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Effects of dapoxetine on cloned Kv1.5 channels expressed in CHO cells.
Jeong, Imju,Yoon, Shin Hee,Hahn, Sang June Springer-Verlag 2012 Naunyn-Schmiedeberg's archives of pharmacology Vol.385 No.7
<P>The effects of dapoxetine were examined on cloned Kv1.5 channels stably expressed in Chinese hamster ovary cells using the whole-cell patch clamp technique. Dapoxetine decreased the peak amplitude of Kv1.5 currents and accelerated the decay rate of current inactivation in a concentration-dependent manner with an IC (50) of 11.6 mu M. Kinetic analysis of the time-dependent effects of dapoxetine on Kv1.5 current decay yielded the apparent association (k (+1) ) and dissociation (k (-1) ) rate constants of 2.8 mu M-1 s(-1) and 34.2 s(-1), respectively. The theoretical K (D) value, derived by k (-1) /k (+1) , yielded 12.3 mu M, which was reasonably similar to the IC (50) value obtained from the concentration-response curve. Dapoxetine decreased the tail current amplitude and slowed the deactivation process of Kv1.5, which resulted in a tail crossover phenomenon. The block by dapoxetine is voltage-dependent and steeply increased at potentials between -10 and +10 mV, which correspond to the voltage range of channel activation. At more depolarized potentials, a weaker voltage dependence was observed (delta = 0.31). Dapoxetine had no effect on the steady-state activation of Kv1.5 but shifted the steady-state inactivation curves in a hyperpolarizing direction. Dapoxetine produced a use-dependent block of Kv1.5 at frequencies of 1 and 2 Hz and slowed the time course for recovery of inactivation. These effects were reversible after washout of the drug. Our results indicate that dapoxetine blocks Kv1.5 currents by interacting with the channel in both the open and inactivated states of the channel.</P>
Jeong, Imju,Yang, Ji Seon,Hong, Yi Jae,Kim, Hee Jung,Hahn, Sang June,Yoon, Shin Hee Elsevier Science B.V., Amsterdam. 2017 european journal of pharmacology Vol.805 No.-
<P>Selective serotonin reuptake inhibitors (SSRIs) have an inhibitory effect on various ion channels including Ca2+ channels. We used fluorescent dye-based digital imaging, whole-cell patch clamping and cytotoxicity assays to examine whether dapoxetine, a novel rapid-acting SSRI, affect glutamate-induced calcium signaling, mitochondrial depolarization and neuronal cell death in cultured rat hippocampal neurons. Pretreatment with dapoxetine for 10 min inhibited glutamate-induced intracellular free Ca2+ concentration ([Ca2+](i)) increases in a concentration-dependent manner (Half maximal inhibitory concentration=4.79 mu M). Dapoxetine (5 mu M) markedly inhibited glutamate-induced [Ca2+](i) increases, whereas other SSRIs such as fluoxetine and citalopram only slightly inhibited them. Dapoxetine significantly inhibited the glutamate-induced [Ca2+](i) responses following depletion of intracellular Ca2+ stores by treatment with thapsigargin. Dapoxetine markedly inhibited the metabotropic glutamate receptor agonist, (S)-3,5-dihydroxyphenylglycine-induced [Ca2+](i) increases. Dapoxetine significantly inhibited the glutamate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced [Ca2+](i) responses in either the presence or absence of nimodipine. Dapoxetine also significantly inhibited AMPA-evoked currents. However, dapoxetine slightly inhibited N-methyl-n-aspartate (NMDA)-induced [Ca2+](i) increases. Dapoxetine markedly inhibited 50 mM K+-induced [Ca2+](i) increases. Dapoxetine significantly inhibited glutamate -induced mitochondrial depolarization. In addition, dapoxetine significantly inhibited glutamate -induced neuronal cell death and its neuroprotective effect was significantly greater than fluoxetine. These data suggest that dapoxetine reduces glutamate -induced [Ca2+](i) increases by inhibiting multiple pathways mainly through AMPA receptors, voltage-gated L-type Ca2+ channels and metabotropic</P>
( Jeong Heo ),( Yeon Seok Seo ),( Hyung Joon Yim ),( Taeho Hahn ),( Sang Hoon Park ),( Sang Hoon Ahn ),( Jun Yong Park ),( Ji Young Park ),( Moon Young Kim ),( Sung Keun Park ),( Mong Cho ),( Soon Ho 대한소화기기능성질환·운동학회 2009 Gut and Liver Vol.3 No.3
Background/Aims: Although early recognition and treatment with effective antibiotics have lead to improvements in the prognosis of patients with spontaneous bacterial peritonitis (SBP), it remains to be a serious complication in cirrhotic patients. This study was designed to evaluate the clinical manifestations and prognosis of patients with liver cirrhosis and SBP in Korea. Methods: This was a multicenter retrospective study examining 157 episodes of SBP in 145 patients with cirrhosis. SBP was diagnosed based on a polymorphonuclear cell count in ascitic fluid of > 250 cells/mm3 in the absence of data compatible with secondary peritonitis. Results: The mean age of the cohort was 56 years, and 121 (77%) of the 157 episodes of SBP occurred in men. Microorganisms were isolated in 66 episodes (42%): Gram-negative bacteria in 54 (81.8%), Gram-positive in 11 (16.7%), and Candida in 1. Isolated Gram-negative organisms were resistant to third-generation cephalosporin in 6 cases (17%), to ciprofloxacin in 11 (20.8%), and to penicillin in 33 (62.3%). The treatment failure and in-hospital mortality rates were 12.1% and 21%, respectively. A high Model of End-Stage Liver Disease (MELD) score, SBP caused by extended-spectrum β-lactamase-producing organisms, and hepatocellular carcinoma were independent prognostic factors of high in-hospital mortality. Conclusions: SBP remains to be a serious complication with high in-hospital mortality, especially in patients with a high MELD score. (Gut and Liver 2009;3:197-204)