• 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.

• Journal of the Korean Academy of Child and Adolescent Psychiatry
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• 제5권1호
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• pp.83-92
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• 1994

본 연구의 목적은, 선택적 serotonin 재흡수 차단제(selective serotonin re-uptake inhibitors : SSRI)로서 불안증상을 동반한 비정신병적 우울증에 효과적인 치료제로 알려지고 있는 paroxetine의 항우울 및 항불안 효과를 검증하고, 성별 및 연령별로 효과의 차이를 파악하는 것이다. 이를 위해 8~55세 사이의 우울신경증 환자 232명을 대상으로 paroxetine과 위약을 이중맹 교차방식으로 투여한 후, 우울 및 불안 증상의 호전도를 Hamilton Depression Scale(HDS)과 Hamilton Anxeity Scale(HAS)로 측정하여 다음과 같은 결과를 얻었다. 1) HDS로 측정된 우울증상에 대해, 성별 및 연령별로 구분된 8개 대상군에서 모두 paroxetine이 위약에 비해 통계적으로 유의하게 높은 호전 효과를 보였다. 2) HAS로 측정된 불안증상에 대해서도, 성별 및 연령별로 구분된 8개 대상군에서 모두 paroxetine이 위약에 비해 통계적으로 유의하게 높은 호전 효과를 보였다. 3) 위약과 비교시, paroxetine의 항우울 효과는 소아 ${\cdot}$ 청소년 여자 환자군에서 가장 두드러졌고, 항불안 효과는 남 ${\cdot}$ 녀 소아 환자군과 35세 이하의 성인 여자 환자군에서 가장 높은 경향을 보였다. 4) 부작용으로는, 전체 232례 중 3례에서 paroxetine 투여 후 경미한 소화불량 및 복통증상을 나타내었으나, 3례 모두 약물의 감량이나 투여중단 없이 회복이 가능했다. 이상의 결과에서 paroxetine은 소아 ${\cdot}$ 청소년 및 성인 우울신경증 환자에서 2주 이내에 위약보다 유의하게 우수한 항우울 및 항불안 효과를 나타내는 것을 알 수 있었다. 향후 보다 장기간의 치료실험을 통하여 이러한 효과의 장기간 지속성에 대한 검증이 필요한 것이다.

• 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.

• 대한불안의학회지
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• 제2권2호
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• pp.101-107
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• 2006

Object : Since autonomic nerve system dysfunction was known as the mechanism of panic disorder, many researchers used heart rate variability (HRV) as means of measuring autonomic nerve function of patients with panic disorder. We aimed to examine the effect of paroxetine medication for 3 months on symptom improvement and change of heart rate variability of the patients with panic disorder. Methods : The subjects were patients with panic disorder who visited the psychiatric outpatient clinic of Samsung Medical Center in Seoul. We included panic disorder patients who were aged from 20 to 50 and in normal BMI range (from 18 to 30) to minimize the effect of age and weight on HRV data. We excluded the patients with EKG abnormalities, hypertension or other major psychiatric disorders. They took 20-40 mg paroxetine medication a day for 3 months. Alprazolam was used only during the first month to control the acute panic symptoms and was tapered off after that. We measured the acute panic inventory (API), Hamilton rating scale for anxiety and depression (HAM-A & HAM-D), Spielberger state-trait anxiety inventory (STAIS, STAIT), and Beck depression inventory (BDI) in order to assess clinical improvement of the patients. And we measured time and frequency domain HRV in the resting, standing and cognitive stress states to assess the change of HRV. All measurements were done before and after paroxetine treatment. Result : After paroxetine medication, patients showed significant improvement in all psychiatric scales. In time domain of HRV, standard deviations of all R-R intervals (SDNN) were significantly increased in all states. In frequency domain of HRV, the ratio of high frequency to total power (HF/TP) in the standing state was significantly increased. Conclusion : After 3 months paroxetine medication, panic disorder patients showed significant clinical improvement and change in HRV data such as SDNN in all states and HF/TP ratio in the standing state. This result suggests that paroxetine medication is effective for the improvement of autonomic nerve system dysfunction in panic disorder patients.

• Journal of Pharmaceutical Investigation
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• 제34권6호
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• pp.499-504
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• 2004

Paroxetine, a potent and selective serotonine reuptake inhibitor, has been used for the treatment of depression, obsessive-compulsive disorder, panic disorder and social phobia. The bioequivalence of two paroxetine preparations was evaluated according to the guidelines of Korea Food & Drug Administration (KFDA). The test product was Samchully Paroxetine $tablet^{\circledR}$ made by Samchully Pharm. Co. and the reference product was Seroxat $tablet^{\circledR}$ made by GlaxoSmithKline. Twenty healthy male subjects, $22.4{\pm}2.6$ years old and $63.8{\pm}4.2\;kg$, were divided into two groups and a randomized $2{\times}2$ cross-over study was employed. After one tablet containing 20 mg paroxetine was orally administered, blood was taken at predetermined time intervals and the concentration of paroxetine in plasma was determined using a validated HPLC method with fluorescence detector. Two pharmacokinetic parameters, $AUC_t$ and $C_{max}$, were calculated and analyzed statistically for the evaluation of bioequivalence of two products. Analysis of variance was carried out using logarithmically transformed parameter values. The 90% confidence intervals of $AUC_t$ and $C_{max}$ were log 0.84-log 1.16 and log 0.85-log 1.14, respectively. These values were within the acceptable bioequivalence intervals of log 0.8 to log 1.25. Thus, the criteria of the KFDA guidelines for the bioequivalence was satisfied, indicating that Samchully Paroxetine tablet is bioequivalent to Seroxat tablet.

• 생물정신의학
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• 제3권2호
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• pp.251-257
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• 1996

Selective serotonin reuptake inhibitors(SSRIs), as haloperidol, ore metabolized in the cytochrome P450IID6. They can cause inhibition of metabolism of antipsychotics to elevate the serum level of antipsychotics and exacerbate the extrapyramidal symptoms when co-administered with antipsychotics. Among these SSRIs, there ore a few studies about paroxetine compared to fluoxetine or sertraline. In this study, we have intended to know the drug interaction of paroxetine and haloperidol when co-administered two drugs for the chronic schizophrenics by assessing the changes of positive, negative symptoms and extrapyramidal symptoms. for this purpose, we selected 29 subjects, the chronic schizophrenics with no physical problems. They were under maintenance therapy of haloperidol. They ore randomly assigned to placebo group(n=12) and drug group(n=17) by using double blind method. And then, placebo or paroxetine 20mg were administered to the subjects of each groups during 8 week period. We have assessed their psychopathology and extrapyramidal symptoms using Positive and Negative Syndrome Scale(PANSS), Hamilton Rating Scale lor Depression(HRSD), Simpson-Angus Scale at 0, 2, 4, 6, 8 weeks and serum haloperidol, reduced haloperidol levels at 0, 4, 8 weeks during the period. The results ore analysed by using repeated measure MANOVA. 27 subjects have completed the study during 8 weeks. among the subjects, 1) PANSS, HRSD ; no significant difference between groups. 2) Simpson-Angus Scale ; no significant change according to the time and no significant difference between the groups(no group and time effect). 3) Haloperidol and reduced haloperidol level ; no significant change. When co-administered paroxetine and haloperidol, there ore no significant changes of the psychopothology and no significant changes of the extrapyramidal symptoms. In this result, paroxetine seems to be not to affect the metabolism of haloperidol.

• International Journal of Oral Biology
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• 제43권1호
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• pp.43-51
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• 2018

$K^+$ channels are key components of the primary and secondary basolateral $Cl^-$ pump systems, which are important for secretion from the salivary glands. Paroxetine is a selective serotonin reuptake inhibitor (SSRI) for psychiatric disorders that can induce QT prolongation, which may lead to torsades de pointes. We studied the effects of paroxetine on a human $K^+$ channel, human ether-a-go-go-related gene (hERG), expressed in Xenopus oocytes and on action potential in guinea pig ventricular myocytes. The hERG encodes the pore-forming subunits of the rapidly-activating delayed rectifier $K^+$ channel ($I_{Kr}$) in the heart. Mutations in hERG reduce $I_{Kr}$ and cause type 2 long QT syndrome (LQT2), a disorder that predisposes individuals to life-threatening arrhythmias. Paroxetine induced concentration-dependent decreases in the current amplitude at the end of the voltage steps and hERG tail currents. The inhibition was concentration-dependent and time-dependent, but voltage-independent during each voltage pulse. In guinea pig ventricular myocytes held at $36^{\circ}C$, treatment with $0.4{\mu}M$ paroxetine for 5 min decreased the action potential duration at 90% of repolarization ($APD_{90}$) by 4.3%. Our results suggest that paroxetine is a blocker of the hERG channels, providing a molecular mechanism for the arrhythmogenic side effects of clinical administration of paroxetine.

• 생물정신의학
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• 제4권2호
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• pp.237-245
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• 1997

The study was designed to evaluate the significant roles of SSRI in rat of depression model. Chronic exposure to mild unpredictable stress has been found to depress the consumption of sweet 1% sucrose solutions in the Sprague-Dawley rats. We applied the variety of 11 types of stress regimens and identified depressive behaviours(developed by Willner) in 70 Sprague-Dawley rats. Rats in experiments were stratified into 6 groups, ie ; 3 kinds of SSRI(paroxetine, fluoxetine, sertraline), clomipramine, choline and saline control. Memory function was evaluated by passive avoidance learning and retention test. The authors determined how long memory retention would remain improved with 24 hour, 1 week, 2 weeks, 3 weeks, and 4 weeks at training-testing interval in depressive states of the Sprague-Dawley rats. The results were as follows ; 1) There were no significant differences between the 6 groups at the 24 hour training-testing interval. 2) The paroxetine treated group showed significant differences from the control group at the 1 week and 2 weeks training-testing interval. 3) The paroxetine and the fluoxetine treated groups showed singificant differences from the control group at 3 week training-testing interval. 4) The paroxetine and the choline treated groups showed significant differences from the control group at 4 week training-testing interval. In summary, paroxetine had an effect on long term memory processing from 1st week to 4th week. Also, fluoxetine(at 3rd week) and choline(at 4th week) had effect on long term memory processing. Sertraline, clomipramine were ineffective on memory processing during 4 weeks observation. Possible explanations why paroxetine had early effect on memory processing than the other selective serotonin reuptake inhibitors are rapid bioavailability, which is the characteristics of pharmacokinetics of paroxetine. In clinical situation, author carefully suggest that SSRI would be beneficial to improve the memory function caused by depressive neurochemical changes.

• 정신신체의학
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• 제8권1호
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• pp.46-57
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• 2000

연구목적 : 본 연구는 선택적 세로토닌 재흡수 차단제인 paroxetine과 sertraline의 마우스에 대한 아급성 처치가 강제수영시험에서의 부동자세 시간과 강제수영시험으로 유발된 면역능의 변화에 미치는 영향을 조사하고자 시행되었다. 방법 : 저자들은 실험동물로 각 군마다 5마리 이상의 BALB/c 마우스를 사용하였다. 본 실험동물에서의 적절한 모델을 구축하기 위하여 Porsolt 등의 강제수영시험을 다소 변형하여 각각의 실험 대상군에 적용하였다. 강제수영시험으로 인한 면역 매개변수의 변화를 보기 위하여, 저자들은 anti-rat RBC 항체의 생성, concanavalin 또는 lipopolysaccharide로 유발된 비장세포의 증식과 사이토카인의 유전자 발현 양상을 연구하였다. 결과 : Paroxetine과 sertraline은 모두 투여량에 따라 마우스의 부동자세 시간을 감소시켰다. 강제수영시험을 수행한 마우스는 비세포의 유사분열 반응이 의미 있게 감소되었고, anti-rat RBC 항체는 약간 증가하였다. 이러한 모든 반응은 paroxetine에 의해 의미 있게 감퇴되었고. sertraline에 의해 약간 감퇴되었다. 강제수영시험을 시행한 마우스에서 Con-A로유발된 비세포는 강제수영을 시행하지 않았던 정상대조군보다 IL-4의 강한 발현과 IL-2의 약화된 발현을 보였고, IFN-$\gamma$나 lymphotoxin의 발현은 차이가 없었다. IL-6과 IL-10은 양 군 모두에서 발현되지 않았다. 마우스에서 paroxetine과 sertraline의 전처치는 강제수영으로 인한 사이토카인 발현의 변화를 감퇴시켰다. 그렇지만 선택적 세로토닌 재흡수 차단제가 전처치된 마우스에서는 강제수영군에서 발현되지 않았던 IL-6과 IL-10의 발현이 약간의 변화를 보였다. 결론 : 강제수영시험을 시행한 마우스에서 paroxetine과 sertraline의 전처치는 강제수영시험으로 유발된 행동 및 면역능의 변화를 감퇴시켰다. 이러한 선택적 세로토닌 재흡수 차단제는 사이토카인 유전자 발현 특히 IL-6과 IL-10의 유도를 통하여 면역 체계에 모종의 조절 효과를 발휘하는 것으로 추정되었다.

• The Korean Journal of Pain
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• 제11권2호
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• pp.201-209
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• 1998

Background: Tricyclic antidepressants (TCA) have been used for various pain syndromes for their analgesic effects. They, however, often have anticholinergic side effects and therefore search for more selective drugs with fewer side effects is justified. Paroxetine, a selective serotonin reuptake inhibitor devoid of autonomic side effects, was evaluated for its role as an analgesic adjuvant in the management of neuropathic pain. Method: According to individual diagnostic group as diabetic neuropathy, postherpetic neuralgia, central pain syndrome and cancer related plexopathy, 10 patients per each group were equally accumulated. Patients have been stabilized in their analgesic regimen at least four weeks prior to enrollment into study. TCA, if taken, was discontinued for two weeks for wash out period. Baseline four point verbal pain intensity score was obtained and oral administration of paroxetine 20 mg was initiated. At two weeks follow-up visit, pain intensity scores, pain improvement scores judged by family, drug efficacy, tolerability and overall evaluation were assessed. The incidence of side effects were also obtained. Result: After two weeks of treatment, pain intensity scores decreased in 77.5% of patients and no patients experienced aggravation. These findings were objectively reflected in pain improvement scores judged by family members. But, the number of nonresponders was different among groups. In drug efficacy, tolerability and overall evaluation, the proportions of patients who scored as excellent or good were 75%, 80% and 80% respectively. Incidence of side effects was 27.5%, but the side effects spontaneously disappeared after discontinuation of medication. Conclusion: Paroxetine, a selective serotonin reuptake inhibitor, appears to be effective as adjuvant analgesic for the management of various neuropathic pain syndromes.