• Biomolecules & Therapeutics
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• 제29권4호
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• pp.392-398
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• 2021

In this study, we determined the effect of 24 different synthetic 4-benzylpiperidine carboxamides on the reuptake of serotonin, norepinephrine, and dopamine (DA), and characterized their structure-activity relationship. The compounds with a two-carbon linker inhibited DA reuptake with much higher potency than those with a three-carbon linker. Among the aromatic ring substituents, biphenyl and diphenyl groups played a critical role in determining the selectivity of the 4-benzylpiperidine carboxamides toward the serotonin transporter (SERT) and dopamine transporter (DAT), respectively. Compounds with a 2-naphthyl ring were found to exhibit a higher degree of inhibition on the norepinephrine transporter (NET) and SERT than those with a 1-naphthyl ring. A docking simulation using a triple reuptake inhibitor 8k and a serotonin/norepinephrine reuptake inhibitor 7j showed that the regions spanning transmembrane domain (TM)1, TM3, and TM6 form the ligand binding pocket. The compound 8k bound tightly to the binding pocket of all three monoamine reuptake transporters; however, 7j showed poor docking with DAT. Co-expression of DAT with the dopamine D₂ receptor (D₂R) significantly inhibited DA-induced endocytosis of D₂R probably by reuptaking DA into the cells. Pretreatment of the cells with 8f, which is one of the compounds with good inhibitory activity on DAT, blocked DAT-induced inhibition of D₂R endocytosis. In summary, this study identified critical structural features contributing to the selectivity of a molecule for each of the monoamine transporters, critical residues on the compounds that bound to the transporters, and the functional role of a DA reuptake inhibitor in regulating D₂R function.

• 한국임상약학회지
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• 제20권3호
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• pp.229-234
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• 2010

섬유근통 증후군은 만성 전신 통증을 나타내며 피곤, 두통, 우울증, 수면장애 등을 동반하는 질환이다. 주로 30-50대의 여성에게서 많이 나타나며 미국에서 2-4%, 한국에서 2%의 발병률을 보이고 있다. 정확한 원인과 기전이 밝혀져 있지 않아서 진단과 치료에 많은 논란과 어려움이 있다. 현재는 증상치료에 목표를 두고 삼환계항우울약을 많이 사용하고 있으나 심각한 부작용의 문제가 있다. 이러한 문제 때문에 최근에는 selective serotonin reuptake inhibitor (SSRI) 또는 serotonin-norepinephrine reuptake inhibitor (SNRI)를 빈번히 사용하고 있다. 본 연구는 SNRI의 하나인 milnacipran의 섬유근통 증후군 치료에 대한 효능 및 안정성을 알아보기 위해, MEDLINE에 등재된 논문을 기한없이 milnacipran과 fibromyalgia로 검색하여 무작위 배정 및 이중맹검 임상연구자료들을 선별하였다. 선별된 6개의 임상연구 결과, milnacipran를 사용했을 때 일관된 효능성과 안정성이 관찰되었고 섬유근통증후군 치료와 그에 수반되는 여러증상에 효과적인 것으로 나타났다.

• 정신신체의학
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• 제21권2호
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• pp.81-92
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• 2013

새로운 항우울제가 개발되고 임상에서 정신과적 질환뿐만이 아니라 만성통증증후군, 섬유근통증증후군, 두통 등의 많은 정신신체질환 그리고 신체질환자의 적응장애 및 우울증 등의 자문조정정신의학 영역에서도 다양하게 자주 사용되고 있다. 다양한 정신의학적 질환을 치료하기 위해 처방하는 새로운 항우울제의 사용 시 치료중단의 가장 큰 원인은 약물부작용이다. 이 논문은 현재 우리나라에서 널리 사용되고 있는 새로운 항우울제 사용 시 나타나는 부작용들 중 정신신체의학과 자문조정정신의학영역에서 관심을 가져야 할 매우 빈번하게 나타나는 세 가지 부작용인 오심과 구토, 체중증가, 성기능장애에 대한 발생기전, 발생빈도, 그리고 약물학적 처치를 위주로 한 해결방안을 알아보았다. 저자는 이 논문을 통하여 정신건강의학과 의사만이 아니라 정신신체의학 영역에 관심을 가지거나 자문조정정신의학과 연계되는 타과 영역의 의사들이 새로운 항우울제를 사용할 때 빈번하게 나타나서 삶의 질을 떨어뜨리고 치료중단을 일으킬 수 있는 이 약물들의 부작용을 잘 인지함으로써 이를 조기에 발견하고 적절히 해결하여 환자 치료에 도움을 주고자 하였다.

• 정신신체의학
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• 제29권2호
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• pp.153-161
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• 2021

연구목적 본 연구는 주요우울장애 환자들을 대상으로, 혈소판기능분석기(Platelet Function Analyzer, PFA-100)를 사용하여 선택적 세로토닌 재흡수 억제제(Selective Serotonin Reuptake Inhibitors, SSRI)와 세로토닌 노르에피네프린 재흡수 억제제(Serotonin Norepinephrine Reuptake Inhibitors, SNRI)의 출혈 경향성을 분석하고, 두 군 사이의 차이를 비교 분석하고자 하였다. 방 법 본 연구는 단일 기관에서 시행된 전향적 개방연구로 DSM-5 진단기준에 의해 주요우울장애로 진단받은 총 41명을 대상으로 하였다. 대상군을 무작위 배정에 따라 각각 SSRI (Escitalopram) 투여군과, SNRI (Duloxetine) 투여군으로 분류하였다. 각 항우울제를 투여 받기 전과 6주가 지난 시점에 혈소판기능분석기(Platelet Function Analyzer, PFA-100)를 이용하여 폐색시간(Closure Time, CT)을 측정하였다. 특정 항우울제가 폐색시간에 영향을 미치는지 알아보기 위해 각 군 내에서 대응표본 t-검정(Paired t-test)을 시행하였고, 두 군 사이에 혈소판 기능의 상대적인 변화를 확인하기 위해 공분산 분석(Analysis Of Covariance, ANCOVA)을 시행하여 두 군의 폐색시간의 변화를 비교 분석하였다. 결 과 SSRI군과 SNRI군에서 약물 투여 전과 6주후 폐색시간(CEPI-CT, CADP-CT)에 대한 유의한 변화는 없었고, 두 군 간의 폐색시간 변화량에도 차이가 없었다. 결 론 혈소판기능분석기(Platelet Function Analyzer, PFA-100)를 통해 SSRI인 Escitalopram과 SNRI인 Duloxetine간의 출혈경향성에 차이가 없음을 보였다. 향후 다양한 항우울제를 대상으로 출혈경향성에 대한 추가적인 대규모 연구가 필요할 것으로 보인다.

• 정신신체의학
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• 제28권1호
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• pp.72-80
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• 2020

연구목적 본 연구는 통증 및 신체증상이 동반된 노인 우울증 환자에서 기분증상 및 통증, 신체 증상에 대한 선택적 세로토닌 재흡수 억제제(Selective Serotonin Reuptake Inhibitor, SSRI)와 세로토닌 노르에피네프린 재흡수 억제제(Serotonin Norepinephrine Reuptake Inhibitor, SNRI)의 치료 효과를 비교하기 위해 실시되었다. 방 법 본 연구는 단일 기관에서 시행된 전향적 개방연구로 DSM-5 진단기준에 의해 주요우울장애로 진단받은 총 43명의 대상자들이 본 연구에 참여하였다(평균연령 : 72.53세, 여성 58.1%). 대상군은 SSRI, SNRI 두 군으로 분류되었고 우울, 통증 및 신체증상은 각각 한국판 해밀턴 우울증 평가척도(Korean version of the Hamilton Depression Rating Scale, K-HDRS), 시각적 비율 척도(Visual Analogue Scale, VAS), 환자 건강 설문지(Patient Health Questionnare-15, PHQ-15)를 사용하여 평가되었다. 이원배치 반복측정 분산분석(Two-way repeated-measure ANOVA)으로 약물 투여 전과 투여 후 6주의 KHDRS, VAS, PHQ-15 점수 변화를 분석하였다. 결 과 SSRI군과 SNRI군에서 K-HDRS, VAS, PHQ-15 모두 약물 투약 전에 비해 6주 후의 점수가 유의하게 호전되었으며, 두 군 간에 호전 정도의 차이는 없었다. 결 론 노인 우울증 환자에서 SSRI, SNRI 모두 통증 및 신체증상을 호전시키는 것으로 나타났다. 본 연구 결과는 통증 및 신체증상을 호소하는 노인 우울증 환자에게 약물치료를 시행할 때 선택할 수 있는 항우울제 처방 결정에 도움을 줄 수 있을 것이라고 생각되며, 약물의 장기적인 효과에 대해서 추가적인 연구가 필요할 것으로 보인다.

• Biomolecules & Therapeutics
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• 제26권2호
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• pp.115-120
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• 2018

Chronic cerebral hypoperfusion (CCH), which is associated with onset of vascular dementia, causes cognitive impairment and neuropathological alterations in the brain. In the present study, we examined the neuroprotective effect of duloxetine (DXT), a potent and balanced serotonin/norepinephrine reuptake inhibitor, on CCH-induced neuronal damage in the hippocampal CA1 region using a rat model of permanent bilateral common carotid arteries occlusion. We found that treatment with 20 mg/kg DXT could attenuate the neuronal damage, the reduction of phosphorylations of mTOR and p70S6K as well as the elevations of $TNF-{\alpha}$ and $IL-1{\beta}$ levels in the hippocampal CA1 region at 28 days following CCH. These results indicate that DXT displays the neuroprotective effect against CCH-induced hippocampal neuronal death, and that neuroprotective effect of DXT may be closely related with the attenuations of CCH-induced decrease of mTOR/p70S6K signaling pathway as well as CCH-induced neuroinflammatory process.

• Journal of Pharmaceutical Investigation
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• 제40권1호
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• pp.33-38
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• 2010

Sibutramine is a serotonin-norepinephrine reuptake inhibitor indicated for the management of obesity in conjunction with a reduced calorie diet. The oral administration of sibutramine is followed by its dose-related side effects. In this study, sibutramine was formulated into drug in adhesive (DIA) patches in an attempt to overcome these problems. The effects of different formulation variables including pressure-sensitive adhesive (PSA), loading amount of drug, thickness of matrix and enhancer on the skin permeation of the drug were evaluated using excised hairless mouse skin. In the acrylic adhesive with carboxyl functional group, low release of sibutramine was observed due to the strong interaction between carboxyl group of adhesive and amine group of sibutramine. The acrylic adhesive without functional group provided good adhesion force and allowed high drug loading. Changing drug load as well as thickness of the matrix was found to alter permeation rate. $Crovol^{(R)}$ PK40 and $Crovol^{(R)}$ A40, were found to be effective enhancers for sibutramine. The optimized patch contained 20% sibutramine, and 5% $Crovol^{(R)}$ A40 as permeation enhancer, in $80\;{\mu}m$ thick Duro-$Tak^{(R)}$ 87-9301 matrix.

• 대한핵의학회지
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• 제38권5호
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• pp.331-337
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• 2004

Cardiac neurotransmission imaging allows in vivo assessment of presynaptic reuptake, neurotransmitter storage and postsynaptic receptors. Among the various neurotransmitter, I-123 MIBG is most available and relatively well-established. Metaiodobenzylguanidine (MIBG) is an analogue of the false neurotransmitter guanethidine. It is taken up to adrenergic neurons by uptake-1 mechanism as same as norepinephrine. As tagged with I-123, it can be used to image sympathetic function in various organs including heart with planar or SPECT techniques. I-123 MIBG imaging has a unique advantage to evaluate myocardial neuronal activity in which the heart has no significant structural abnormality or even no functional derangement measured with other conventional examination. In patients with cardiomyopathy and heart failure, this imaging has most sensitive technique to predict prognosis and treatment response of betablocker or ACE inhibitor. In diabetic patients, it allow very early detection of autonomic neuropathy. In patients with dangerous arrhythmia such as ventricular tachycardia or fibrillation, MIBG imaging may be only an abnormal result among various exams. In patients with ischemic heart disease, sympathetic derangement may be used as the method of risk stratification. In heart transplanted patients, sympathetic reinnervation is well evaluated. Adriamycin-induced cardiotoxicity is detected earlier than ventricular dysfunction with sympathetic dysfunction. Neurodegenerative disorder such as Parkinson's disease or dementia with Lewy bodies has also cardiac sympathetic dysfunction. Noninvasive assessment of cardiac sympathetic nerve activity with I-123 MIBG imaging nay be improve understanding of the pathophysiology of cardiac disease and make a contribution to predict survival and therapy efficacy.

• Toxicological Research
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• 제32권3호
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• pp.207-213
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• 2016

Although propolis is one of the most popular functional foods for human health, there have been no comprehensive studies of herb-drug interactions through cytochrome P450 (CYP) inhibition. The purpose of this study was to determine the inhibitory effects of propolis on the activities of CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and 3A4 using pooled human liver microsomes (HLMs). Propolis inhibited CYP1A2, CYP2E1 and CYP2C19 with an $IC_{50}$ value of 6.9, 16.8, and $43.1{\mu}g/mL$, respectively, whereas CYP2A6, 2B6, 2C9, 2D6, and 3A4 were unaffected. Based on half-maximal inhibitory concentration shifts between microsomes incubated with and without nicotinamide adenine dinucleotide phosphate, propolis-induced CYP1A2, CYP2C19, and CYP2E1 inhibition was metabolism-independent. To evaluate the interaction potential between propolis and therapeutic drugs, the effects of propolis on metabolism of duloxetine, a serotonin-norepinephrine reuptake inhibitor, were determined in HLMs. CYP1A2 and CYP2D6 are involved in hydroxylation of duloxetine to 4-hydroxy duloxetine, the major metabolite, which was decreased following propolis addition in HLMs. These results raise the possibility of interactions between propolis and therapeutic drugs metabolized by CYP1A2.

• The Korean Journal of Pain
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• 제29권3호
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• pp.153-157
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• 2016

Tapentadol is a novel oral analgesic with a dual mode of action as an agonist of the ${\mu}$-opioid receptor (MOR), and as a norepinephrine reuptake inhibitor (NRI) all in a single molecule. Immediate release (IR) tapentadol shows its analgesic effect quickly, at around 30 minutes. Its MOR agonistic action produces acute nociceptive pain relief; its role as an NRI brings about chronic neuropathic pain relief. Absorption is rapid, with a mean maximal serum concentration at 1.25-1.5 h after oral intake. It is present primarily in the form of conjugated metabolites after glucuronidation, and excretes rapidly and completely via the kidneys. The most common adverse reactions are nausea, dizziness, vomiting, and somnolence. Constipation is more common in use of the ER formulation. Precautions against concomitant use of central nervous system depressants, including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and alcohol, or use of tapentadol within 14 days of the cessation of monoamine oxidase inhibitors, are advised. The safety and efficacy have not been established for use during pregnancy, labor, and delivery, or for nursing mothers, pediatric patients less than 18 years of age, and cases of severe renal impairment and severe hepatic impairment. The major concerns for tapentadol are abuse, addiction, seeking behavior, withdrawal, and physical dependence. The presumed problem for use of tapentadol is to control the ratio of MOR agonist and NRI. In conclusion, tapentadol produces both nociceptive and neuropathic pain relief, but with worries about abuse and dependence.