The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Kinji Ohno - One of the best experts on this subject based on the ideXlab platform.
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Clinical dosage of Meclozine promotes longitudinal bone growth, bone volume, and trabecular bone quality in transgenic mice with achondroplasia
Scientific reports, 2017Co-Authors: Masaki Matsushita, Naoki Ishiguro, Kinji Ohno, Kenichi Mishima, Ryusaku Esaki, Hiroshi KitohAbstract: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 (Cmax) 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.
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Maternal administration of Meclozine for the treatment of foramen magnum stenosis in transgenic mice with achondroplasia.
Journal of neurosurgery. Pediatrics, 2016Co-Authors: Masaki Matsushita, Naoki Ishiguro, Kinji Ohno, Kenichi Mishima, Ryusaku Esaki, Hiroshi KitohAbstract:OBJECTIVE Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia caused by gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Foramen magnum stenosis (FMS) is one of the serious neurological complications in ACH. Through comprehensive drug screening, the authors identified that Meclozine, an over-the-counter drug for motion sickness, inhibited activation of FGFR3 signaling. Oral administration of Meclozine to the growing ACH mice promoted longitudinal bone growth, but it did not prevent FMS. In the current study, the authors evaluated the effects of maternal administration of Meclozine on FMS in ACH mice. METHODS The area of the foramen magnum was measured in 17-day-old Fgfr3ach mice and wild-type mice using micro-CT scanning. Meclozine was administered to the pregnant mice carrying Fgfr3ach offspring from embryonic Day (ED) 14.5 to postnatal Day (PD) 4.5. Spheno-occipital and anterior intraoccipital synchondroses were histologically examined, and the bony...
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Meclozine Promotes Longitudinal Skeletal Growth in Transgenic Mice with Achondroplasia Carrying a Gain-of-Function Mutation in the FGFR3 Gene
Endocrinology, 2014Co-Authors: Masaki Matsushita, Satoru Hasegawa, Hiroshi Kitoh, Kensaku Mori, Bisei Ohkawara, Akihiro Yasoda, Akio Masuda, Naoki Ishiguro, Kinji OhnoAbstract:Achondroplasia (ACH) is one of the most common skeletal dysplasias causing short stature owing to a gain-of-function mutation in the FGFR3 gene, which encodes the fibroblast growth factor receptor 3. We found that Meclozine, an over-the-counter drug for motion sickness, inhibited elevated FGFR3 signaling in chondrocytic cells. To examine the feasibility of Meclozine administration in clinical settings, we investigated the effects of Meclozine on ACH model mice carrying the heterozygous Fgfr3(ach) transgene. We quantified the effect of Meclozine in bone explant cultures employing limb rudiments isolated from developing embryonic tibiae from Fgfr3(ach) mice. We found that Meclozine significantly increased the full-length and cartilaginous primordia of embryonic tibiae isolated from Fgfr3(ach) mice. We next analyzed the skeletal phenotypes of growing Fgfr3(ach) mice and wild-type mice with or without Meclozine treatment. In Fgfr3(ach) mice, Meclozine significantly increased the body length after 2 weeks of administration. At skeletal maturity, the bone lengths including the cranium, radius, ulna, femur, tibia, and vertebrae were significantly longer in Meclozine-treated Fgfr3(ach) mice than in untreated Fgfr3(ach) mice. Interestingly, Meclozine also increased bone growth in wild-type mice. The plasma concentration of Meclozine during treatment was within the range that has been used in clinical settings for motion sickness. Increased longitudinal bone growth in Fgfr3(ach) mice by oral administration of Meclozine in a growth period suggests potential clinical feasibility of Meclozine for the improvement of short stature in ACH.
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Meclozine Facilitates Proliferation and Differentiation of Chondrocytes by Attenuating Abnormally Activated FGFR3 Signaling in Achondroplasia
PloS one, 2013Co-Authors: Masaki Matsushita, Hiroshi Kitoh, Bisei Ohkawara, Akio Masuda, Naoki Ishiguro, Kenichi Mishima, Hiroshi Kaneko, Mikako Ito, Kinji OhnoAbstract:Achondroplasia (ACH) is one of the most common skeletal dysplasias with short stature caused by gain-of-function mutations in FGFR3 encoding the fibroblast growth factor receptor 3. We used the drug repositioning strategy to identify an FDA-approved drug that suppresses abnormally activated FGFR3 signaling in ACH. We found that Meclozine, an anti-histamine drug that has long been used for motion sickness, facilitates chondrocyte proliferation and mitigates loss of extracellular matrix in FGF2-treated rat chondrosarcoma (RCS) cells. Meclozine also ameliorated abnormally suppressed proliferation of human chondrosarcoma (HCS-2/8) cells that were infected with lentivirus expressing constitutively active mutants of FGFR3-K650E causing thanatophoric dysplasia, FGFR3-K650M causing SADDAN, and FGFR3-G380R causing ACH. Similarly, Meclozine alleviated abnormally suppressed differentiation of ATDC5 chondrogenic cells expressing FGFR3-K650E and -G380R in micromass culture. We also confirmed that Meclozine alleviates FGF2-mediated longitudinal growth inhibition of embryonic tibia in bone explant culture. Interestingly, Meclozine enhanced growth of embryonic tibia in explant culture even in the absence of FGF2 treatment. Analyses of intracellular FGFR3 signaling disclosed that Meclozine downregulates phosphorylation of ERK but not of MEK in FGF2-treated RCS cells. Similarly, Meclozine enhanced proliferation of RCS cells expressing constitutively active mutants of MEK and RAF but not of ERK, which suggests that Meclozine downregulates the FGFR3 signaling by possibly attenuating ERK phosphorylation. We used the C-natriuretic peptide (CNP) as a potent inhibitor of the FGFR3 signaling throughout our experiments, and found that Meclozine was as efficient as CNP in attenuating the abnormal FGFR3 signaling. We propose that Meclozine is a potential therapeutic agent for treating ACH and other FGFR3-related skeletal dysplasias.
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Meclozine attenuates FGFR3-mediated ERK phosphorylation in FGF2-treated RCS cells.
2013Co-Authors: Masaki Matsushita, Hiroshi Kitoh, Bisei Ohkawara, Akio Masuda, Naoki Ishiguro, Kenichi Mishima, Hiroshi Kaneko, Mikako Ito, Kinji OhnoAbstract:(A) RCS cells were pretreated with 20 µM Meclozine for 30 minutes before adding 5 ng/ml FGF2 and the levels of ERK and MEK phosphorylation were determined by Western blotting. As a loading control, the membranes were reprobed with antibodies against MEK and ERK. Meclozine suppressed FGF2-mediated ERK phosphorylation but not MEK phosphorylation after adding FGF2. (B) RCS cells were infected by lentivirus expressing constitutively active (ca) ERK, MEK, and RAF mutants. Cells were treated with 20 µM Meclozine and their proliferation potencies were quantified using the MTS assay. The 490-nm absorbance was normalized to that without Meclozine and the mean and SD are presented (n = 3). Meclozine rescued caMEK- and caRAF-mediated growth arrest, but had no effect on caERK-mediated growth arrest.
Masaki Matsushita - One of the best experts on this subject based on the ideXlab platform.
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Clinical dosage of Meclozine promotes longitudinal bone growth, bone volume, and trabecular bone quality in transgenic mice with achondroplasia
Scientific reports, 2017Co-Authors: Masaki Matsushita, Naoki Ishiguro, Kinji Ohno, Kenichi Mishima, Ryusaku Esaki, Hiroshi KitohAbstract: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 (Cmax) 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.
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Maternal administration of Meclozine for the treatment of foramen magnum stenosis in transgenic mice with achondroplasia.
Journal of neurosurgery. Pediatrics, 2016Co-Authors: Masaki Matsushita, Naoki Ishiguro, Kinji Ohno, Kenichi Mishima, Ryusaku Esaki, Hiroshi KitohAbstract:OBJECTIVE Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia caused by gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Foramen magnum stenosis (FMS) is one of the serious neurological complications in ACH. Through comprehensive drug screening, the authors identified that Meclozine, an over-the-counter drug for motion sickness, inhibited activation of FGFR3 signaling. Oral administration of Meclozine to the growing ACH mice promoted longitudinal bone growth, but it did not prevent FMS. In the current study, the authors evaluated the effects of maternal administration of Meclozine on FMS in ACH mice. METHODS The area of the foramen magnum was measured in 17-day-old Fgfr3ach mice and wild-type mice using micro-CT scanning. Meclozine was administered to the pregnant mice carrying Fgfr3ach offspring from embryonic Day (ED) 14.5 to postnatal Day (PD) 4.5. Spheno-occipital and anterior intraoccipital synchondroses were histologically examined, and the bony...
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Meclozine Facilitates Proliferation and Differentiation of Chondrocytes by Attenuating Abnormally Activated FGFR3 Signaling in Achondroplasia
2016Co-Authors: Masaki Matsushita, Hiroshi Kitoh, Bisei Ohkawara, Kenichi Mishima, Hiroshi KanekoAbstract:Achondroplasia (ACH) is one of the most common skeletal dysplasias with short stature caused by gain-of-function mutations in FGFR3 encoding the fibroblast growth factor receptor 3. We used the drug repositioning strategy to identify an FDA-approved drug that suppresses abnormally activated FGFR3 signaling in ACH. We found that Meclozine, an anti-histamine drug that has long been used for motion sickness, facilitates chondrocyte proliferation and mitigates loss of extracellular matrix in FGF2-treated rat chondrosarcoma (RCS) cells. Meclozine also ameliorated abnormally suppressed proliferation of human chondrosarcoma (HCS-2/8) cells that were infected with lentivirus expressing constitutively active mutants of FGFR3-K650E causing thanatophoric dysplasia, FGFR3-K650M causing SADDAN, and FGFR3-G380R causing ACH. Similarly, Meclozine alleviated abnormally suppressed differentiation of ATDC5 chondrogenic cells expressing FGFR3-K650E and-G380R in micromass culture. We also confirmed that Meclozine alleviates FGF2-mediated longitudinal growth inhibition of embryonic tibia in bone explant culture. Interestingly, Meclozine enhanced growth of embryonic tibia in explant culture even in the absence of FGF2 treatment. Analyses of intracellular FGFR3 signaling disclosed that Meclozine downregulates phosphorylation of ERK but not of MEK in FGF2-treated RCS cells. Similarly, Meclozine enhanced proliferation of RCS cells expressing constitutively active mutants of MEK and RAF but not of ERK, which suggests that Meclozine downregulates the FGFR3 signaling by possibly attenuating ERK phosphorylation. We used the C-natriureti
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Meclozine Promotes Longitudinal Skeletal Growth in Transgenic Mice with Achondroplasia Carrying a Gain-of-Function Mutation in the FGFR3 Gene
Endocrinology, 2014Co-Authors: Masaki Matsushita, Satoru Hasegawa, Hiroshi Kitoh, Kensaku Mori, Bisei Ohkawara, Akihiro Yasoda, Akio Masuda, Naoki Ishiguro, Kinji OhnoAbstract:Achondroplasia (ACH) is one of the most common skeletal dysplasias causing short stature owing to a gain-of-function mutation in the FGFR3 gene, which encodes the fibroblast growth factor receptor 3. We found that Meclozine, an over-the-counter drug for motion sickness, inhibited elevated FGFR3 signaling in chondrocytic cells. To examine the feasibility of Meclozine administration in clinical settings, we investigated the effects of Meclozine on ACH model mice carrying the heterozygous Fgfr3(ach) transgene. We quantified the effect of Meclozine in bone explant cultures employing limb rudiments isolated from developing embryonic tibiae from Fgfr3(ach) mice. We found that Meclozine significantly increased the full-length and cartilaginous primordia of embryonic tibiae isolated from Fgfr3(ach) mice. We next analyzed the skeletal phenotypes of growing Fgfr3(ach) mice and wild-type mice with or without Meclozine treatment. In Fgfr3(ach) mice, Meclozine significantly increased the body length after 2 weeks of administration. At skeletal maturity, the bone lengths including the cranium, radius, ulna, femur, tibia, and vertebrae were significantly longer in Meclozine-treated Fgfr3(ach) mice than in untreated Fgfr3(ach) mice. Interestingly, Meclozine also increased bone growth in wild-type mice. The plasma concentration of Meclozine during treatment was within the range that has been used in clinical settings for motion sickness. Increased longitudinal bone growth in Fgfr3(ach) mice by oral administration of Meclozine in a growth period suggests potential clinical feasibility of Meclozine for the improvement of short stature in ACH.
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Meclozine Facilitates Proliferation and Differentiation of Chondrocytes by Attenuating Abnormally Activated FGFR3 Signaling in Achondroplasia
PloS one, 2013Co-Authors: Masaki Matsushita, Hiroshi Kitoh, Bisei Ohkawara, Akio Masuda, Naoki Ishiguro, Kenichi Mishima, Hiroshi Kaneko, Mikako Ito, Kinji OhnoAbstract:Achondroplasia (ACH) is one of the most common skeletal dysplasias with short stature caused by gain-of-function mutations in FGFR3 encoding the fibroblast growth factor receptor 3. We used the drug repositioning strategy to identify an FDA-approved drug that suppresses abnormally activated FGFR3 signaling in ACH. We found that Meclozine, an anti-histamine drug that has long been used for motion sickness, facilitates chondrocyte proliferation and mitigates loss of extracellular matrix in FGF2-treated rat chondrosarcoma (RCS) cells. Meclozine also ameliorated abnormally suppressed proliferation of human chondrosarcoma (HCS-2/8) cells that were infected with lentivirus expressing constitutively active mutants of FGFR3-K650E causing thanatophoric dysplasia, FGFR3-K650M causing SADDAN, and FGFR3-G380R causing ACH. Similarly, Meclozine alleviated abnormally suppressed differentiation of ATDC5 chondrogenic cells expressing FGFR3-K650E and -G380R in micromass culture. We also confirmed that Meclozine alleviates FGF2-mediated longitudinal growth inhibition of embryonic tibia in bone explant culture. Interestingly, Meclozine enhanced growth of embryonic tibia in explant culture even in the absence of FGF2 treatment. Analyses of intracellular FGFR3 signaling disclosed that Meclozine downregulates phosphorylation of ERK but not of MEK in FGF2-treated RCS cells. Similarly, Meclozine enhanced proliferation of RCS cells expressing constitutively active mutants of MEK and RAF but not of ERK, which suggests that Meclozine downregulates the FGFR3 signaling by possibly attenuating ERK phosphorylation. We used the C-natriuretic peptide (CNP) as a potent inhibitor of the FGFR3 signaling throughout our experiments, and found that Meclozine was as efficient as CNP in attenuating the abnormal FGFR3 signaling. We propose that Meclozine is a potential therapeutic agent for treating ACH and other FGFR3-related skeletal dysplasias.
Hiroshi Kitoh - One of the best experts on this subject based on the ideXlab platform.
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Clinical dosage of Meclozine promotes longitudinal bone growth, bone volume, and trabecular bone quality in transgenic mice with achondroplasia
Scientific reports, 2017Co-Authors: Masaki Matsushita, Naoki Ishiguro, Kinji Ohno, Kenichi Mishima, Ryusaku Esaki, Hiroshi KitohAbstract: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 (Cmax) 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.
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Maternal administration of Meclozine for the treatment of foramen magnum stenosis in transgenic mice with achondroplasia.
Journal of neurosurgery. Pediatrics, 2016Co-Authors: Masaki Matsushita, Naoki Ishiguro, Kinji Ohno, Kenichi Mishima, Ryusaku Esaki, Hiroshi KitohAbstract:OBJECTIVE Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia caused by gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Foramen magnum stenosis (FMS) is one of the serious neurological complications in ACH. Through comprehensive drug screening, the authors identified that Meclozine, an over-the-counter drug for motion sickness, inhibited activation of FGFR3 signaling. Oral administration of Meclozine to the growing ACH mice promoted longitudinal bone growth, but it did not prevent FMS. In the current study, the authors evaluated the effects of maternal administration of Meclozine on FMS in ACH mice. METHODS The area of the foramen magnum was measured in 17-day-old Fgfr3ach mice and wild-type mice using micro-CT scanning. Meclozine was administered to the pregnant mice carrying Fgfr3ach offspring from embryonic Day (ED) 14.5 to postnatal Day (PD) 4.5. Spheno-occipital and anterior intraoccipital synchondroses were histologically examined, and the bony...
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Meclozine Facilitates Proliferation and Differentiation of Chondrocytes by Attenuating Abnormally Activated FGFR3 Signaling in Achondroplasia
2016Co-Authors: Masaki Matsushita, Hiroshi Kitoh, Bisei Ohkawara, Kenichi Mishima, Hiroshi KanekoAbstract:Achondroplasia (ACH) is one of the most common skeletal dysplasias with short stature caused by gain-of-function mutations in FGFR3 encoding the fibroblast growth factor receptor 3. We used the drug repositioning strategy to identify an FDA-approved drug that suppresses abnormally activated FGFR3 signaling in ACH. We found that Meclozine, an anti-histamine drug that has long been used for motion sickness, facilitates chondrocyte proliferation and mitigates loss of extracellular matrix in FGF2-treated rat chondrosarcoma (RCS) cells. Meclozine also ameliorated abnormally suppressed proliferation of human chondrosarcoma (HCS-2/8) cells that were infected with lentivirus expressing constitutively active mutants of FGFR3-K650E causing thanatophoric dysplasia, FGFR3-K650M causing SADDAN, and FGFR3-G380R causing ACH. Similarly, Meclozine alleviated abnormally suppressed differentiation of ATDC5 chondrogenic cells expressing FGFR3-K650E and-G380R in micromass culture. We also confirmed that Meclozine alleviates FGF2-mediated longitudinal growth inhibition of embryonic tibia in bone explant culture. Interestingly, Meclozine enhanced growth of embryonic tibia in explant culture even in the absence of FGF2 treatment. Analyses of intracellular FGFR3 signaling disclosed that Meclozine downregulates phosphorylation of ERK but not of MEK in FGF2-treated RCS cells. Similarly, Meclozine enhanced proliferation of RCS cells expressing constitutively active mutants of MEK and RAF but not of ERK, which suggests that Meclozine downregulates the FGFR3 signaling by possibly attenuating ERK phosphorylation. We used the C-natriureti
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Meclozine Promotes Longitudinal Skeletal Growth in Transgenic Mice with Achondroplasia Carrying a Gain-of-Function Mutation in the FGFR3 Gene
Endocrinology, 2014Co-Authors: Masaki Matsushita, Satoru Hasegawa, Hiroshi Kitoh, Kensaku Mori, Bisei Ohkawara, Akihiro Yasoda, Akio Masuda, Naoki Ishiguro, Kinji OhnoAbstract:Achondroplasia (ACH) is one of the most common skeletal dysplasias causing short stature owing to a gain-of-function mutation in the FGFR3 gene, which encodes the fibroblast growth factor receptor 3. We found that Meclozine, an over-the-counter drug for motion sickness, inhibited elevated FGFR3 signaling in chondrocytic cells. To examine the feasibility of Meclozine administration in clinical settings, we investigated the effects of Meclozine on ACH model mice carrying the heterozygous Fgfr3(ach) transgene. We quantified the effect of Meclozine in bone explant cultures employing limb rudiments isolated from developing embryonic tibiae from Fgfr3(ach) mice. We found that Meclozine significantly increased the full-length and cartilaginous primordia of embryonic tibiae isolated from Fgfr3(ach) mice. We next analyzed the skeletal phenotypes of growing Fgfr3(ach) mice and wild-type mice with or without Meclozine treatment. In Fgfr3(ach) mice, Meclozine significantly increased the body length after 2 weeks of administration. At skeletal maturity, the bone lengths including the cranium, radius, ulna, femur, tibia, and vertebrae were significantly longer in Meclozine-treated Fgfr3(ach) mice than in untreated Fgfr3(ach) mice. Interestingly, Meclozine also increased bone growth in wild-type mice. The plasma concentration of Meclozine during treatment was within the range that has been used in clinical settings for motion sickness. Increased longitudinal bone growth in Fgfr3(ach) mice by oral administration of Meclozine in a growth period suggests potential clinical feasibility of Meclozine for the improvement of short stature in ACH.
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Meclozine Facilitates Proliferation and Differentiation of Chondrocytes by Attenuating Abnormally Activated FGFR3 Signaling in Achondroplasia
PloS one, 2013Co-Authors: Masaki Matsushita, Hiroshi Kitoh, Bisei Ohkawara, Akio Masuda, Naoki Ishiguro, Kenichi Mishima, Hiroshi Kaneko, Mikako Ito, Kinji OhnoAbstract:Achondroplasia (ACH) is one of the most common skeletal dysplasias with short stature caused by gain-of-function mutations in FGFR3 encoding the fibroblast growth factor receptor 3. We used the drug repositioning strategy to identify an FDA-approved drug that suppresses abnormally activated FGFR3 signaling in ACH. We found that Meclozine, an anti-histamine drug that has long been used for motion sickness, facilitates chondrocyte proliferation and mitigates loss of extracellular matrix in FGF2-treated rat chondrosarcoma (RCS) cells. Meclozine also ameliorated abnormally suppressed proliferation of human chondrosarcoma (HCS-2/8) cells that were infected with lentivirus expressing constitutively active mutants of FGFR3-K650E causing thanatophoric dysplasia, FGFR3-K650M causing SADDAN, and FGFR3-G380R causing ACH. Similarly, Meclozine alleviated abnormally suppressed differentiation of ATDC5 chondrogenic cells expressing FGFR3-K650E and -G380R in micromass culture. We also confirmed that Meclozine alleviates FGF2-mediated longitudinal growth inhibition of embryonic tibia in bone explant culture. Interestingly, Meclozine enhanced growth of embryonic tibia in explant culture even in the absence of FGF2 treatment. Analyses of intracellular FGFR3 signaling disclosed that Meclozine downregulates phosphorylation of ERK but not of MEK in FGF2-treated RCS cells. Similarly, Meclozine enhanced proliferation of RCS cells expressing constitutively active mutants of MEK and RAF but not of ERK, which suggests that Meclozine downregulates the FGFR3 signaling by possibly attenuating ERK phosphorylation. We used the C-natriuretic peptide (CNP) as a potent inhibitor of the FGFR3 signaling throughout our experiments, and found that Meclozine was as efficient as CNP in attenuating the abnormal FGFR3 signaling. We propose that Meclozine is a potential therapeutic agent for treating ACH and other FGFR3-related skeletal dysplasias.
Roman Grabic - One of the best experts on this subject based on the ideXlab platform.
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Frequency and use of pharmaceuticals in selected Slovakian town via wastewater analysis
Monatshefte für Chemie - Chemical Monthly, 2017Co-Authors: Milota Fáberová, Roman Grabic, Igor Bodík, Lucia Ivanová, Tomáš MackuľakAbstract:The aim of this study was to analyze pharmaceuticals in wastewater from eight selected wastewater treatment plants (WWTPs) in Slovakia. We analyzed 125 pharmaceutical compounds and selected 14 from the most common therapeutic classes, i.e., antibiotics (ciprofloxacin, azithromycin, and clarithromycin), antifungal (fluconazole and clotrimazole), antihistaminic (fexofenadine and Meclozine), antithrombotic (dipyridamole), hypertension (eprosartan, telmisartan, and valsartan), analgetics (diclofenac), and psychiatric (tramadol and carbamazepine). The results show the presence of pharmaceutical compounds in wastewater in concentrations ranging from low ng dm^−3 to a few µg dm^−3. The highest maximum concentrations were detected for cardiovascular pharmaceuticals (32.98 µg dm^−3 valsartan; 17.10 µg dm^−3 telmisartan) and antibiotics (25.66 µg dm^−3 ciprofloxacin, 13.98 µg dm^−3 clarithromycin). We also analyzed the daily load of pharmaceuticals compounds in Slovak WWTPs. The study shows that telmisartan has the highest median load (2270 mg/day/1000 inhabitants) followed by ciprofloxacin (2210 mg/day/1000 inhabitants) in Piešťany town. Graphical abstract
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seasonal changes in antibiotics antidepressants psychiatric drugs antihistamines and lipid regulators in a wastewater treatment plant
Chemosphere, 2014Co-Authors: Oksana Golovko, Vimal Kumar, Ganna Fedorova, Tomas Randak, Roman GrabicAbstract:Abstract Seasonal changes in the concentration of 21 pharmaceuticals in a wastewater treatment plant (WWTP) in Ceske Budějovice were investigated over 12 months. The target compounds were 10 antibiotics, 4 antidepressants, 3 psychiatric drugs, 2 antihistamines and 2 lipid regulators. 272 Wastewater samples (136 influents and 136 effluents) were collected from March 2011 to February 2012 and analyzed using two-dimensional liquid chromatography coupled with tandem mass spectrometry. All studied pharmaceuticals were frequently detected in both the influent and the effluent wastewater samples, except for Meclozine, which was only found in the influent. The mean concentration of pharmaceuticals varied from 0.006 μg L −1 to 1.48 μg L −1 in the influent and from 0.003 μg L −1 to 0.93 μg L −1 in the effluent. The concentration of most pharmaceuticals was higher during winter.
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Seasonal changes in antibiotics, antidepressants/psychiatric drugs, antihistamines and lipid regulators in a wastewater treatment plant
Chemosphere, 2014Co-Authors: Oksana Golovko, Vimal Kumar, Ganna Fedorova, Tomas Randak, Roman GrabicAbstract:Abstract Seasonal changes in the concentration of 21 pharmaceuticals in a wastewater treatment plant (WWTP) in Ceske Budějovice were investigated over 12 months. The target compounds were 10 antibiotics, 4 antidepressants, 3 psychiatric drugs, 2 antihistamines and 2 lipid regulators. 272 Wastewater samples (136 influents and 136 effluents) were collected from March 2011 to February 2012 and analyzed using two-dimensional liquid chromatography coupled with tandem mass spectrometry. All studied pharmaceuticals were frequently detected in both the influent and the effluent wastewater samples, except for Meclozine, which was only found in the influent. The mean concentration of pharmaceuticals varied from 0.006 μg L −1 to 1.48 μg L −1 in the influent and from 0.003 μg L −1 to 0.93 μg L −1 in the effluent. The concentration of most pharmaceuticals was higher during winter.
Naoki Ishiguro - One of the best experts on this subject based on the ideXlab platform.
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Clinical dosage of Meclozine promotes longitudinal bone growth, bone volume, and trabecular bone quality in transgenic mice with achondroplasia
Scientific reports, 2017Co-Authors: Masaki Matsushita, Naoki Ishiguro, Kinji Ohno, Kenichi Mishima, Ryusaku Esaki, Hiroshi KitohAbstract: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 (Cmax) 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.
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Maternal administration of Meclozine for the treatment of foramen magnum stenosis in transgenic mice with achondroplasia.
Journal of neurosurgery. Pediatrics, 2016Co-Authors: Masaki Matsushita, Naoki Ishiguro, Kinji Ohno, Kenichi Mishima, Ryusaku Esaki, Hiroshi KitohAbstract:OBJECTIVE Achondroplasia (ACH) is the most common short-limbed skeletal dysplasia caused by gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Foramen magnum stenosis (FMS) is one of the serious neurological complications in ACH. Through comprehensive drug screening, the authors identified that Meclozine, an over-the-counter drug for motion sickness, inhibited activation of FGFR3 signaling. Oral administration of Meclozine to the growing ACH mice promoted longitudinal bone growth, but it did not prevent FMS. In the current study, the authors evaluated the effects of maternal administration of Meclozine on FMS in ACH mice. METHODS The area of the foramen magnum was measured in 17-day-old Fgfr3ach mice and wild-type mice using micro-CT scanning. Meclozine was administered to the pregnant mice carrying Fgfr3ach offspring from embryonic Day (ED) 14.5 to postnatal Day (PD) 4.5. Spheno-occipital and anterior intraoccipital synchondroses were histologically examined, and the bony...
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Meclozine Promotes Longitudinal Skeletal Growth in Transgenic Mice with Achondroplasia Carrying a Gain-of-Function Mutation in the FGFR3 Gene
Endocrinology, 2014Co-Authors: Masaki Matsushita, Satoru Hasegawa, Hiroshi Kitoh, Kensaku Mori, Bisei Ohkawara, Akihiro Yasoda, Akio Masuda, Naoki Ishiguro, Kinji OhnoAbstract:Achondroplasia (ACH) is one of the most common skeletal dysplasias causing short stature owing to a gain-of-function mutation in the FGFR3 gene, which encodes the fibroblast growth factor receptor 3. We found that Meclozine, an over-the-counter drug for motion sickness, inhibited elevated FGFR3 signaling in chondrocytic cells. To examine the feasibility of Meclozine administration in clinical settings, we investigated the effects of Meclozine on ACH model mice carrying the heterozygous Fgfr3(ach) transgene. We quantified the effect of Meclozine in bone explant cultures employing limb rudiments isolated from developing embryonic tibiae from Fgfr3(ach) mice. We found that Meclozine significantly increased the full-length and cartilaginous primordia of embryonic tibiae isolated from Fgfr3(ach) mice. We next analyzed the skeletal phenotypes of growing Fgfr3(ach) mice and wild-type mice with or without Meclozine treatment. In Fgfr3(ach) mice, Meclozine significantly increased the body length after 2 weeks of administration. At skeletal maturity, the bone lengths including the cranium, radius, ulna, femur, tibia, and vertebrae were significantly longer in Meclozine-treated Fgfr3(ach) mice than in untreated Fgfr3(ach) mice. Interestingly, Meclozine also increased bone growth in wild-type mice. The plasma concentration of Meclozine during treatment was within the range that has been used in clinical settings for motion sickness. Increased longitudinal bone growth in Fgfr3(ach) mice by oral administration of Meclozine in a growth period suggests potential clinical feasibility of Meclozine for the improvement of short stature in ACH.
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Meclozine Facilitates Proliferation and Differentiation of Chondrocytes by Attenuating Abnormally Activated FGFR3 Signaling in Achondroplasia
PloS one, 2013Co-Authors: Masaki Matsushita, Hiroshi Kitoh, Bisei Ohkawara, Akio Masuda, Naoki Ishiguro, Kenichi Mishima, Hiroshi Kaneko, Mikako Ito, Kinji OhnoAbstract:Achondroplasia (ACH) is one of the most common skeletal dysplasias with short stature caused by gain-of-function mutations in FGFR3 encoding the fibroblast growth factor receptor 3. We used the drug repositioning strategy to identify an FDA-approved drug that suppresses abnormally activated FGFR3 signaling in ACH. We found that Meclozine, an anti-histamine drug that has long been used for motion sickness, facilitates chondrocyte proliferation and mitigates loss of extracellular matrix in FGF2-treated rat chondrosarcoma (RCS) cells. Meclozine also ameliorated abnormally suppressed proliferation of human chondrosarcoma (HCS-2/8) cells that were infected with lentivirus expressing constitutively active mutants of FGFR3-K650E causing thanatophoric dysplasia, FGFR3-K650M causing SADDAN, and FGFR3-G380R causing ACH. Similarly, Meclozine alleviated abnormally suppressed differentiation of ATDC5 chondrogenic cells expressing FGFR3-K650E and -G380R in micromass culture. We also confirmed that Meclozine alleviates FGF2-mediated longitudinal growth inhibition of embryonic tibia in bone explant culture. Interestingly, Meclozine enhanced growth of embryonic tibia in explant culture even in the absence of FGF2 treatment. Analyses of intracellular FGFR3 signaling disclosed that Meclozine downregulates phosphorylation of ERK but not of MEK in FGF2-treated RCS cells. Similarly, Meclozine enhanced proliferation of RCS cells expressing constitutively active mutants of MEK and RAF but not of ERK, which suggests that Meclozine downregulates the FGFR3 signaling by possibly attenuating ERK phosphorylation. We used the C-natriuretic peptide (CNP) as a potent inhibitor of the FGFR3 signaling throughout our experiments, and found that Meclozine was as efficient as CNP in attenuating the abnormal FGFR3 signaling. We propose that Meclozine is a potential therapeutic agent for treating ACH and other FGFR3-related skeletal dysplasias.
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Meclozine attenuates FGFR3-mediated ERK phosphorylation in FGF2-treated RCS cells.
2013Co-Authors: Masaki Matsushita, Hiroshi Kitoh, Bisei Ohkawara, Akio Masuda, Naoki Ishiguro, Kenichi Mishima, Hiroshi Kaneko, Mikako Ito, Kinji OhnoAbstract:(A) RCS cells were pretreated with 20 µM Meclozine for 30 minutes before adding 5 ng/ml FGF2 and the levels of ERK and MEK phosphorylation were determined by Western blotting. As a loading control, the membranes were reprobed with antibodies against MEK and ERK. Meclozine suppressed FGF2-mediated ERK phosphorylation but not MEK phosphorylation after adding FGF2. (B) RCS cells were infected by lentivirus expressing constitutively active (ca) ERK, MEK, and RAF mutants. Cells were treated with 20 µM Meclozine and their proliferation potencies were quantified using the MTS assay. The 490-nm absorbance was normalized to that without Meclozine and the mean and SD are presented (n = 3). Meclozine rescued caMEK- and caRAF-mediated growth arrest, but had no effect on caERK-mediated growth arrest.