• 통합자연과학논문집
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• 제5권3호
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• pp.168-174
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• 2012

Gal (1-3) receptors are members of GPCR superfamily with seven transmembrane helices. The neuropeptide galanin mediates its effects through the receptor subtypes Gal1, Gal2, and Gal3 and has been implicated in anxiety and depression related behaviors. Galanin receptors are considered to be important targets for the development of novel antidepressant drugs. Owing to the importance of these receptors, a short communication about the sequential and structural studies about the functional Galanin (1-3) receptors has been reported. Structural studies have been hampered due to the lack of X-ray crystal structures. However with the availability of templates with close homologs comparative modeling could be encouraging. Sequence analysis was done for each receptors and homology modeling of each receptors were done with recently reported templates. Comparative analyses were done between these receptors to identify the relationships between them sequentially. Phylogram was generated between these receptors to identify the close homologue between this receptor and found that Gal2 and Gal3 receptors are closer. Our results could be useful for further structure based drug design targeting Gal1, Gal2 and Gal3 receptors.

• The Korean Journal of Physiology and Pharmacology
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• 제25권3호
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• pp.189-195
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• 2021

Fluoxetine (FLX), a selective serotonin reuptake inhibitor antidepressant, exhibits various other mechanisms of action in numerous cell types and has been shown to induce cell death in cancer cells, paving the way for its potential use in cancer therapy. The aim of this study was to determine the off-target effects of the anti-depressant drug FLX, on the human ovarian granulosa tumor COV434 cells stimulated by forskolin (FSK), by measuring the real-time kinetics of intracellular cyclic AMP (cAMP), ATP level, cytoplasmic calcium ([Ca2+]cyt) and survival of COV434 cells. We show that incubating COV434 cells with FLX (between 0.6 and 10 μM) induces a decrease in intracellular cAMP response to FSK, a drop in ATP content and stimulates cytoplasmic Ca2+ accumulation in COV434 cells. Only the highest concentrations of FLX (5-10 μM) diminished cell viability. The present report is the first to identify an action mechanism of FLX in human tumor ovarian cells COV434 cells and thus opening the way to potential use of fluoxetine as a complementary tool, in granulosa tumor treatments.

• Clinical Psychopharmacology and Neuroscience
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• 제16권4호
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• pp.469-480
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• 2018

Objective: Pharmacogenomic-based antidepressant treatment (PGATx) may result in more precise pharmacotherapy of major depressive disorder (MDD) with better drug therapy guidance. Methods: An 8-week, randomized, single-blind clinical trial was conducted to evaluate the effectiveness and tolerability of PGATx in 100 patients with MDD. All recruited patients were randomly allocated either to PGATx (n=52) or treatment as usual (TAU, n=48) groups. The primary endpoint was a change of total score of the Hamilton Depression Rating Scale-17 (HAMD-17) from baseline to end of treatment. Response rate (at least 50% reduction in HAMD-17 score from baseline), remission rate (HAMD-17 score ${\leq}7$ at the end of treatment) as well as the change of total score of Frequency, Intensity, and Burden of Side Effects Ratings (FIBSER) from baseline to end of treatment were also investigated. Results: The mean change of HAMD-17 score was significantly different between two groups favoring PGATx by -4.1 point of difference (p=0.010) at the end of treatment. The mean change in the FIBSER score from baseline was significantly different between two treatment groups favoring PGATx by -2.5 point of difference (p=0.028). The response rate (71.7 % vs. 43.6%, p=0.014) were also significantly higher in PGATx than in TAU at the end of treatment, while the remission rate was numerically higher in PGATx than in TAU groups without statistical difference (45.5% vs. 25.6%, p=0.071). The reason for early drop-out associated with adverse events was also numerically higher in TAU (n=9, 50.0%) than in PGATx (n=4, 30.8%). Conclusion: The present study clearly demonstrate that PGATx may be a better treatment option in the treatment of MDD in terms of effectiveness and tolerability; however, study shortcomings may limit a generalization. Adequately-powered, well-designed, subsequent studies should be mandatory to prove its practicability and clinical utility for routine practice.

• 생물정신의학
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• 제24권4호
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• pp.167-174
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• 2017

Based on advances in biotechnology and neuroscience, neuromodulation is poised to gain clinical importance as a treatment modality for psychiatric disorders. In addition to old-established electroconvulsive therapy (ECT), clinicians are expected to understand newer forms of neurostimulation, such as deep brain stimulation (DBS), vagus nerve stimulation (VNS), repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS). Given the growing interest in non-invasive neuromodulation technologies, clinicians may seek sufficient information about neuromodulation to inform their clinical practice. A growing literature suggests that applications of non-invasive neuromodulation have evidence particularly for indications where treatments are currently insufficient, such as drug-resistant depression. However, positive neuromodulation studies require replication, and the precise interactions among stimulation, antidepressant medication, and psychotherapy are unknown. Further studies of long-term safety and the impact on the developing brain are needed. Non-invasive neuromodulatory devices could enable more individualized treatment. However, do-it-yourself (DIY) stimulation kits require a better understanding of the effects of more frequent patterns of stimulation and raise concerns about clinical supervision, regulation, and reimbursement. Wide spread enthusiasm for therapeutic potential of neuromodulation in clinical practice settings should be mitigated by the fact that there are still research gaps and challenges associated with non-invasive neuromodulatory devices.

• 동의신경정신과학회지
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• 제14권1호
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• pp.27-44
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• 2003

Objective : The aim of this study was to assess protective effects of Whangryonhaedoktang on the chronic mild stress (CMS) animal model of depression. Method : Male Sprague-Dawley rats were used for this study. The subjects were divided into 3 groups (CMS-drug group: Whangryonhaedoktang was administered during CMS procedure, CMS-vehicle: water was administered during CMS procedure, normal control group: without CMS procedure). After 4 weeks of CMS procedure, Morris water maze (MWM) test and open field test were executed and tyrosine hydroxylase (TH) was measured in ventral tegmental area (VTA) and locus coeruleus (LC) of rat brain. Result : 1. CMS procedure induced defects of spatial learning in early period of MWM test. 2. CMS Whangryonhaedoktang group showed shorter escape latency in comparison with CMS control group in MWM test on the first day of the test. 3. CMS Whangryonhaedoktang group and CMS control group showed no significant difference of activities and emotional behaviors in comparison with normal control group in open field test. 4. CMS Whangryonhaedoktang group showed significant inhibition effects of TH expression in VTA and LC areas in comparison with CMS control group. Conclusion : These results suggest that Whangryonhaedoktang may have inhibition effects to early period defects of spatial learning and protective antidepressant effects in CMS model rats.

• 정신신체의학
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• 제7권2호
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• pp.274-280
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• 1999

중추신경계와 말초신경계의 손상으로 인한 다양한 기전에 의해서 신경병성 통증이 생길 수 있다. 특정한 질병과 관련된 기전에 의해서 생기는 경우는 거의 없고, 진단과는 상관없이 한 환자에서 여러 가지 기전이 동시에 관여하여 생긴다. 신경병성 통증은 신경학적 검사와 환자의 문진으로부터 쉽게 진단할 수 있으나 치료는 아직 만족할 만하지 못하다. 신경병성 통증의 치료가 어렵다 하더라도 의사가 치료시 문제점을 완전히 이해하고 있다면 적절한 치료에 도달될 수 있을 것이다. 적절한 약물의 선택은 환자마다 효과가 있는 약제, 용량, 혈중농도 등이 각기 다르기 때문에 치료의 시도와 실패의 반복을 통해서 얻어질 수 있다. 효과가 있다고 알려진 각 약물들의 적절한 치료연구는 신경병성 통증의 약물치료에 있어 핵심일 것이다. 삼환계 항우울제는 일차약물로 알려져 있고 이에 대한 효과가 만족스럽지 못할 경우에는 항경련제, 국소마취성 항부정맥제제, clonidine, 마약성 진통제, 국소도포제 순으로 사용해 볼 수 있다. Venlafaxine, nefazodone 같은 항우울제가 최근에 삼환계 항우울제 보다 부작용이 적고 비슷한 효과가 있으며, 항경련제인 gabapentine도 효과있는 약물로 널리 사용되고 있다.

• The Korean Journal of Physiology and Pharmacology
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• 제20권2호
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• pp.193-200
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• 2016

Sertraline, a selective serotonin reuptake inhibitor (SSRI), has been reported to lead to cardiac toxicity even at therapeutic doses including sudden cardiac death and ventricular arrhythmia. And in a SSRI-independent manner, sertraline has been known to inhibit various voltage-dependent channels, which play an important role in regulation of cardiovascular system. In the present study, we investigated the action of sertraline on Kv1.5, which is one of cardiac ion channels. The effect of sertraline on the cloned neuronal rat Kv1.5 channels stably expressed in Chinese hamster ovary cells was investigated using the whole-cell patch-clamp technique. Sertraline reduced Kv1.5 whole-cell currents in a reversible concentration-dependent manner, with an $IC_{50}$ value and a Hill coefficient of $0.71{\mu}M$ and 1.29, respectively. Sertraline accelerated the decay rate of inactivation of Kv1.5 currents without modifying the kinetics of current activation. The inhibition increased steeply between -20 and 0 mV, which corresponded with the voltage range for channel opening. In the voltage range positive to +10 mV, inhibition displayed a weak voltage dependence, consistent with an electrical distance ${\delta}$ of 0.16. Sertraline slowed the deactivation time course, resulting in a tail crossover phenomenon when the tail currents, recorded in the presence and absence of sertraline, were superimposed. Inhibition of Kv1.5 by sertraline was use-dependent. The present results suggest that sertraline acts on Kv1.5 currents as an open-channel blocker.

• The Korean Journal of Physiology and Pharmacology
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• 제22권1호
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• pp.71-80
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• 2018

In patients with epilepsy, depression is a common comorbidity but difficult to be treated because many antidepressants cause pro-convulsive effects. Thus, it is important to identify the risk of seizures associated with antidepressants. To determine whether paroxetine, a very potent selective serotonin reuptake inhibitor (SSRI), interacts with ion channels that modulate neuronal excitability, we examined the effects of paroxetine on Kv3.1 potassium channels, which contribute to high-frequency firing of interneurons, using the whole-cell patch-clamp technique. Kv3.1 channels were cloned from rat neurons and expressed in Chinese hamster ovary cells. Paroxetine reversibly reduced the amplitude of Kv3.1 current, with an $IC_{50}$ value of $9.43{\mu}M$ and a Hill coefficient of 1.43, and also accelerated the decay of Kv3.1 current. The paroxetine-induced inhibition of Kv3.1 channels was voltage-dependent even when the channels were fully open. The binding ($k_{+1}$) and unbinding ($k_{-1}$) rate constants for the paroxetine effect were $4.5{\mu}M^{-1}s^{-1}$ and $35.8s^{-1}$, respectively, yielding a calculated $K_D$ value of $7.9{\mu}M$. The analyses of Kv3.1 tail current indicated that paroxetine did not affect ion selectivity and slowed its deactivation time course, resulting in a tail crossover phenomenon. Paroxetine inhibited Kv3.1 channels in a use-dependent manner. Taken together, these results suggest that paroxetine blocks the open state of Kv3.1 channels. Given the role of Kv3.1 in fast spiking of interneurons, our data imply that the blockade of Kv3.1 by paroxetine might elevate epileptic activity of neural networks by interfering with repetitive firing of inhibitory neurons.

• The Korean Journal of Physiology and Pharmacology
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• 제20권1호
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• pp.75-82
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• 2016

Paroxetine, a selective serotonin reuptake inhibitor (SSRI), has been reported to have an effect on several ion channels including human ether-a-go-go-related gene in a SSRI-independent manner. These results suggest that paroxetine may cause side effects on cardiac system. In this study, we investigated the effect of paroxetine on Kv1.5, which is one of cardiac ion channels. The action of paroxetine on the cloned neuronal rat Kv1.5 channels stably expressed in Chinese hamster ovary cells was investigated using the whole-cell patch-clamp technique. Paroxetine reduced Kv1.5 whole-cell currents in a reversible concentration-dependent manner, with an $IC_{50}$ value and a Hill coefficient of $4.11{\mu}M$ and 0.98, respectively. Paroxetine accelerated the decay rate of inactivation of Kv1.5 currents without modifying the kinetics of current activation. The inhibition increased steeply between -30 and 0 mV, which corresponded with the voltage range for channel opening. In the voltage range positive to 0 mV, inhibition displayed a weak voltage dependence, consistent with an electrical distance ${\delta}$ of 0.32. The binding ($k_{+1}$) and unbinding ($k_{-1}$) rate constants for paroxetine-induced block of Kv1.5 were $4.9{\mu}M^{-1}s^{-1}$ and $16.1s^{-1}$, respectively. The theoretical $K_D$ value derived by $k_{-1}/k_{+1}$ yielded $3.3{\mu}M$. Paroxetine slowed the deactivation time course, resulting in a tail crossover phenomenon when the tail currents, recorded in the presence and absence of paroxetine, were superimposed. Inhibition of Kv1.5 by paroxetine was use-dependent. The present results suggest that paroxetine acts on Kv1.5 currents as an open-channel blocker.

• 약학회지
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• 제42권5호
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• pp.513-518
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• 1998

Fluoxetine is a nontricyclic antidepressant which blocks serotonin reuptake selectively. Its N-demethyl metabolite, norfluoxetine is also selective inhibitor of serotonin uptake . This study was carried out to compare the bioavailability of Myung-in fluoxetine (20mg/cap.) with that of Prozac$^{\circde{R}}$. The bioavailability was conducted on 24 healthy volunteers who received a single dose (80mg) of each drug in the fasting state, in a randomized balanced 2-way crossover design. After closing, serial blood samples were collected for a period of 48 hours, Plasma was analyzed for fluoxetine and norfluoxetine by a sensitive and validated HPLC assay. The major pharmacokinetic parameters ($AUC_{0-48\;hr}$, Cmax, Tmax , $AUC_{inf.}$, MRT. $T_{1/2}$, Vd and Cl) were, calculated from the plasma fluoxetine concentration-time data of each volunteer. The microcomputer program, 'WinNonlin' was used for compartmental analysis. A two-compartment model with first-order input, first-order output and no lag time was chosen as the most appropriate pharmacokinetic model. The data were best described by using a weighting factor of $1/y^2$. Though the plasma fluoxetine concentrations of Myung-in fluoxetine were higher than those of Prozac$^{\circde{R}}$ at all observed time from 7.9% to 16.9% (P<0.05 at 6.7 and 10 hr), the bioavailability of Myung-in fluoxetine appeared to be bioequivalent with that of Prozac$^{\circde{R}}$. There were no statistical significant differences between the two drugs in all pharmacokinetic parameters including $AUC_{0-48\;hr}$ of norfluoxetine.