularly receives inquiries from breastfeeding women asking about antiemetics for nausea and vomiting during...
The medicines information service, SafeMotherMedicine, regularly receives inquiries from breastfeeding women asking about antiemetics for nausea and vomiting during pregnancy (NVP) or hyperemesis gravidarum (HG). However, treatment guidelines for NVP or HG do not address the use of antiemetics in women who are breastfeeding while becoming pregnant again. Our objective was to characterize inquiries to describe the need for lactation risk information among women with NVP or HG and also to raise awareness of this topic. We conducted a review of inquiries to the Norwegian web-based medicines information service, SafeMotherMedicine. In total, 97 inquiries addressing the use of antiemetics for NVP or HG during breastfeeding were identified. The following medications were addressed in the inquiries ( = 97): meclizine (51%), metoclopramide (33%), promethazine (16%), ondansetron (9%), and others (6%). The breastfed child was older than 6 months and 1 year in 96% and 71% of the inquiries, respectively. There was a preponderance of general inquiries (unclear motivation/double checking) (64%); however, one-third of the inquiries were generated by restrictive information from sources such as product information. Based on our small review of spontaneous inquiries, there seems to be an information need about the use of antiemetics during lactation among women breastfeeding an older infant whilst suffering from NVP or HG. Addressing such use in guidelines for NVP and HG and/or other easily available information sources may be considered in order to balance out the restrictive information provided by the manufacturers. This could avoid potential unnecessary weaning of breastfeeding in an otherwise challenging situation.
PubMed: 38094894
DOI: 10.3389/fphar.2023.1238875 -
Advanced Science (Weinheim,... Feb 2024Meclizine (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,...
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.
Topics: Meclizine; Molecular Docking Simulation; Electrons; Receptors, Histamine H1; Proteins; Histamine Antagonists
PubMed: 38044280
DOI: 10.1002/advs.202306435 -
GeroScience Feb 2024In genetically heterogeneous (UM-HET3) mice produced by the CByB6F1 × C3D2F1 cross, the Nrf2 activator astaxanthin (Asta) extended the median male lifespan by 12%...
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.
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.
Topics: Female; Mice; Male; Animals; Longevity; Meclizine; Hydrogen Sulfide; Dimethyl Fumarate; Mycophenolic Acid; Phenylbutyrates; Xanthophylls; Flavonols
PubMed: 38041783
DOI: 10.1007/s11357-023-01011-0 -
Molecules (Basel, Switzerland) Oct 2023The 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...
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.
Topics: Antiemetics; Least-Squares Analysis; Meclizine; Calibration; Chromatography, High Pressure Liquid
PubMed: 37894524
DOI: 10.3390/molecules28207044 -
BioRxiv : the Preprint Server For... Sep 2023Meclizine (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,...
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. In this study, we used microcrystal electron diffraction (MicroED) to determine the three-dimensional (3D) crystal structure of meclizine dihydrochloride directly from a seemingly amorphous powder. Two racemic enantiomers (R/S) were found in the unit cell, which packed as repetitive double layers in the crystal lattice. The packing was made of multiple strong N-H⋯Cl hydrogen bonding interactions and weak interactions like C-H⋯Cl and pi-stacking. Molecular docking revealed 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) showed the conserved binding sites. This research illustrates the combined use of MicroED and molecular docking in unraveling protein-drug interactions for precision drug design and optimization.
PubMed: 37786674
DOI: 10.1101/2023.09.05.556418