• Biomolecules & Therapeutics
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• 제11권4호
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• pp.232-237
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• 2003

The present study examined functional effects of a new selective phosphodiesterase type 5 inhibitor, 1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-thioxo-3-propyl-1H-pyrazolo[ 4,3]pyrimidin-5-yl)phenylsulphonyl]-4-methyl piperazine (KJH-1002), in the isolated rabbit corpus cavernosum (RCC). Relaxing effects of KJH-1002 were also compared with those of sildenafil, which is currently used as an oral therapy for penile erectile dysfunction. In the isolated RCC precontracted with phenylephrine, both KJH-1002 and sildenafil in the concentration range of 1 to 1000 nM, produced a comparable potentiation of the electical field stimulation-induced relaxation in a concentration-dependent manner. In the sodium nitroprusside (SNP)-induced relaxation, the $IC_{50}$/ values, concentrations of SNP required to produce a 50％ relaxation of the phenylephrine-induced contraction, were significantly decreased to the similar extent by treatments with KJH-1002 and sildenafil. The results suggest that a new selective phosphodiesterase type 5 inhibitor, KJH-1002, has an augmentative effect on penile erection comparable to that of sildenafil and can be useful for the treatment of erectile dysfunction.

• 생약학회지
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• 제43권2호
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• pp.184-191
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• 2012

The aim of this study was to explore the potent phosphodiesterase type 5 (PDE %) inhibitor from various herbal medicines for erectile dysfunctions. In this study, 61 herbal medicines, which were extracted with ethanol, have been investigated with PDE 5 assay using enzyme inhibitory activity on 22 species of herbal medicines. Of these, 5 species of herbal medicines, Cnidium monieri, Cuscuta chinensis, Epimedium koreanum, Morinda officinalis, and Tribulus terrestris were exhibited stronger inhibitory effect against phosphodiesterase 5 (PDE 5) among 61 species; Cnidium monieri ($IC_{50}=33.7{\mu}g/ml$), Cuscuta chinensis ($IC_{50}=65.7{\mu}g/ml$), Epimedium koreanum ($IC_{50}=90.3{\mu}g/ml$), Morinda officinalis ($IC_{50}=48.7{\mu}g/ml$) and Tribulus terrestris ($IC_{50}=32.5{\mu}g/ml$).

• 생약학회지
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• 제45권3호
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• pp.268-274
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• 2014

The aim of this study is to explore the potent phosphodiesterase 4 and 7 inhibitor from various herbal medicines for atopy treatment. In this study, 51 kinds of each herbal medicine, which were extracted with ethanol, was carried out the screening of PDE 4 and 7 inhibition using enzyme inhibitory assay. Of these, 8 species of herbal medicines, Rubus coreanus, Duchesnea chrysantha, Alisma orientale, Rehmannia glutinosa, Angelica dahurica, Thuja orientalis, Astragalus membranaceus and Perilla frutescens were screened as potential inhibitor against PDE 4 and 7. Among 8 species, Duchesnea chrysantha showed poteinial anti-atopic effect on DNCB-induced atopic model. Duchesnea chrysantha extract decreased serum IgE and histamine release significantly.

• Childhood Kidney Diseases
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• 제6권1호
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• pp.85-91
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• 2002

서 론 : Phosphodiesterase (PDE) 억제제는 세포내 cAMP를 증가시키며, cAMP는 TGF-${\beta}1$에 의한 connective tissue growth factor (CTGF)의 발현을 억제하는 것으로 알러져 있다. 그러므로 저자들은 PDE 억제재가 TGF-${\beta}1$의 변화 없이 긴 섬유화를 억제할 수 있는지를 확인해 보고자 본 연구를 시행하였다. 방 법 : 백서에서 일측성 요관 결찰로 신 간질 섬유화를 유발하였다. 실험군에서는 PDE3 억제제인 cilostazol (1 g/L)이나 PDE5, PDE6, PDE8의 hybrid 억제제인 dipyridamole (750 mg/L)이 첨가된 음료수를 공급하였다. 일주일 후 신장을 적출하여 Masson-trichrome score를 평가하고, 신조직 조건배지에서 fibronectin과 TGF-${\beta}1$을 ELISA법으로 정량하였다. 결 과 : 대조군에 비해 cilostazol 군에서 Masson-trichrome score와 신조직 조건배지의 fibronectin 농도가 유의하게 낮았다(P<0.05). Dipyridamole군의 Masson-trichrome score와 조건배지의 fibronectin 농도도 대조군에 비해 낮아 보였으나 통계적 유의성을 보여주지 못했다. 신조직 조건배지의 TGF-${\beta}1$ 농도는 대조군, cilostazol군, dipyridamole군간에 차이가 없었다. 결 론 : 선택적 PDE3 억제제인 cilostazol은 TGF-${\beta}1$의 억제에 의존하지 않고 일측성 요로 폐쇄에 의한 신 섬유화를 억제하였다.

• Biomolecules & Therapeutics
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• 제10권2호
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• pp.117-123
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• 2002

CJ-10882, (E)-[(3-Cyclopentyloxy-4-methoxyphenyl)methylene]hydrazine-carboxamide, is a newly developed type IV phosphodiesterase isozyme (PDE IV) inhibitor. To investigate the subacute toxic effects of CJ-10882, it was administered to both male and female dogs at 0, 25, 50, 100 or 200 mg/kg/day orally for up to 2 weeks. During the test period, clinical signs, mortality, body weight, food consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross finding, organ weight, and histopathology were evacuated. Several clinical signs were observed in treated dogs at above 25 mg/kg, including salivation and vomiting. A reduction in the body weight was observed in both sexes at above 50 mg/kg. There were no treatment-related effects on mortality, ophthalmoscopy, urinalysis, hematology, sect biochemistry, necropsy findings, and histopathology in any treatment group. The results of this study demonstrate that CJ-10882, a selective Inhibitor of the type IV class of PDE, may cause effects on gastrointestinal tract and salivary glands. Therefore, these organs should be closely examined in studies with other PDE IV inhibitors.

• 약학회지
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• 제48권3호
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• pp.197-201
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• 2004

Phosphodiesterases (PDEs) are enzymes that degrade intracellular cAMP. In the present study, pentoxifylline, a PDE inhibitor, induced osteoclast formation in co-cultures of mouse bone marrow cells and calvarial osteoblasts. To address the involvement of the osteoclast differentiation factor TNF-related activation-induced cytokine (TRANCE, identical to RANKL, ODF, and OPGL), mouse bone marrow cells and calvarial osteoblasts were co-cultured with pentoxifylline in the presence of OPG, a decoy receptor for TRANCE. The osteoclastogenic effect of pentoxifylline was completely blocked by addition of OPG, suggesting that TRANCE is involved in the osteoclast formation induced by pentoxifylline, Northern blot analysis revealed that pentoxifylline significantly induced TRANCE mRNA expression in calvarial osteoblasts. These results suggests that pentoxifylline regulates TRANCE expression in osteoblasts, which in turn controls osteoclast formation.

• Archives of Pharmacal Research
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• 제23권5호
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• pp.471-476
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• 2000

DA-8159, a new phosphodiesterase 5 inhibitor, was assessed for its erectogenic potential by a penile erection test in rats, the relaxation of isolated rabbit corpus cavernosum (CC), and estimation of the intracavernous pressure (ICP) in the anesthetized dog. Oral administration of DA-8159 (0.3 to 1 ${\mu}g/kg$ ) increased the number of erections in rats with increasing dosage, with the highest penile erection index at 10 ${\mu}g/kg$ DA-8159 induced the relaxation of phenylephrine (PHE)-induced contractions in the rabbit CC and decreased the $IC_{50}$ of the nitric oxide donor sodium nitroprusside (SNP) in a dose-dependent fashion. In pentobarbital-anesthetized dogs, the intravenous administration of DA-8159 (1~300 ${\mu}g/kg$ ) potentiated the increase in ICP induced by the intracavernosal SNP in a dose-related manner. These findings suggest that DA-8159 has significant therapeutic potential in the treatment of erectile dysfunction.

• Applied Biological Chemistry
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• 제13권2호
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• pp.111-129
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• 1970

핵산 및 그 관련물질 연구의 일환으로서 미생물 효소에 의하여 핵산을 분해하여 5'-mononucleotides 생성을 목적으로 미생물에서 5'-phosphodiesterase 생성균주를 얻기위하여 전국 각지 76개 지역에서 논, 밭, 산, 하천의 토양 그리고 퇴비, 누룩, 메주 등 시료 210종을 수집하였다. 이 수집 시료로 부터 dilution pour plate method 로서 Aspergillus속 240주, Penicillium속 232주, Neurospora속, 19주, Monascus속 16주, 그리고 Streptomyces속 265주로 총 758주를 순수 분리하였다. 분리된 모든 균주에 대하여 RNA-depolymerase 균의 crude enzyme 중에는 5'-AMP deaminase가 공존하고 있으므로 효소반응 중에 RNA 가 5'-mononucleotide로 분해 축적하는 동안에 5'-AMP의 adenine의 6위치에 붙은 $NH_2$기를 탈아미노하여 hypoxanthine으로 하기 때문에 5'-IMP 로 되는 것이라 생각된다. 분리 동정 된 Penicillium citreo-viride PO 2-11 strain과 Streptomyces aureus SOA 4-21 strain 이 생성한 5'-phosphodiesterase 로서 RNA를 효소 분해하여 5'-mononucleotide 의 정량한 결과는 Table 10과 같다. productivities를 1차 screening 하고 5'-phosphodiesterase productivities로서 2차 screening 하여 우수균주를 얻고 동정하였다. 우수균주의 5'-phosphodiesterase productivity에 대하여 배양상의 optimum condition을 검토하고 5'-phosphodiesterse activity에 미치는 여러 화합물의 영향과 효소반응의 최적 조건을 구명하였다. 우수균주가 생성한 5'-phosphodiesterase에 의하여 RNA 분해로 반응 최종 산물을 ion exchange column chromatography법으로 정량하고 최종 분해 산물엔 5'-mononucleotide를 paper chromatography, thinlayer chromatography, UV-absorption spectra, carbazole reaction 및 Schiff's reaction 등으로 동정한 결과는 다음과 같다. [1] 5'-phosphodiesterase productivity가 가장 우수한 두 균주를 선정하였고 이들은 토양에서 분리 되었으며 선정된 푸른 곰팡이는 Penicillium citreoviride PO 2-11로 동정되었고 방사선균은 Streptomyces aureus SOA 4-21로 동정되었다. [2] 분리 선정 된 Penicillium citreo-viride PO 2-11 strain은 배양상의 optimum condition 이 pH 5.0이고 temperature는 $30^{\circ}C$이었고 이 균이 생성한 5'-phosphodiesterase의 효소 반응상의 optimum condition 이 pH 4.2이고 temperature는 $60^{\circ}C$이었다. 그리고 5'-phosphodiesterase 생성에서 최적 탄소원은 sucrose이고 질소원은 $NH_4NO_3$이고 corn steep liquor나 혹은 yeast extract를 각각 0.01%씩 첨가한 구는 첨가하지 않은 control 구보다 20%의 5'-phosphodiesterase 생성 증가를 나타 내었다. 이 균이 생성한 5'-phosphodiestrase는 $Mg^{++},\;Ca^{++},\;Zn^{++},\;Mn^{++}$ 등 금속이온은 activator이고 EDTA, citrate, $Cu^{++},\;Co^{++}$ 등은 inhibitor 임을 알았다. 이 균이 생성한 5'-phosphodiesterase는 RNA를 분해하여 분해율 65.81%이었고 5'-AMP, 5'-GMP, 5'-UMP 및 5'-CMP를 생성하며 이때 축적되는 5'-mononucleotides중 5'-GMP 만이 정미성이 있음을 알았고 이균은 5'-AMP deamaminase가 없음을 확인하였다. 이 균의 효소에 의하여 RNA에서 정미성 5'-GMP 186.7 mg/RNA(g)를 생산할수 있음을 알았다. [3] 분리 선정된 Streptomyces aureus SOA 4-21 strain은 배양상의 optimum condition이 pH 7.0이고 temperature는 $28^{\circ}C$이었고 이 균이 생성한 5'-phosphodiesterase의 효소반응상의 optimum condition이 pH 7.3이고 temperature는 $50^{\circ}C$이었다. 그리고 5'-phosphodiesterase 생성에서 최적탄소원은 glucose이고 질소원은 asparagine이고 yeast extract 0.01%첨가구가 control 구보다 40%의 5'-phosphodiesterase 생성증가를 나타내었다. 이 균이 생성한 5'-phosphodiesterase는 $Ca^{++},\;Zn^{++},\;Mn^{++}$ 등 금속이온은 activator 이고 citrate, EDTA, $Cu^{++}$ 등은 inhibitor 임을 알았다. 또한 이 균은 5'-phosphodiesterase 뿐만 아니라 5'-AMP deaminase도 생성함을 확인하였다. 그러므로 RNA 분해율은 63.58% 이었고 RNA를 분해하여 5'-AMP, 5'-CMP, 5'-GMP 및 5'-UMP로 축적시키고 RNA가 효소 분해됨과 동시에 5'-AMP deaminase도 작용하며 생성된 5'-AMP 의 60% 상당을 5'-IMP로 전환시키는 특성이 있어서 정미성 5'-mononucleotide 생성이 전자의 균보다 두드러지게 증가함을 밝혔다. 이 균에 의하여 RNA에서 정미성 5'-IMP 171.8 mg/RNA(g) 및 5'-GMP 148.2 mg/RNA(g)생산할 수 있어 정미성 5'-mononucleotide 320mg/RNA(g)를 생산할 수 있음을 알았다.

• 대한수의학회지
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• 제40권3호
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• pp.479-487
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• 2000

Several recent studies demonstrate that receptor-mediated cAMP (adenosine 3',5'-monophosphate) production evokes marked change in magnesium ($Mg^{2+}$) homeostasis. The effects of dimaprit or/and phosphodiesterase (PDE) inhibitors on the $Mg^{2+}$ release from perfused guinea pig heart and collagenase-dispersed myocytes was studied to clarify an association of $H_2-histaminergic$ receptor-mediated $Mg^{2+}$ regulation with intracellular cAMP-degradation system. $Mg^{2+}$ efflux was stimulated in perfused hearts and myocytes by IBMX (3-isobutyl-1-methylxanthine), a calmodulin-sensitive PDE inhibitor, but not by RO 20-1724(4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone) or papaverine, cAMP-specific PDE inhibitors. $Mg^{2+}$ efflux was also be induced by dimaprit, a H-2-agonist. $Mg^{2+}$ effluxes induced by dimaprit were augmented by the presence of the PDE inhibitors. The augmentation of dimaprit-induced $Mg^{2+}$ effluxes by the PDE inhibitors were inhibited by ranitidine, a $H_2-antagonist$, and imipramine, a $Na^{+}-Mg^{2+}$ exchange inhibitor, in perfused hearts and myocytes and were also inhibited by amiloride in perfused hearts. These results suggest that the $H_2$-stimulated $Mg^{2+}$ effluxes from guinea pig heart can be regulated by the cytosolic nonspecific-dependent PDE systems and that it is induced by the $Na^{+}-Mg^{2+}$ exchanger stimulation.

• Clinical and Experimental Reproductive Medicine
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• 제48권4호
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• pp.352-361
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• 2021

Objective: The study assessed the developmental potential of germinal vesicle (GV) oocytes subjected to in vitro maturation (IVM) after prematuration culture with cilostamide (a phosphodiesterase-3 inhibitor) and the impact of cilostamide exposure on the morphology of meiosis II (MII) oocytes and subsequent embryo quality. Methods: In total, 994 oocytes were collected from 63 patients. Among 307 GV oocytes, 140 oocytes were selected for the experimental group and 130 oocytes for the control group. The denuded GV-stage oocytes were cultured for 6 hours with cilostamide in the experimental group and without cilostamide in the control group. After 6 hours, the oocytes in the experimental group were washed and transferred to fresh IVM medium. The maturational status of the oocytes in both groups was examined at 26, 36, and 48 hours. Fertilization was assessed at 18 hours post-intracytoplasmic sperm injection. Embryo quality was assessed on days 3 and 5. Results: In total, 92.1% of the oocytes remained in the GV stage, while 6.4% converted to the MI stage (p<0.01) after cilostamide exposure. In both groups, more MII oocytes were observed at 36 hours (25.8% vs. 21.5%) than at 26 hours (10.8% vs. 14.6%) and 48 hours (13% vs. 7.9%) (p>0.05). With the advent of cilostamide, blastocyst quality was better in the experimental group than in the control group (p<0.05). Conclusion: Cilostamide effectively blocked nuclear maturation and promoted cytoplasmic growth. Prematuration culture with cilostamide enabled synchronization between cytoplasmic and nuclear maturity, resulting in better blastocyst outcomes.