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Christoph A. Karle - One of the best experts on this subject based on the ideXlab platform.

  • Inhibition of cardiac hERG potassium channels by Tetracyclic Antidepressant mianserin
    Naunyn-Schmiedeberg's archives of pharmacology, 2008
    Co-Authors: Daniel Scherer, Sven Kathöfer, Edgar Zitron, Eberhard P. Scholz, Dierk Thomas, Hugo A. Katus, Alexander Bauer, Katharina Von Löwenstern, Ramona Bloehs, Christoph A. Karle
    Abstract:

    The Antidepressant mianserin exhibits a Tetracyclic structure that is different from typical tricyclic Antidepressants (TCA) and that of selective serotonin reuptake inhibitors. In comparison to the older TCA, mianserin has been shown to have a superior risk profile regarding proarrhythmic effects, both in vitro and in vivo. However, the underlying molecular electrophysiological basis has not been elucidated to date. Therefore, we studied the effects of mianserin on cardiac hERG potassium channels, the predominant target of drug-induced proarrhythmia. HERG channels were expressed in the Xenopus oocyte expression system and in human embryonic kidney (HEK) cells and currents were measured with two-microelectrode voltage-clamp and whole-cell patch-clamp, respectively. Mianserin inhibited hERG currents in a dose-dependent manner with an IC50 of 3.2 μmol/l in HEK cells. Onset of blockade was slow and the inhibitory effect was not reversible upon wash-out of the drug. In hERG channel mutants, Y652A and F656A, lacking aromatic residues in the S6 domain, the effect of mianserin was significantly reduced in comparison to the wild type. Mianserin inhibited hERG currents in the open and inactivated state, but not in the closed states. HERG inactivation kinetics were significantly altered by mianserin without marked effects on channel activation kinetics. The inhibitory effect was not frequency dependent. In conclusion, mianserin is a low-affinity hERG-blocking agent. However, taken together with the lack of APD-prolongation shown in other studies, mianserin seems to have a good safety profile. Lack of consistent QT prolonging effects of mianserin in previous studies may therefore be linked to additional effects such as inhibition of other cardiac ion channels. However, as demonstrated by clinical case reports, mianserin can induce proarrhythmic effects in susceptible patients. Therefore, in patients with complex co-medication (i.e., additional hERG-blocking agents) and in patients with risk factors for acquired long QT syndrome as well as in cases of overdose, adequate monitoring should be recommended.

  • Atypical Tetracyclic Antidepressant maprotiline is an antagonist at cardiac hERG potassium channels.
    Naunyn-Schmiedeberg's Archives of Pharmacology, 2006
    Co-Authors: Claudia Kiesecker, Markus Alter, Sven Kathöfer, Edgar Zitron, Eberhard P. Scholz, Dierk Thomas, Jörg Kreuzer, Hugo A. Katus, Alexander Bauer, Christoph A. Karle
    Abstract:

    Maprotiline is an Antidepressant compound with an atypical Tetracyclic structure that is widely used in elderly patients due to its favourable side-effect profile. However, there have been reports of proarrhythmia associated with maprotiline and in vitro studies of its electrophysiological properties have been lacking. Therefore, we characterised the effects of maprotiline on cardiac hERG channels. hERG channels were expressed in HEK cells and in the Xenopus oocyte expression system. Currents were measured using a whole-cell patch clamp and a two-microelectrode voltage-clamp. Maprotiline inhibited hERG currents with an IC50 of 8.2 μmol/l in HEK cells and 29.2 μmol/l in Xenopus oocytes. Onset of the effect was rather slow and took several minutes. No wash-out of effect was observed. Maprotiline blocked hERG channels in the open and inactivated states, but not in the closed states. In mutant hERG channels Y652A and F656A, the effect was markedly attenuated (hERG-F656A) or completely abolished (hERG-Y652A). Voltage dependence of hERG current activation and inactivation was not affected by maprotiline. hERG inactivation was accelerated at positive potentials. The effect of maprotiline on hERG currents was voltage-dependent with a marked reduction at a more positive potential. hERG blockade by maprotiline was not frequency-dependent. Maprotiline is an antagonist of cardiac hERG potassium channels that preferably accesses the putative pore binding site Y652/F656. Although the affinity of maprotiline to hERG channels is low, its use in patients with risk factors for acquired long QT syndrome should be monitored appropriately.

Lili Zhu - One of the best experts on this subject based on the ideXlab platform.

  • Maprotiline Prevents Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats.
    Frontiers in Pharmacology, 2018
    Co-Authors: Yi Tong, Qian Jiao, Yuanru Liu, Rui Wang, Lili Zhu
    Abstract:

    Pulmonary arterial hypertension (PAH) is a progressive disease caused by increased pulmonary artery pressure and pulmonary vascular resistance, eventually leading to right heart failure until death. Soluble guanylate cyclase (sGC) has been regarded as an attractive drug target in treating PAH. In this study, we discovered that maprotiline, a Tetracyclic Antidepressant, bound to the full-length recombinant sGC with a high affinity (KD = 0.307 μM). Further study demonstrated that maprotiline concentration-dependently inhibited the proliferation of hypoxia-induced human pulmonary artery smooth muscle cells. Moreover, in a monocrotaline (MCT) rat model of PAH, maprotiline (ip, 10 mg/kg once daily) reduced pulmonary hypertension, inhibited the development of right ventricular hypertrophy and pathological changes of the pulmonary vascular remodeling. Taken together, our studies showed that maprotiline may contribute to attenuate disease progression of pulmonary hypertension.

  • Table_1_Maprotiline Prevents Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats.DOCX
    2018
    Co-Authors: Yi Tong, Qian Jiao, Yuanru Liu, Rui Wang, Lili Zhu
    Abstract:

    Pulmonary arterial hypertension (PAH) is a progressive disease caused by increased pulmonary artery pressure and pulmonary vascular resistance, eventually leading to right heart failure until death. Soluble guanylate cyclase (sGC) has been regarded as an attractive drug target in treating PAH. In this study, we discovered that maprotiline, a Tetracyclic Antidepressant, bound to the full-length recombinant sGC with a high affinity (KD = 0.307 μM). Further study demonstrated that maprotiline concentration-dependently inhibited the proliferation of hypoxia-induced human pulmonary artery smooth muscle cells. Moreover, in a monocrotaline (MCT) rat model of PAH, maprotiline (ip, 10 mg/kg once daily) reduced pulmonary hypertension, inhibited the development of right ventricular hypertrophy and pathological changes of the pulmonary vascular remodeling. Taken together, our studies showed that maprotiline may contribute to attenuate disease progression of pulmonary hypertension.

Yi Tong - One of the best experts on this subject based on the ideXlab platform.

  • Maprotiline Prevents Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats.
    Frontiers in Pharmacology, 2018
    Co-Authors: Yi Tong, Qian Jiao, Yuanru Liu, Rui Wang, Lili Zhu
    Abstract:

    Pulmonary arterial hypertension (PAH) is a progressive disease caused by increased pulmonary artery pressure and pulmonary vascular resistance, eventually leading to right heart failure until death. Soluble guanylate cyclase (sGC) has been regarded as an attractive drug target in treating PAH. In this study, we discovered that maprotiline, a Tetracyclic Antidepressant, bound to the full-length recombinant sGC with a high affinity (KD = 0.307 μM). Further study demonstrated that maprotiline concentration-dependently inhibited the proliferation of hypoxia-induced human pulmonary artery smooth muscle cells. Moreover, in a monocrotaline (MCT) rat model of PAH, maprotiline (ip, 10 mg/kg once daily) reduced pulmonary hypertension, inhibited the development of right ventricular hypertrophy and pathological changes of the pulmonary vascular remodeling. Taken together, our studies showed that maprotiline may contribute to attenuate disease progression of pulmonary hypertension.

  • Table_1_Maprotiline Prevents Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats.DOCX
    2018
    Co-Authors: Yi Tong, Qian Jiao, Yuanru Liu, Rui Wang, Lili Zhu
    Abstract:

    Pulmonary arterial hypertension (PAH) is a progressive disease caused by increased pulmonary artery pressure and pulmonary vascular resistance, eventually leading to right heart failure until death. Soluble guanylate cyclase (sGC) has been regarded as an attractive drug target in treating PAH. In this study, we discovered that maprotiline, a Tetracyclic Antidepressant, bound to the full-length recombinant sGC with a high affinity (KD = 0.307 μM). Further study demonstrated that maprotiline concentration-dependently inhibited the proliferation of hypoxia-induced human pulmonary artery smooth muscle cells. Moreover, in a monocrotaline (MCT) rat model of PAH, maprotiline (ip, 10 mg/kg once daily) reduced pulmonary hypertension, inhibited the development of right ventricular hypertrophy and pathological changes of the pulmonary vascular remodeling. Taken together, our studies showed that maprotiline may contribute to attenuate disease progression of pulmonary hypertension.

Kinji Ohno - One of the best experts on this subject based on the ideXlab platform.

  • mianserin suppresses r spondin 2 induced activation of wnt β catenin signaling in chondrocytes and prevents cartilage degradation in a rat model of osteoarthritis
    Scientific Reports, 2019
    Co-Authors: Toshiaki Okura, Bisei Ohkawara, Yasuhiko Takegami, Mikako Ito, Akio Masuda, Taisuke Seki, Naoki Ishiguro, Kinji Ohno
    Abstract:

    Aberrant activation of the Wnt/β-catenin signaling pathway promotes the progression of osteoarthritis (OA). We previously reported that R-spondin 2 (Rspo2), an activator of the Wnt/β-catenin signaling, facilitates differentiation of proliferating chondrocytes into hypertrophic chondrocytes by enhancing Wnt/β-catenin signaling in endochondral ossification. However, the role of Rspo2 in OA remains elusive. Here, we showed that the amounts of Rspo2 protein in synovial fluid were increased in OA patients. We searched for a preapproved drug that suppresses Rspo2-induced Wnt/β-catenin signaling in chondrogenic cells and reduces joint pathology in a rat model of OA. In Rspo2-treated ATDC5 cells, mianserin, a Tetracyclic Antidepressant, inhibited Wnt/β-catenin signaling, increased proteoglycan production, and upregulated chondrogenic marker genes. Mianserin suppressed Rspo2-induced accumulation of β-catenin and phosphorylation of Lrp6. We identified that mianserin blocked binding of Rspo2 to its receptor Lgr5. We also observed that intraarticular administration of mianserin suppressed β-catenin accumulation and prevented OA progression in a rat model of OA. We conclude that mianserin suppresses abnormally activated Wnt/β-catenin signaling in OA by inhibiting binding of Rspo2 to Lgr5.

  • Mianserin suppresses R-spondin 2-induced activation of Wnt/β-catenin signaling in chondrocytes and prevents cartilage degradation in a rat model of osteoarthritis
    Nature Publishing Group, 2019
    Co-Authors: Toshiaki Okura, Bisei Ohkawara, Yasuhiko Takegami, Mikako Ito, Akio Masuda, Taisuke Seki, Naoki Ishiguro, Kinji Ohno
    Abstract:

    Abstract Aberrant activation of the Wnt/β-catenin signaling pathway promotes the progression of osteoarthritis (OA). We previously reported that R-spondin 2 (Rspo2), an activator of the Wnt/β-catenin signaling, facilitates differentiation of proliferating chondrocytes into hypertrophic chondrocytes by enhancing Wnt/β-catenin signaling in endochondral ossification. However, the role of Rspo2 in OA remains elusive. Here, we showed that the amounts of Rspo2 protein in synovial fluid were increased in OA patients. We searched for a preapproved drug that suppresses Rspo2-induced Wnt/β-catenin signaling in chondrogenic cells and reduces joint pathology in a rat model of OA. In Rspo2-treated ATDC5 cells, mianserin, a Tetracyclic Antidepressant, inhibited Wnt/β-catenin signaling, increased proteoglycan production, and upregulated chondrogenic marker genes. Mianserin suppressed Rspo2-induced accumulation of β-catenin and phosphorylation of Lrp6. We identified that mianserin blocked binding of Rspo2 to its receptor Lgr5. We also observed that intraarticular administration of mianserin suppressed β-catenin accumulation and prevented OA progression in a rat model of OA. We conclude that mianserin suppresses abnormally activated Wnt/β-catenin signaling in OA by inhibiting binding of Rspo2 to Lgr5

Pierre Baumann - One of the best experts on this subject based on the ideXlab platform.

  • Steady-State Concentrations of Mirtazapine, N-Desmethylmirtazapine, 8-Hydroxymirtazapine and their Enantiomers in Relation to Cytochrome P450 2D6 Genotype, Age and Smoking Behaviour
    Clinical Pharmacokinetics, 2009
    Co-Authors: Anna-britta Lind, Margareta Reis, Michele Jonzier-perey, Kerry Powell Golay, Finn Bengtsson, Johan Ahlner, Pierre Baumann
    Abstract:

    Background and objective Mirtazapine is a Tetracyclic Antidepressant drug available as a racemic mixture of S (+)- and R (−)-mirtazapine. These enantiomers have different pharmacological properties, and both contribute to the clinical and adverse effects of the drug. Cytochrome P450 (CYP) 2D6 has been implicated in the metabolism of S (+)-mirtazapine. However, the effect of CYP2D6 on serum concentrations of the enantiomers of mirtazapine and its metabolites has not been assessed in patients on long-term treatment. The main objective of the study was to evaluate the effect of the CYP2D6 genotype on enantiomeric steady-state trough serum concentrations of mirtazapine and its metabolites N -desmethylmirtazapine and 8-hydroxymirtazapine. The effects of sex, age and smoking behaviour were also assessed. Subjects and methods The study included 95 patients who had depression according to the Diagnostic and Statistical Manual of Mental Disorders — 4th Edition and were treated for 4 weeks with a daily dose of mirtazapine 30 mg. The serum concentrations of the enantiomers of mirtazapine and its metabolites were analysed by liquid chromatography-mass spectrometry, and the subjects were genotyped for CYP2D6 alleles *3, *4, *5 and *6 and gene duplication. Results Three subjects (3%) were classified as ultrarapid metabolizers (UMs), 56 (59%) as homozygous extensive metabolizers (EMs), 30 (32%) as heterozygous EMs and 6 (6%) as poor metabolizers (PMs) of CYP2D6 . The median trough serum concentrations of S (+)-mirtazapine were higher in PMs (59 nmol/L, p = 0.016) and in heterozygous EMs (39 nmol/L, p = 0.013) than in homozygous EMs (28 nmol/L). PMs and heterozygous EMs also had higher mirtazapine S (+)/ R (−) ratios (0.4) than homozygous EMs (0.3, p = 0.015 and 0.004, respectively). The S (+)- N -desmethylmirtazapine concentration was higher in PMs (16 nmol/L) than in homozygous EMs (7 nmol/L, p = 0.043). There was an association between the CYP2D6 genotype and the ratio between S (+)-8-hydroxymirtazapine and S (+)-mirtazapine, with a significantly higher ratio in homozygous EMs than in heterozygous EMs (0.11 vs 0.05, p = 0.007). The influence of the CYP2D6 genotype on S (+)-mirtazapine, the mirtazapine S (+)/ R (−) ratio and S (+)- N -desmethylmirtazapine remained significant after correction for the influence of sex, age and smoking. Smokers had significantly lower concentrations of S(+)-mirtazapine (23 vs 39 nmol/L, p = 0.026) and R (−)- N -desmethylmirtazapine (39 vs 51 nmol/L, p = 0.036) and a significantly lower mirtazapine S(+)/R(−) ratio (0.28 vs 0.37, p = 0.014) than nonsmokers, and the effect of smoking remained significant after multivariate analysis. Conclusions This study is the first to show the impact of the CYP2D6 genotype on steady-state serum concentrations of the enantiomers of mirtazapine and its metabolites. Our results also support the role of CYP1A2 in the metabolism of mirtazapine, with lower serum concentrations in smokers than in nonsmokers.

  • steady state concentrations of mirtazapine n desmethylmirtazapine 8 hydroxymirtazapine and their enantiomers in relation to cytochrome p450 2d6 genotype age and smoking behaviour
    Clinical Pharmacokinectics, 2009
    Co-Authors: Anna-britta Lind, Margareta Reis, Kerry Powell Golay, Pierre Baumann, Finn Bengtsson, Johan Ahlner, Michele Jonzierperey, Marjaliisa Dahl
    Abstract:

    Mirtazapine is a Tetracyclic Antidepressant drug available as a racemic mixture of S(+)- and R(−)-mirtazapine. These enantiomers have different pharmacological properties, and both contribute to the clinical and adverse effects of the drug. Cytochrome P450 (CYP) 2D6 has been implicated in the metabolism of S(+)-mirtazapine. However, the effect of CYP2D6 on serum concentrations of the enantiomers of mirtazapine and its metabolites has not been assessed in patients on long-term treatment. The main objective of the study was to evaluate the effect of the CYP2D6 genotype on enantiomeric steady-state trough serum concentrations of mirtazapine and its metabolites N-desmethylmirtazapine and 8-hydroxymirtazapine. The effects of sex, age and smoking behaviour were also assessed. The study included 95 patients who had depression according to the Diagnostic and Statistical Manual of Mental Disorders — 4th Edition and were treated for 4 weeks with a daily dose of mirtazapine 30 mg. The serum concentrations of the enantiomers of mirtazapine and its metabolites were analysed by liquid chromatography-mass spectrometry, and the subjects were genotyped for CYP2D6 alleles *3, *4, *5 and *6 and gene duplication. Three subjects (3%) were classified as ultrarapid metabolizers (UMs), 56 (59%) as homozygous extensive metabolizers (EMs), 30 (32%) as heterozygous EMs and 6 (6%) as poor metabolizers (PMs) of CYP2D6. The median trough serum concentrations of S(+)-mirtazapine were higher in PMs (59 nmol/L, p = 0.016) and in heterozygous EMs (39 nmol/L, p = 0.013) than in homozygous EMs (28 nmol/L). PMs and heterozygous EMs also had higher mirtazapine S(+)/ R(−) ratios (0.4) than homozygous EMs (0.3, p = 0.015 and 0.004, respectively). The S(+)- N-desmethylmirtazapine concentration was higher in PMs (16 nmol/L) than in homozygous EMs (7 nmol/L, p = 0.043). There was an association between the CYP2D6 genotype and the ratio between S(+)-8-hydroxymirtazapine and S(+)-mirtazapine, with a significantly higher ratio in homozygous EMs than in heterozygous EMs (0.11 vs 0.05, p = 0.007). The influence of the CYP2D6 genotype on S(+)-mirtazapine, the mirtazapine S(+)/ R(−) ratio and S(+)- N-desmethylmirtazapine remained significant after correction for the influence of sex, age and smoking. Smokers had significantly lower concentrations of S(+)-mirtazapine (23 vs 39 nmol/L, p = 0.026) and R(−)- N-desmethylmirtazapine (39 vs 51 nmol/L, p = 0.036) and a significantly lower mirtazapine S(+)/R(−) ratio (0.28 vs 0.37, p = 0.014) than nonsmokers, and the effect of smoking remained significant after multivariate analysis. This study is the first to show the impact of the CYP2D6 genotype on steady-state serum concentrations of the enantiomers of mirtazapine and its metabolites. Our results also support the role of CYP1A2 in the metabolism of mirtazapine, with lower serum concentrations in smokers than in nonsmokers.