• 동의생리병리학회지
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• 제32권1호
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• pp.24-29
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• 2018

In order to define the effect of Torilis Fructus(TF) extract which has been used for the treatment of erectile dysfunction, experiments were carried out by organ bath study, histochemical and immunohistochemical methods. First, in the organ bath study, when TF extract was administered to the maxillary contracted corpus cavernosum by PE ($10^{-6}M$), there was a significant relaxation effect on corpus cavernosum at concentration of 1, $3mg/m{\ell}$. Compared with the absence of $\text\tiny{L}$-NNA pretreatmen, pretreatment of $\text\tiny{L}$-NNA was inhibited the relaxation effect of penile corpus cavernosum. In the immunohistochemical study, the eNOS positive reaction was significantly increased, and the PDE5 positive reaction was significantly decreased due to the administration of TF extract. Therefore, it show that the TF enhances the production of eNOS and NO, inhibits PDE5 which blocks the action of increased cGMP, relaxes the corpus cavernosum. So TF relaxes the corpus cavernosum and it can be used as a safer erectile dysfunction treatment.

• Journal of Korean Neurosurgical Society
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• 제65권5호
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• pp.665-679
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• 2022

Objective : Patients with mild ischemic stroke experience various sequela and residual symptoms, such as anxious behavior and deficits in movement. Few approaches have been proved to be effective and safe therapeutic approaches for patients with mild ischemic stroke by acute stroke. Sildenafil (SIL), a phosphodiesterase-5 inhibitor (PDE5i), is a known remedy for neurodegenerative disorders and vascular dementia through its angiogenesis and neurogenesis effects. In this study, we investigated the efficacy of PDE5i in the emotional and behavioral abnormalities in rats with mild ischemic stroke. Methods : We divided the rats into four groups as follows (n=20, respectively) : group 1, naïve; group 2, middle cerebral artery occlusion (MCAo30); group 3, MCAo30+SIL-pre; and group 4, MCAo30+SIL-post. In the case of drug administration groups, single dose of PDE5i (sildenafil citrate, 20 mg/kg) was given at 30-minute before and after reperfusion of MCAo in rats. After surgery, we investigated and confirmed the therapeutic effect of sildenafil on histology, immunofluorescence, behavioral assays and neural oscillations. Results : Sildenafil alleviated a neuronal loss and reduced the infarction volume. And results of behavior task and immunofluorescence shown possibility that anti-inflammation process and improve motor deficits sildenafil treatment after mild ischemic stroke. Furthermore, sildenafil treatment attenuated the alteration of theta-frequency rhythm in the CA1 region of the hippocampus, a known neural oscillatory marker for anxiety disorder in rodents, induced by mild ischemic stroke. Conclusion : PDE5i as effective therapeutic agents for anxiety and movement disorders and provide robust preclinical evidence to support the development and use of PDE5i for the treatment of mild ischemic stroke residual disorders.

• Mass Spectrometry Letters
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• 제3권1호
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• pp.15-17
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• 2012

Eighteen of the PDE-5 inhibitors and their analogues were analyzed using GC-EI-MS. Fourteen of them could be identified by simple GC-MS method without derivatization, but hydroxyhongdenafil, hydroxyvardenafil, xanthoanthrafil and mirodenafil could not be identified without derivatization for the high polarity due to the presence of hydroxyl groups. N,O-bis(trimethylsilyl) trifluoroacetamide (BSTFA) and N-methyl-N-(tert-butyldimethylsilyl)trifluoroacetamide (MTBSTFA), widely used trimethylsilyl (TMS) derivatizing reagents, were used to improve the sensitivity of the hydroxylated analogues. And the analytes could be identified by GC-MS after the derivatization.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1994년도 춘계학술대회 and 제3회 신약개발 연구발표회
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• pp.286-286
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• 1994

Thrombin (0.25 U/ml : TB), 소-피부 collagen (200 $\mu\textrm{g}$/ml : CG), adenosine 5'-diphesphate (4,0 $\times$ $10^{-5}$M : ADP), 및 epinephrine (4,0 $\times$ 10 $^{-5}$M : EPI)의 가토-혈소판 응집과 단백인산화작용에 미치는 PDE-I (3-isobutyl-1-methylxanthine : IBMX, 및 KR 30075), amitriptyline (AP), chlorpromazine (CP), 및 sodium nitrogrosside (SNP)의 염향을 비교-검토하였다. 그 결과, KR은 2,2 $\times$ $10^{-7}$M 이하의 $IC_{50}$/에서 EPI > ADP > CG > TB 순으로 각각을 억제하였으며, SNP 보다도 강하였고; KR-30075보다 약하나 IBMX, AP, 및 CP도 각 응집재의 작용을 억제하였으며 특히 EPI에 대하여 $10^{-8}$M 이하의 $IC_{50}$/에서 유의한 억제력을 보였다. 각 응집제들은 41 kD 인산화는 유의하게 증가시키며 47 kD와 20 kD 단백인산화는 감소시켰는데; 모든 항응집성 약물이 41 kD 인산화-증가는 유의하게 억제하였다, 아울러, AP와 CP는 47 kD 단백인산화-감소에 영향을 미치지 않았으나 20 kD 단백인산화-감소는 억제하였다. PDE-I (IBMX와 KR)와 SNP는 47 kD와 20 kD 단백인산화-감소를 다소 약화시켰으며, 43 kD와 22 kD 단백인산화를 KR > IBMX > SNP순으로 유의하게 증가시켰고, KR의 22 kD 단백인산화작용은 현저하였다.

• 한국식품영양과학회지
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• 제45권11호
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• pp.1571-1579
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• 2016

본 연구는 땅콩나물 열수 추출물이 남성 갱년기 관련 증상인 전립선 비대증과 발기부전에 대해 어떠한 영향을 미치는지 알아보기 위하여 phosphodiesterase(PDE) 저해 효과, 5-alpha reductase 활성 억제능, RAW264.7 세포에서 NO 함량 측정 및 TM3 세포에서 testosterone 함량을 측정하였다. 땅콩나물 추출물은 높은 PDE 저해능을 확인되었다. 또한, 5AR2 활성을 억제하였다. 전립선 비대와 관련된 염증에 대한 영향으로 RAW264.7 세포에서 lipopolysaccharide에 대한 NO 함량 억제능을 확인한 결과 땅콩나물 열수 추출물에 의해 NO 생성이 억제되었고 염증 인자가 감소하는 것으로 나타났다. TM3 세포에서 과산화수소로 유도된 산화적 손상에서는 땅콩나물 추출물 처리 시에 높은 세포보호능을 보였으며, 땅콩나물 추출물에 의해 testosterone 함량도 증가하는 것을 확인할 수 있었다. 결과적으로 땅콩나물 열수추출물은 5AR2 억제 활성을 증대시키고 항염증 효과가 전립선 비대증의 유발을 억제시킬 수 있다는 선행연구로 볼 때 땅콩나물 추출물은 전립선 비대 유발에 직접 관계된 효소와 유전자를 제어함과 동시에 항염증 효능을 가짐으로써 전립선 비대 증상 개선에 매우 효과적일 것으로 판단된다. 또한, 땅콩나물 추출물은 PDE 활성을 저해함으로써 발기부전 증상을 완화시키고 고환 내 세포의 산화적 스트레스를 완화하며, testosterone과 같은 호르몬 합성을 증가시켜 전립선 비대증 외에 발기부전 및 호르몬 저하로 인해 발생하는 남성갱년기 증상에도 효과를 보일 것으로 기대된다. 이상의 결과로 볼 때 땅콩나물 열수 추출물은 전립선 비대를 비롯한 남성갱년기 증상을 완화시키는 기능성 소재로 활용할 수 있을 것으로 보인다.

• 대한약리학회지
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• 제27권2호
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• pp.119-123
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• 1991

${\beta}-$수용체 효능약물 ((-)-NE), 길항약물 $((\pm)-propranolol,\;labetalol)$ 및 PDE 억제약물(imazodan, KR-30045, KR-30075 등)에 대한 ${\beta}-adrenoceptor$ binding 실험을 ${\beta}_1/{\beta}_2$ 비선택적 radioligand인 $(-)-[^3H]-DHA$를 사용하여 실시하였다. Saturation 실험에서 ${\beta}_1$ 및 ${\beta}_2$ 수용체를 모두 갖고 있는 rat 좌심실의 ${\beta}$ 수용체에 대한 $(-)-[^3H]-DHA$의 $K_d$ 값은 $1.5{\pm}0.43\;nM$, $B_{max}$는 $22.0{\pm}0.9\;fmol/mg$ protein이었다. $({\pm})propranolol$, labetalol 및 (-)NE는 단일상으로 $(-)-[^3H]-DHA$의 결합을 억제하였으며 Ki 값은 각각 $17.0{\pm}0.43\;nM$, $57.3{\pm}1.30\;nM$, $1.57{\pm}0.95\;{\mu}M$로 나타났다. 실험에 사용한 모든 PDE 억제약물들은 $(-)-[^3H]-DHA$ 결합을 $10^{-3}\;M$의 고농도에서도 10% 미만으로 억제했다. 실험결과, propraolol, labetalol 및 NE는 ${\beta}_1/{\beta}_2$ 수용체에 대해 비선택적인 약물로 나타났으며, imazodan 및 신합성 PDE 억제약물들은 rat 심근에 있는 ${\beta}-$수용체에 친화성이 거의 없음을 알 수 있었다.

• Mass Spectrometry Letters
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• 제6권2호
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• pp.38-42
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• 2015

Roflumilast analogs are a group of drugs which act as selective photodiesterase (PDE-4) inhibitor for the treatment severe chronic pulmonary disease associated with chronic brochnonities. Structural identification of degradation products using high resolution mass spectrometry and theoretical investigation by density functional theory have been successfully carried out on roflumilast to identify four degradation products namely, 3,5-dichloropyridin-4-amine, N-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-3-hydroxy benzamide, N-(3,5-dichloropyridin-4-yl)-3-(cyclopropylmethoxy)-4-(difluoromethoxy) benzamide and 3-(cyclopropylmethoxy)-N-(3,5-dichloro-1-oxidopyridin-4-yl)-4-(difluoro methoxy) benzamide, generated in alkali, acidic and oxidative conditions.

• Natural Product Sciences
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• 제23권3호
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• pp.169-174
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• 2017

The aim of this study was to investigate the effect and action mechanism of quercetin on penile corpus cavernosum smooth muscle (PCCSM). PCCSM precontracted with phenylephrine (Phe) was treated with four different concentrations of quercetin ($10^{-7}$, $10^{-6}$, $10^{-5}$ and $10^{-4}M$). PCCSM were preincubated with N-Nitro-L-arginine methyl ester hydrochloride (L-NAME) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) to block nitric oxide synthase and guanylate cyclase, respectively. The changes in PCCSM tension were recorded, and cyclic nucleotides in the perfusate were measured by radioimmunoassay. The interactions of quercetin with phosphodiesterase type 5 inhibitors (PDE5-Is) such as sildenafil, udenafil and mirodenafil, were also evaluated. PCCSM relaxation induced by quercetin occurred in a concentrationdependent manner. The application of quercetin to PCCSM pre-treated with L-NAME and ODQ significantly inhibited the relaxation. Quercetin significantly increased cGMP in the perfusate. Furthermore, quercetin enhanced PDE5-Is-induced relaxation of PCCSM. Quercetin relaxed the PCCSM by activating the NO-cGMP signaling pathway, and it may be a therapeutic candidate or an alternative treatment for patients with erectile dysfunction who do not completely respond to PDE5-Is.

• Journal of Pharmaceutical Investigation
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• 제40권2호
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• pp.117-123
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• 2010

Ibudilast, 3-isobutyryl-2-isopropyrazolo[1,5-a]pyridine, is a nonselective inhibitor of cyclic nucleotide phosphodiesterase (PDE). It preferentially inhibits PDE 3A, PDE4, PDE10 and PDE11 as well as a number of the other PDE families, albeit to a lesser extent. Ibudilast is used clinically to treat bronchial asthma and cerebrovascular disorders. Thes e clinical uses are based on the ability of ibudilast to inhibit platelet aggregation, improve cerebral blood flow and attenuate allergic reactions. The purpose of the present study was to evaluate the bioequivalence of two ibudilast capsules, Ketas capsule (Handok Pharmaceuticals Co., Ltd.) and Pinatos capsule (Sam Chun Dang Pharm. Co., Ltd.), according to the guidelines of the Korea Food and Drug Administration (KFDA). The in vitro release of ibudilast from the two ibudilast formulations was tested using KP Apparatus method with various dissolution media. Twenty six healthy male subjects, 23.31${\pm}$1.09 years in age and 70.45${\pm}$8.51 kg in body weight, were divided into two groups and a randomized $2{\times}2$ cross-over study was employed. After a single capsule containing 10 mg as ibudilast was orally administered, blood samples were taken at predetermined time intervals and the concentrations of ibudilast in serum were determined using HPLC/UV detector. The dissolution profiles of two formulations were similar in all tested dissolution media. The pharmacokinetic parameters such as $AUC_t$, $C_{max}$ and $T_{max}$ were calculated, and computer programs (Equiv Test and K-BE Test 2002) were utilized for the statistical analysis of the parameters using logarithmically transformed $AUC_t$, $C_{max}$ and untransformed $T_{max}$. The results showed that the differences between two formulations based on the reference drug, Ketas, were 6.99%, -2.48% and 9.93% for $AUC_t$, $C_{max}$ and $T_{max}$, respectively. There were no sequence effects between two formulations in these parameters. The 90% confidence intervals using logarithmically transformed data were within the acceptance range of log 0.8 to log 1.25 (e.g., log 0.8791~log 1.1861 and log 0.8347~log 1.1199 for $AUC_t$ and $C_{max}$, respectively). Thus, the criteria of the KFDA bioequivalence guideline were satisfied, indicating Pinatos capsule was bioequivalent to Ketas capsule.

• 동의생리병리학회지
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• 제30권5호
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• pp.308-313
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• 2016

The purpose of this study is to investigate the effects of Oja-Shingiwhan(OS) in contracted corpus cavernosum smooth muscle and its mechanism. To evaluate the relaxation of OS in contracted corpus cavernosum, OS was treated in strips which were precontracted with phenylephrine(PE). To examine its mechanism, OS was treated into corporal strips contracted by PE after pretreatment of Nω-nitro-L-arginine(L-NNA) and compared with non-pretreatment of _L-NNA. In calcium chloride(Ca²⁺)-free krebs solution, Ca²⁺ 1 mM was treated into corporal strips contracted by PE after pretreatment of OS and compared with non-pretreatment of OS. action were measured by histochemical, immunohistochemical methods. OS significantly affected on the relaxation of corporal strips, and the relaxation effects were inhibited by pretreatment of L-NNA. Contractions induced by Ca²⁺ influx were inhibited by pretreatment of OS in Ca²⁺-free krebs solution. OS increased eNOS positive reaction in corpus cavernosum, but decreased PDE-5 positive reaction. These result suggest that the effect of OS in contracted corpus cavernosum smooth muscle are shown by suppressing extracellular Ca²⁺ influx and increase of eNOS, NO production and decrease of PDE-5.