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European Journal of Clinical... Apr 2018In Sweden, information on drug use during pregnancy is obtained through an interview and recorded in a standardized medical record at every visit to the antenatal care...
PURPOSE
In Sweden, information on drug use during pregnancy is obtained through an interview and recorded in a standardized medical record at every visit to the antenatal care clinic throughout the pregnancy. Antenatal, delivery, and neonatal records constitute the basis for the Swedish Medical Birth Register (MBR). The purpose of this exploratory study was to investigate the reliability of reported drug use by simultaneous screening for drug substances in the blood stream of the pregnant woman and thereby validate self-reported data in the MBR.
METHODS
Plasma samples from 200 women were obtained at gestational weeks 10-12 and 25 and screened for drugs by using ultra-high performance liquid chromatography with time of flight mass spectrometry (UHPLC-TOF-MS). The results from the analysis were then compared to medical records.
RESULTS
At the first sampling occasion, the drugs found by screening had been reported by 86% of the women and on the second sampling, 85.5%. Missed reported information was clearly associated with drugs for occasional use. The most common drugs in plasma taken in early and mid-pregnancy were meclizine and paracetamol. Two types of continuously used drugs, selective serotonin reuptake inhibitors and propranolol, were used. All women using them reported it and the drug screening revealed a 100% coherence.
CONCLUSIONS
This study shows good coherence between reported drug intake and the drugs found in plasma samples, which in turn positively validates the MBR.
Topics: Biomarkers; Chromatography, High Pressure Liquid; Drug Monitoring; Drug Therapy; Female; Gestational Age; Humans; Mass Spectrometry; Pilot Projects; Predictive Value of Tests; Pregnancy; Registries; Reproducibility of Results; Self Report; Sweden
PubMed: 29264642
DOI: 10.1007/s00228-017-2402-4 -
Frontiers in Pharmacology 2017Pregnane X receptor (PXR) which belongs to the nuclear hormone receptor superfamily plays vital roles in several biological functions, especially in the inflammatory...
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 and . 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 and . 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.
PubMed: 29046637
DOI: 10.3389/fphar.2017.00693 -
Scientific Reports Aug 2017Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia caused by gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3). No...
Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia caused by gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3). No effective FGFR3-targeted therapies for ACH are currently available. By drug repositioning strategies, we identified that meclozine, which has been used as an anti-motion-sickness, suppressed FGFR3 signaling in chondrocytes and rescued short-limbed phenotype in ACH mouse model. Here, we conducted various pharmacological tests for future clinical application in ACH. Pharmacokinetic analyses demonstrated that peak drug concentration (C) and area under the concentration-time curve (AUC) of 2 mg/kg of meclozine to mice was lower than that of 25 mg/body to human, which is a clinical usage for anti-motion-sickness. Pharmacokinetic simulation studies showed that repeated dose of 2 mg/kg of meclozine showed no accumulation effects. Short stature phenotype in the transgenic mice was significantly rescued by twice-daily oral administration of 2 mg/kg/day of meclozine. In addition to stimulation of longitudinal bone growth, bone volume and metaphyseal trabecular bone quality were improved by meclozine treatment. We confirmed a preclinical proof of concept for applying meclozine for the treatment of short stature in ACH, although toxicity and adverse events associated with long-term administration of this drug should be examined.
Topics: Achondroplasia; Animals; Bone Development; Bone and Bones; Cancellous Bone; Disease Models, Animal; Meclizine; Mice; Mice, Knockout; Phenotype; Receptor, Fibroblast Growth Factor, Type 3
PubMed: 28785080
DOI: 10.1038/s41598-017-07044-8 -
Lipids in Health and Disease Apr 2017Antiemetic agent Meclizine HCl, widely prescribed in vertigo, is available only in immediate release dosage forms. The approved therapeutic dose and shorter elimination... (Comparative Study)
Comparative Study
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 (e) varied with type and concentration of lipids: Geleol (e = 0.891-0.997), Precirol (e = 0.611-0.743), Compritol (e = 0.665-0.729) and Carnauba wax (e = 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 (R = 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 (R = 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.
Topics: Administration, Oral; Antiemetics; Delayed-Action Preparations; Diglycerides; Drug Compounding; Drug Liberation; Drug Stability; Drug Storage; Fatty Acids; Glycerides; Humans; Hydrogen-Ion Concentration; Lipids; Meclizine; Microscopy, Electron, Scanning; Pharmaceutical Vehicles; Solubility; Spectroscopy, Fourier Transform Infrared; Water; Waxes
PubMed: 28403892
DOI: 10.1186/s12944-017-0466-x -
Molecular Neurobiology Dec 2017Chemotherapy-induced neurotoxicity of peripheral nervous system (PNS) hinders efficacy of cancer treatments. Mechanisms initiating PNS injury by anticancer drugs are...
Chemotherapy-induced neurotoxicity of peripheral nervous system (PNS) hinders efficacy of cancer treatments. Mechanisms initiating PNS injury by anticancer drugs are incompletely understood delaying development of effective management strategies. To understand events triggered in PNS by cancer drugs, we exposed dorsal root ganglion (DRG) neurons to cisplatin, a drug from platinum-based class of chemotherapeutics frequently implicated in peripheral neuropathies. While cisplatin enters cancer cells and forms cisplatin/DNA crosslinks that block cell proliferation, circulating cisplatin can also reach the PNS and produce crosslinks that impede critical DNA transactions in postmitotic neurons. Cisplatin forms crosslinks with both, nuclear and mitochondrial DNA (mtDNA). Crosslinks are repairable primarily via the nucleotide excision repair (NER) pathway, which is present in nuclei but absent from mitochondrial compartment. Hence, high mitochondrial content and limited shielding by blood nerve barrier make DRG neurons particularly vulnerable to mitochondrial injury by cisplatin. We report that in DRG neurons, cisplatin elevates reactive oxygen species, depletes mtDNA, and impairs mitochondrial respiration, whereas concomitant meclizine supplementation preserves redox balance, attenuates mitochondrial compromise, and augments DNA repair. Meclizine is an antihistamine drug recently implicated in neuroprotection via modulation of energy metabolism. Our data demonstrate that in the mitochondria-rich DRG neurons, meclizine mitigates cisplatin-induced mitochondrial compromise via enhancement of pentose phosphate pathway and repletion of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione stores. The findings suggest that meclizine-mediated preservation of redox balance sustains mitochondrial respiration and supports execution of cellular processes, including timely removal of cisplatin crosslinks from nuclear DNA, thereby attenuating cisplatin toxicity in DRG neurons. Collectively, the findings reveal potential for pharmacologic modulation of dorsal root ganglion neurons metabolism for protection against toxicity of chemotherapeutic drugs.
Topics: Animals; Antineoplastic Agents; Cells, Cultured; Cisplatin; DNA Damage; DNA, Mitochondrial; Ganglia, Spinal; Male; Meclizine; Mice, Inbred C57BL; Mitochondria; Neurons; Peripheral Nervous System; Peripheral Nervous System Diseases; Reactive Oxygen Species
PubMed: 27858292
DOI: 10.1007/s12035-016-0273-9 -
Free Radical Biology & Medicine Oct 2016To meet energy demands, dorsal root ganglion (DRG) neurons harbor high mitochondrial content, which renders them acutely vulnerable to disruptions of energy homeostasis....
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.
Topics: Adenosine Triphosphate; Animals; Astrocytes; Cell Hypoxia; Ganglia, Spinal; Glucose; Glycolysis; Histamine H1 Antagonists; Hydrogen-Ion Concentration; Lactic Acid; Male; Meclizine; Mice; Mice, Inbred C57BL; Mitochondria; Neurons; Oxygen Consumption; Primary Cell Culture; Protective Agents; Stress, Physiological
PubMed: 27458119
DOI: 10.1016/j.freeradbiomed.2016.07.022 -
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 -
EBioMedicine Sep 2015Global or local ischemia contributes to the pathogenesis of acute kidney injury (AKI). Currently there are no specific therapies to prevent AKI. Potentiation of...
Global or local ischemia contributes to the pathogenesis of acute kidney injury (AKI). Currently there are no specific therapies to prevent AKI. Potentiation of glycolytic metabolism and attenuation of mitochondrial respiration may decrease cell injury and reduce reactive oxygen species generation from the mitochondria. Meclizine, an over-the-counter anti-nausea and -dizziness drug, was identified in a 'nutrient-sensitized' chemical screen. Pretreatment with 100 mg/kg of meclizine, 17 h prior to ischemia protected mice from IRI. Serum creatinine levels at 24 h after IRI were 0.13 ± 0.06 mg/dl (sham, n = 3), 1.59 ± 0.10 mg/dl (vehicle, n = 8) and 0.89 ± 0.11 mg/dl (meclizine, n = 8). Kidney injury was significantly decreased in meclizine treated mice compared with vehicle group (p < 0.001). Protection was also seen when meclizine was administered 24 h prior to ischemia. Meclizine reduced inflammation, mitochondrial oxygen consumption, oxidative stress, mitochondrial fragmentation, and tubular injury. Meclizine preconditioned kidney tubular epithelial cells, exposed to blockade of glycolytic and oxidative metabolism with 2-deoxyglucose and NaCN, had reduced LDH and cytochrome c release. Meclizine upregulated glycolysis in glucose-containing media and reduced cellular ATP levels in galactose-containing media. Meclizine inhibited the Kennedy pathway and caused rapid accumulation of phosphoethanolamine. Phosphoethanolamine recapitulated meclizine-induced protection both in vitro and in vivo.
Topics: Acute Kidney Injury; Adenosine Triphosphate; Animals; Cell Respiration; Cytochromes c; Deoxyglucose; Disease Models, Animal; Epithelial Cells; Ethanolamines; Galactose; Glycolysis; Humans; Inflammation; Ischemic Preconditioning; Kidney; Kidney Tubules; L-Lactate Dehydrogenase; LLC-PK1 Cells; Male; Meclizine; Mice, Inbred C57BL; Mitochondria; Protective Agents; Reperfusion Injury; Sodium Cyanide; Swine; Up-Regulation
PubMed: 26501107
DOI: 10.1016/j.ebiom.2015.07.035