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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 -
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 -
Journal of the American Geriatrics... Feb 2016Benign paroxysmal positional vertigo (BPPV) is the most common cause of vertigo in older adults. Beyond the unpleasant sensation of vertigo, BPPV also negatively affects... (Review)
Review
Benign paroxysmal positional vertigo (BPPV) is the most common cause of vertigo in older adults. Beyond the unpleasant sensation of vertigo, BPPV also negatively affects older adults' gait and balance and increases their risk of falling. As such it has a profound effect on function, independence, and quality of life. Otoconia are the inner ear structures that help detect horizontal and vertical movements. Aging contributes to the fragmentation of otoconia, whose displacement into the semicircular, most commonly posterior canals, can produce rotatory movement sensations with head movement. BPPV is more commonly idiopathic in older adults than in younger individuals, can present atypically, and has a more-protracted course and higher risk of recurrence. Medications such as meclizine that are commonly prescribed for BPPV can be associated with significant side effects. Dix-Hallpike and Head Roll tests can generally identify the involved canal. Symptoms resolve as otoconia fragments dissolve into the endolymph, but appropriate canalith repositioning (e.g., Epley maneuver) can expedite recovery and reduce the burden of this disorder. Observations suggesting an association between idiopathic BPPV and vitamin D deficiency and osteoporosis indicate that BPPV may share risk factors with other common geriatric conditions, which highlights the importance of moving beyond purely otological considerations and addressing the needs of older adults with vertigo through a systems-based multidisciplinary approach.
Topics: Aged; Benign Paroxysmal Positional Vertigo; Diagnosis, Differential; Humans
PubMed: 26804483
DOI: 10.1111/jgs.13926 -
Revue Neurologique Nov 2023According to recent findings, Phosphoglycerate Kinase 1 (pgk-1) enzyme is linked to Parkinson's disease (PD). Mutations in the PGK-1 gene lead to decreases in the pgk-1... (Review)
Review
Importance of glucose and its metabolism in neurodegenerative disorder, as well as the combination of multiple therapeutic strategies targeting α-synuclein and neuroprotection in the treatment of Parkinson's disease.
According to recent findings, Phosphoglycerate Kinase 1 (pgk-1) enzyme is linked to Parkinson's disease (PD). Mutations in the PGK-1 gene lead to decreases in the pgk-1 enzyme which causes an imbalance in the levels of energy demand and supply. An increase in glycolytic adenosine triphosphate (ATP) production would help alleviate energy deficiency and sustain the acute energetic need of neurons. Neurodegeneration is caused by an imbalance or reduction in ATP levels. Recent data suggest that medications that increase glycolysis and neuroprotection can be used to treat PD. The current study focuses on treatment options for disorders associated with the pgk-1 enzyme, GLP-1, and A receptor which can be utilized to treat PD. A combination of metformin and terazosin, exenatide and meclizine, istradefylline and salbutamol treatments may benefit parkinsonism. The review also looked at potential target-specific new techniques that might assist in satisfying unfulfilled requirements in the treatment of PD.
PubMed: 38040547
DOI: 10.1016/j.neurol.2023.08.011 -
BMC Musculoskeletal Disorders Mar 2023Postmenopausal osteoporosis is a widespread health concern due to its prevalence among older adults and an associated high risk of fracture. The downregulation of bone...
BACKGROUND
Postmenopausal osteoporosis is a widespread health concern due to its prevalence among older adults and an associated high risk of fracture. The downregulation of bone regeneration delays fracture healing. Activated fibroblast growth factor receptor 3 (FGFR3) accelerates bone regeneration at juvenile age and downregulates bone mineralization at all ages. However, the impact of FGFR3 signaling on bone regeneration and bone mineralization post-menopause is still unknown. This study aimed to evaluate the impact of FGFR3 signaling on bone regeneration and bone mineralization during menopause by developing a distraction osteogenesis (DO) mouse model after ovariectomy (OVX) using transgenic mice with activated FGFR3 driven by Col2a1 promoter (Fgfr3 mice).
METHODS
The OVX or sham operations were performed in 8-week-old female Fgfr3 and wild-type mice. After 8 weeks of OVX surgery, DO surgery in the lower limb was performed. The 5-day-latency period followed by performing distraction for 9 days. Bone mineral density (BMD) and bone regeneration was assessed by micro-computed tomography (micro-CT) scan and soft X-ray. Bone volume in the distraction area was also evaluated by histological analysis after 7 days at the end of distraction. Osteogenic differentiation and mineralization of bone marrow-derived mesenchymal stem cells (BMSCs) derived from each mouse after 8 weeks of the OVX or sham operations were also evaluated with and without an inhibitor for FGFR3 signaling (meclozine).
RESULTS
BMD decreased after OVX in both groups, and it further deteriorated in Fgfr3 mice. Poor callus formation after DO was also observed in both groups with OVX, and the amount of regenerated bone was further decreased in Fgfr3 mice. Similarly, histological analysis revealed that Fgfr3 OVX mice showed lower bone volume. Osteogenic differentiation and mineralization of BMSCs were also deteriorated in Fgfr3 OVX mice. An inhibitor for FGFR3 signaling dramatically reversed the inhibitory effect of OVX and FGFR3 signaling on BMSC mineralization.
CONCLUSION
Upregulated FGFR3 decreased newly regenerated bone after DO and BMD in OVX mice. FGFR3 signaling can be a potential therapeutic target in patients with postmenopausal osteoporosis.
Topics: Animals; Female; Humans; Mice; Bone Density; Bone Regeneration; Calcification, Physiologic; Disease Models, Animal; Osteogenesis; Osteoporosis, Postmenopausal; Ovariectomy; Receptor, Fibroblast Growth Factor, Type 3; X-Ray Microtomography
PubMed: 36927417
DOI: 10.1186/s12891-023-06318-9 -
Spectrochimica Acta. Part A, Molecular... May 2017In this paper, three rapid, simple, accurate and precise spectrophotometric methods were developed for the determination of meclizine hydrochloride in the presence of...
In this paper, three rapid, simple, accurate and precise spectrophotometric methods were developed for the determination of meclizine hydrochloride in the presence of pyridoxine hydrochloride without previous separation. The methods under study are dual wavelength (DWL), ratio difference (RD) and continuous wavelet transform (CWT). On the other hand, pyridoxine hydrochloride (PYH) was determined directly at 291nm. The methods obey Beer's law in the range of (5-50μg/mL) for both compounds. All the methods were validated according to the ICH guidelines where the accuracy was found to be 98.29, 99.59, 100.42 and 100.62% for DWL, RD, CWT and PYH; respectively. Moreover the precision of the methods were calculated in terms of %RSD and it was found to be 0.545, 0.372, 1.287 and 0.759 for DWL, RD,CWT and PYH; respectively. The selectivity of the proposed methods was tested using laboratory prepared mixtures and assessed by applying the standard addition technique. So, they can be used for the routine analysis of pyridoxine hydrochloride and meclizine hydrochloride in quality-control laboratories.
Topics: Chemistry, Pharmaceutical; Meclizine; Pyridoxine; Reference Standards; Reproducibility of Results; Spectrophotometry; Wavelet Analysis
PubMed: 28199928
DOI: 10.1016/j.saa.2017.02.013 -
Metabolic Brain Disease Dec 2023Neuroinflammation is identified as significant inflammatory reactions occurring in the central nervous system. Lipopolysaccharide (LPS) stimulates innate immune...
Neuroinflammation is identified as significant inflammatory reactions occurring in the central nervous system. Lipopolysaccharide (LPS) stimulates innate immune reactions and is used as an in vivo animal model for the investigation of inflammation. Meclizine (MCLZ) is a histamine antagonist with potential neuroprotective qualities. Forty adult male Swiss albino mice were divided into four groups (n = 10). Group 1 served as a control negative group. Groups 2-4 were injected with LPS (5 mg/kg; i.p). Group 2 served as LPS-control. Groups 3 & 4 were given MCLZ (12.5 & 25 mg/kg; p.o) respectively for 14 days. LPS administration resulted in significant neuroinflammation in mice as was revealed by significant inflammatory histopathological changes and positive immunohistochemical staining of glial fibrillary acidic proteins (GFAP) accompanied by significant elevations of brain tissue contents of interleukin-1-beta (IL-1β), tumor necrosis factor-alpha (TNF-α), nuclear factor kappa-beta (NF-κβ), protein kinase B (AKT), extracellular signal-regulated kinase (ERK) and C-Jun N-Terminal Kinases (JNK). MCLZ treatment significantly down-regulated all the aforementioned parameters in mice brains. Moreover, MCLZ treatment ameliorated the inflammatory histopathological changes and GFAP immunostaining in brain tissues. The current study identifies for the first time the protective anti-neuroinflammatory effects of MCLZ against LPS-induced neuroinflammation in mice. MCLZ protected against neuroinflammation via the amelioration of inflammatory histopathological changes as well as neuronal GFAP immunostaining and down-regulated the AKT/NF-κβ/ERK/JNK signaling pathway. MCLZ is anticipated as a potential protective candidate for the addition to the treatment protocol of neuroinflammation.
Topics: Animals; Male; Mice; Anti-Inflammatory Agents; Cytokines; Extracellular Signal-Regulated MAP Kinases; Inflammation; Lipopolysaccharides; MAP Kinase Signaling System; Meclizine; Neuroinflammatory Diseases; NF-kappa B; Proto-Oncogene Proteins c-akt; Tumor Necrosis Factor-alpha
PubMed: 37733253
DOI: 10.1007/s11011-023-01295-3 -
Archives of Biochemistry and Biophysics Jan 2022The identification of biomolecules associated with papillary thyroid cancer (PTC) has upmost importance for the elucidation of the disease mechanism and the development... (Meta-Analysis)
Meta-Analysis
The identification of biomolecules associated with papillary thyroid cancer (PTC) has upmost importance for the elucidation of the disease mechanism and the development of effective diagnostic and treatment strategies. Despite particular findings in this regard, a holistic analysis encompassing molecular data from different biological levels has been lacking. In the present study, a meta-analysis of four transcriptome datasets was performed to identify gene expression signatures in PTC, and reporter molecules were determined by mapping gene expression data onto three major cellular networks, i.e., transcriptional regulatory, protein-protein interaction, and metabolic networks. We identified 282 common genes that were differentially expressed in all PTC datasets. In addition, six proteins (FYN, JUN, LYN, PML, SIN3A, and RARA), two Erb-B2 receptors (ERBB2 and ERBB4), two cyclin-dependent receptors (CDK1 and CDK2), and three histone deacetylase receptors (HDAC1, HDAC2, and HDAC3) came into prominence as proteomic signatures in addition to several metabolites including lactaldehyde and proline at the metabolome level. Significant associations with calcium and MAPK signaling pathways and transcriptional and post-transcriptional activities of 12 TFs and 110 miRNAs were also observed at the regulatory level. Among them, six miRNAs (miR-30b-3p, miR-15b-5p, let-7a-5p, miR-130b-3p, miR-424-5p, and miR-193b-3p) were associated with PTC for the first time in the literature, and the expression levels of miR-30b-3p, miR-15b-5p, and let-7a-5p were found to be predictive of disease prognosis. Drug repositioning and molecular docking simulations revealed that 5 drugs (prochlorperazine, meclizine, rottlerin, cephaeline, and tretinoin) may be useful in the treatment of PTC. Consequently, we report here biomolecule candidates that may be considered as prognostic biomarkers or potential therapeutic targets for further experimental and clinical trials for PTC.
Topics: Antineoplastic Agents; Biomarkers, Tumor; Drug Repositioning; Gene Expression; Gene Expression Profiling; Humans; MicroRNAs; Molecular Docking Simulation; Protein Binding; Proteomics; Thyroid Cancer, Papillary; Thyroid Neoplasms; Transcriptome
PubMed: 34800440
DOI: 10.1016/j.abb.2021.109085 -
Scientific Reports Sep 2020This study is based on the QbD development of extended-release (ER) extruded-spheronized pellets of Meclizine HCl and its comparative pharmacokinetic evaluation with...
QbD based Eudragit coated Meclizine HCl immediate and extended release multiparticulates: formulation, characterization and pharmacokinetic evaluation using HPLC-Fluorescence detection method.
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 R > 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 AUC and AUC of ER pellets were not significantly different with geometric mean ratio 1.0096 and 1.0093, respectively. The C of IR pellets (98.051 ng/ml) was higher than the ER pellets (84.052 ng/ml) and the T 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.
Topics: Adult; Anti-Allergic Agents; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Delayed-Action Preparations; Female; Fluorescence; Humans; Male; Meclizine; Polymethacrylic Acids; Young Adult
PubMed: 32913337
DOI: 10.1038/s41598-020-71751-y -
The Journal of Emergency Medicine Jan 2017Vertigo is a debilitating disease that is commonly encountered in the emergency department (ED). Diazepam and meclizine are oral medications that are commonly used to... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Vertigo is a debilitating disease that is commonly encountered in the emergency department (ED). Diazepam and meclizine are oral medications that are commonly used to alleviate symptoms.
OBJECTIVES
We sought to determine whether meclizine or diazepam is superior in the treatment of patients with peripheral vertigo in the ED.
METHODS
We performed a double-blind clinical trial at a suburban, teaching ED. We randomized a convenience sample of adult patients with acute peripheral vertigo (APV) to diazepam 5 mg or meclizine 25 mg orally. Demographic and historical features were recorded on a standardized data form. Patients recorded their initial level (t0) of vertigo on a 100-mm visual analog scale (VAS) and after 30 min (t30) and 60 min (t60). The primary outcome parameter was the mean change in VAS score from t0 to t60. Differences between groups and 95% confidence intervals were calculated. Our a priori power calculation estimated that a sample size of 20 patients in each group was required to have an 80% power to detect a difference of 20 mm between treatment groups.
RESULTS
There were 20 patients in the diazepam group and 20 in the meclizine group. The two groups were similar with respect to patient demographics and presenting signs and symptoms. At t60, the mean improvements in the diazepam and meclizine groups were 36 and 40, respectively (difference -4; 95% confidence interval -20 to 12; p = 0.60).
CONCLUSION
We found no difference between oral diazepam and oral meclizine for the treatment of ED patients with acute peripheral vertigo.
Topics: Adult; Diazepam; Double-Blind Method; Emergency Service, Hospital; Female; Humans; Male; Meclizine; Middle Aged; Prospective Studies; Treatment Outcome; Vertigo
PubMed: 27789115
DOI: 10.1016/j.jemermed.2016.09.016