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Endocrine Development 2016Fibroblast growth factor receptor 3 (FGFR3) is an important regulator of bone formation. Gain-of-function mutations in the FGFR3 gene result in chondrodysplasias which... (Review)
Review
Fibroblast growth factor receptor 3 (FGFR3) is an important regulator of bone formation. Gain-of-function mutations in the FGFR3 gene result in chondrodysplasias which include achondroplasia (ACH), the most common form of dwarfism, in which skull, appendicular and axial skeletons are affected. The skeletal phenotype of patients with ACH showed defective proliferation and differentiation of the chondrocytes in the growth plate cartilage. Both endochondral and membranous ossification processes are disrupted during development. At cellular level, Fgfr3 mutations induce increased phosphorylation of the tyrosine kinase receptor FGFR3, which correlate with an enhanced activation of its downstream signaling pathways. Potential therapeutic strategies have emerged for ACH. Several preclinical studies have been conducted such as the C-type natriuretic peptide (CNP) analog (BMN111), intermittent parathyroid hormone injections, soluble FGFR3 therapy, and meclozine and statin treatments. Among the putative targets to antagonize FGFR3 signaling, CNP (or BMN111) is one of the most promising strategies. BMN111 acts as a key regulator of longitudinal bone growth by downregulating the mitogen-activated protein kinase pathway, which is activated as a result of a FGFR3 gain-of-function mutation. Preclinical studies showed that BMN111 treatment led to a large improvement in skeletal parameters in Fgfr3Y367C/+ mice mimicking ACH. In 2014, a clinical trial (phase 2) of BMN111 in pediatric patients with ACH has started. This first clinical trial marks the first big step towards real treatment for these patients.
Topics: Achondroplasia; Animals; Humans; Natriuretic Peptide, C-Type; Receptor, Fibroblast Growth Factor, Type 3
PubMed: 26684019
DOI: 10.1159/000439334 -
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 -
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 -
Canadian Journal of Physiology and... Jun 2020Pregnane X receptors (PXRs) regulate the expression of ATP-binding cassette proteins transporters and organic anion transporting polypeptides responsible for...
Pregnane X receptors (PXRs) regulate the expression of ATP-binding cassette proteins transporters and organic anion transporting polypeptides responsible for influx/efflux of xenobiotics across the brain. Ligand activation of PXR augments the expression of P-gp and promotes amyloid-β clearance across the blood-brain barrier. Dementia was induced in mice by intacerebroventricular administration of streptozotocin (STZ) followed by treatment with meclizine, a PXR agonist, and subsequently exposed to the Morris water maze test and biochemical and histopathological analysis to evaluate the effect on cognition. STZ-treated mice exhibited significant enhancement in brain thiobarbituric acid reactive species, interleukin-1β, tumour necrosis factor-α, myeloperoxidase, and acetylcholinestrase activity in addition to diminution in glutathione levels and superoxide dismutase activity in comparison to untreated mice. Administration of meclizine to STZ mice recuperated cognition and biochemical alterations. Concomitant administration of ketoconazole, a PXR antagonist, with meclizine prevented the protective effects. The upshots of our study proclaim that meclizine protects cognitive deficits by virtue of its antioxidant, anticholinesterase, and antiinflammatory properties. Results also signify the potential of PXR in neuroprotective actions of meclizine in dementia.
Topics: Animals; Brain; Dementia; Disease Models, Animal; Female; Glutathione; Interleukin-1beta; Male; Meclizine; Memory Disorders; Mice; Neuroprotective Agents; Pregnane X Receptor; Streptozocin; Superoxide Dismutase; Tumor Necrosis Factor-alpha
PubMed: 31935134
DOI: 10.1139/cjpp-2019-0421 -
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 -
Reproductive Toxicology (Elmsford, N.Y.) Aug 2019Nausea and vomiting of pregnancy (NVP) is the most common medical complaint during pregnancy affecting up to 70% of pregnant women worldwide. Some antiemetic medications...
Nausea and vomiting of pregnancy (NVP) is the most common medical complaint during pregnancy affecting up to 70% of pregnant women worldwide. Some antiemetic medications (AEM) (droperidol, domperidone, granisetron, metoclopramide and trifluoperazine) used to treat NVP have the unwanted side effect of hERG blockade. The hERG potassium channel is essential for normal heart rhythm in both the adult human and the human and rat embryo. Animal studies show hERG blockade in the embryo causes bradycardia and arrhythmia leading to cardiovascular malformations and other birth defects. Whole rat embryo in vitro culture was used to determine the effect of the above listed AEM and meclizine on the heart rate of Gestational day 13 rat embryos. These embryos are similar in size and heart development to 5-6-week human embryo. The results showed that all of the AEMs caused a concentration-dependent bradycardia. Droperidol had the lowest margin of safety.
Topics: Animals; Antiemetics; Bradycardia; Domperidone; Droperidol; Embryo, Mammalian; Granisetron; Heart; Heart Rate; Meclizine; Metoclopramide; Rats, Sprague-Dawley; Trifluoperazine
PubMed: 31199962
DOI: 10.1016/j.reprotox.2019.06.002 -
Biochemical Pharmacology Oct 2015Meclizine is an agonist of human pregnane X receptor (PXR). It increases CYP3A4 mRNA expression, but decreases CYP3A-catalyzed testosterone 6β-hydroxylation in primary...
Meclizine is an agonist of human pregnane X receptor (PXR). It increases CYP3A4 mRNA expression, but decreases CYP3A-catalyzed testosterone 6β-hydroxylation in primary cultures of human hepatocytes, as assessed at 24h after the last dose of meclizine. Therefore, the hypothesis to be tested is that meclizine inactivates human CYP3A enzymes. Our findings indicated that meclizine directly inhibited testosterone 6β-hydroxylation catalyzed by human liver microsomes, recombinant CYP3A4, and recombinant CYP3A5. The inhibition of human liver microsomal testosterone 6β-hydroxylation by meclizine occurred by a mixed mode and with an apparent Ki of 31±6μM. Preincubation of meclizine with human liver microsomes and NADPH resulted in a time- and concentration-dependent decrease in testosterone 6β-hydroxylation. The extent of inactivation required the presence of NADPH, was unaffected by nucleophilic trapping agents or reactive oxygen species scavengers, attenuated by a CYP3A substrate, and not reversed by dialysis. Meclizine selectively inactivated CYP3A4, but not CYP3A5. In contrast to meclizine, which has a di-substituted piperazine ring, norchlorcyclizine, which is a N-debenzylated meclizine metabolite with a mono-substituted piperazine ring, did not inactivate but directly inhibited hepatic microsomal CYP3A activity. In conclusion, meclizine inhibited human CYP3A enzymes by both direct inhibition and mechanism-based inactivation. In contrast, norchlorcyclizine is a direct inhibitor but not a mechanism-based inactivator. Furthermore, a PXR agonist may also be an inhibitor of a PXR-regulated enzyme, thereby giving rise to opposing effects on the functional activity of the enzyme and indicating the importance of measuring the catalytic activity of nuclear receptor-regulated enzymes.
Topics: Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Dose-Response Relationship, Drug; Humans; In Vitro Techniques; Kinetics; Meclizine; Microsomes, Liver; Models, Biological; Molecular Structure; Piperazines; Pregnane X Receptor; Receptors, Steroid; Recombinant Proteins
PubMed: 26239802
DOI: 10.1016/j.bcp.2015.07.036 -
Otology & Neurotology : Official... Mar 2023To examine the risk factors for hip fracture in patients with vestibular disorders and the association between antihistamine use and hip fracture in patients with...
OBJECTIVES
To examine the risk factors for hip fracture in patients with vestibular disorders and the association between antihistamine use and hip fracture in patients with vestibular disorders.
STUDY DESIGN
Retrospective case series with chart review.
SETTING
Tertiary academic medical center.
METHODS
A retrospective review of adult patients with hip fracture based on International Classification of Diseases, Tenth Revision (ICD-10) code S72 from January 2013 to December 2019 who had previously been diagnosed with a vestibular disorder based on ICD-10 codes H81-83, A88.1, and R42.
RESULTS
A total of 201 patients were identified meeting the inclusion criteria. The average age at the time of hip fracture was 78.8 years and the majority were female (64.7%). Most patients were diagnosed with nonspecific dizziness (60.2%) or vertigo (23.9%). Those with a peripheral vestibular disorder included benign paroxysmal positional vertigo (BPPV) in 13.4% and Ménière's disease in 2.5%. Overall, meclizine was prescribed to 38.3% of patients, including 29.9% of patients before hip fracture. Meclizine was prescribed to 66.7% of patients with BPPV. Patients were seen for vestibular symptoms 0.67 ± 2.51 years before hip fracture, and 98 patients (48.8%) presented with vestibular concerns within 1 year prior.
CONCLUSION
Patients with vestibular disorders who sustain a ground level fall resulting in hip fracture are a vulnerable population of predominantly older adults with multiple comorbidities. Patients were frequently diagnosed with dizziness or vertigo rather than more specific causes being identified. Multifactorial interventions to prevent hip fractures in older adults have been recommended; however, this study suggests that meclizine use was common among patients diagnosed with dizziness, vertigo, or BPPV before hip fracture.
Topics: Humans; Female; Male; Aged; Dizziness; Meclizine; Retrospective Studies; Vestibular Diseases; Benign Paroxysmal Positional Vertigo; Hip Fractures
PubMed: 36728629
DOI: 10.1097/MAO.0000000000003792