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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 -
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 -
Journal of the Association For Research... Oct 2021Management of vestibular dysfunction may include treatment with medications that are thought to act to suppress vestibular function and reduce or eliminate abnormal...
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.
Topics: Animals; Diazepam; Indoles; Meclizine; Mice; Piperazines; Vestibular System; Vestibule, Labyrinth
PubMed: 34009490
DOI: 10.1007/s10162-021-00803-5 -
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 -
Stem Cell Research & Therapy Sep 2023Cardiovascular complications significantly augment the overall COVID-19 mortality, largely due to the susceptibility of human cardiomyocytes (CMs) to SARS-CoV-2 virus....
BACKGROUND
Cardiovascular complications significantly augment the overall COVID-19 mortality, largely due to the susceptibility of human cardiomyocytes (CMs) to SARS-CoV-2 virus. SARS-CoV-2 virus encodes 27 genes, whose specific impacts on CM health are not fully understood. This study elucidates the deleterious effects of SARS-CoV-2 genes Nsp6, M, and Nsp8 on human CMs.
METHODS
CMs were derived from human pluripotent stem cells (hPSCs), including human embryonic stem cells and induced pluripotent stem cells, using 2D and 3D differentiation methods. We overexpressed Nsp6, M, or Nsp8 in hPSCs and then applied whole mRNA-seq and mass spectrometry for multi-omics analysis. Co-immunoprecipitation mass spectrometry was utilized to map the protein interaction networks of Nsp6, M, and Nsp8 within host hiPSC-CMs.
RESULTS
Nsp6, Nsp8, and M globally perturb the transcriptome and proteome of hPSC-CMs. SARS-CoV-2 infection and the overexpression of Nsp6, Nsp8, or M coherently upregulated genes associated with apoptosis and immune/inflammation pathways, whereas downregulated genes linked to heart contraction and functions. Global interactome analysis revealed interactions between Nsp6, Nsp8, and M with ATPase subunits. Overexpression of Nsp6, Nsp8, or M significantly reduced cellular ATP levels, markedly increased apoptosis, and compromised Ca handling in hPSC-CMs. Importantly, administration of FDA-approved drugs, ivermectin and meclizine, could restore ATP levels, thereby mitigating apoptosis and dysfunction in hPSC-CMs overexpressing Nsp6, Nsp8, or M.
CONCLUSION
Overall, our findings uncover the extensive damaging effects of Nsp6, Nsp8, and M on hPSC-CMs, underlining the crucial role of ATP homeostasis in CM death and functional abnormalities induced by these SARS-CoV-2 genes, and reveal the potential therapeutic strategies to alleviate these detrimental effects with FDA-approved drugs.
Topics: Humans; Myocytes, Cardiac; SARS-CoV-2; COVID-19; Pluripotent Stem Cells; Genes, Viral; Adenosine Triphosphate
PubMed: 37705046
DOI: 10.1186/s13287-023-03485-3 -
Scientific Reports May 2016Meclizine is a well-tolerated drug routinely used as an anti-histamine agent in the management of disequilibrium. Recently, meclizine has been assessed for its...
Meclizine is a well-tolerated drug routinely used as an anti-histamine agent in the management of disequilibrium. Recently, meclizine has been assessed for its neuroprotective properties in ischemic stroke and Huntington disease models. We found that meclizine protected against 6-hydroxydopamine-induced apoptosis and cell death in both SH-SY5Y cells and rat primary cortical cultures. Meclizine increases the level of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), which activates phosphofructokinase, a rate-determining enzyme of glycolysis. This protection is therefore mediated by meclizine's ability to enhance glycolysis and increase mitochondrial hyperpolarization. Meclizine represents an interesting candidate for further investigation to re-purpose for its potential to be neuroprotective in Parkinson disease.
Topics: Animals; Apoptosis; Cell Line; Fructosediphosphates; Gene Expression Regulation; Glycolysis; Humans; Meclizine; Mice; Mitochondria; Models, Biological; Neurons; Neuroprotective Agents; Oxidopamine; Parkinson Disease; Phosphofructokinase-2; Phosphofructokinases; Rats
PubMed: 27145922
DOI: 10.1038/srep25344 -
British Journal of Clinical Pharmacology Aug 2020Antihistamines make up the first line of treatments against motion-sickness. Still, their efficacy and specific mechanism have come into question. The aim of this study... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
Antihistamines make up the first line of treatments against motion-sickness. Still, their efficacy and specific mechanism have come into question. The aim of this study was to investigate the effect of meclizine on motion-sensitivity.
METHODS
This study was carried out as a triple-blinded randomized trial involving 12 healthy subjects who were exposed to (i) vestibular (VES), (ii) visual (VIS) and (iii) visual-vestibular (VIS+VES) stimulations in the roll plane. Subjects were divided into 2 groups by stratified randomization, receiving either meclizine or a placebo. Stimulations were carried out before, and after, drug administration, presented at 2 intensity levels of 14 and 28°/s . Eye movements were tracked, and torsional slow-phase velocities, amplitudes and nystagmus beats were retrieved. Subjects initially graded for their motion-sickness susceptibility.
RESULTS
Susceptibility had no effect on intervention outcome. Despite large variations, repeated ANOVAS showed that meclizine led to a relative increase in torsional velocity compared to placebo during vestibular stimulation for both intensities: 2.36 (7.65) from -0.01 (4.17) during low intensities, and 2.61 (6.67) from -3.49 (4.76) during high. The visual-vestibular stimuli yielded a decrease during low acceleration, -0.40 (3.87) from 3.75 (5.62), but increased during high, 3.88 (6.51) from -3.88 (8.55).
CONCLUSIONS
Meclizine had an inhibitory effect on eye movement reflexes for low accelerations during VIS+VES trials. This indicates that meclizine may not primarily work through sensory-specific mechanisms, but rather on a more central level. Practically, meclizine shows promise in targeting motion-sickness evoked by everyday activities, but its use may be counterproductive in high-acceleration environments.
Topics: Eye Movements; Humans; Meclizine; Motion Sickness
PubMed: 32077140
DOI: 10.1111/bcp.14257 -
Scientific Reports Apr 2022Repurposing FDA-approved drugs is an efficient and cost-effective approach in the development of therapeutics for a broad range of diseases. However, prediction of...
Repurposing FDA-approved drugs is an efficient and cost-effective approach in the development of therapeutics for a broad range of diseases. However, prediction of function can be challenging, especially in the brain. We screened a small-molecule library with FDA-approved drugs for effects on behavior. The studies were carried out using zebrafish larvae, imaged in a 384-well format. We found that various drugs affect activity, habituation, startle responses, excitability, and optomotor responses. The changes in behavior were organized in behavioral profiles, which were examined by hierarchical cluster analysis. One of the identified clusters includes the calcineurin inhibitors cyclosporine (CsA) and tacrolimus (FK506), which are immunosuppressants and potential therapeutics in the prevention of Alzheimer's disease. The calcineurin inhibitors form a functional cluster with seemingly unrelated drugs, including bromocriptine, tetrabenazine, rosiglitazone, nebivolol, sorafenib, cabozantinib, tamoxifen, meclizine, and salmeterol. We propose that drugs with 'CsA-type' behavioral profiles are promising candidates for the prevention and treatment of Alzheimer's disease.
Topics: Alzheimer Disease; Animals; Calcineurin; Calcineurin Inhibitors; Cluster Analysis; Cyclosporine; Immunosuppressive Agents; Tacrolimus; Zebrafish
PubMed: 35449173
DOI: 10.1038/s41598-022-10133-y -
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 -
Australian Family Physician Jun 2008Vertigo is a common clinical problem managed by general practitioners. (Review)
Review
BACKGROUND
Vertigo is a common clinical problem managed by general practitioners.
OBJECTIVE
This article focuses on the acute management of a vertigo attack, specific management of conditions causing vertigo, and the long term management issues associated with chronic vertigo.
DISCUSSION
Supportive treatment, antiemetic and vestibular blocking agents help relieve an acute vertigo attack, however the prolonged use of such medications is not recommended. Specific treatments for various conditions causing vertigo are available, however, the majority of patients are managed symptomatically. The patient's ability to drive safely should be carefully assessed according to Austroads guidelines and advice from an ear, nose and throat surgeon should be sought when in doubt. There is evidence to support the efficacy of vestibular rehabilitation programs for unilateral peripheral vestibular disorder and these programs should be considered. A simple program including patient education and home based exercises can be sufficient.
Topics: Acute Disease; Antiemetics; Automobile Driving; Brain Stem; Chronic Disease; Family Practice; Humans; Meclizine; Methylprednisolone; Patient Education as Topic; Physical Therapy Modalities; Posture; Vertigo
PubMed: 18523693
DOI: No ID Found