• Archives of Pharmacal Research
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• v.27 no.12
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• pp.1258-1262
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• 2004

Phosphodiesterase (PDE) 4 is an enzyme that degrades intracellular cAMP. In the present study, the effect of rolipram, a specific phosphodiesterase (PDE) 4 inhibitor, on osteoclast formation was investigated. Rolipram induced osteoclast formation in cocultures of mouse bone marrow cells and calvarial osteoblasts. This activity was not observed in the absence of calvarial osteoblasts, suggesting that calvarial osteoblasts are likely target cells of rolipram. Osteoclast formation by rolipram was completely blocked by the addition of osteoprotegerin (OPG), a soluble decoy receptor for the osteoclast differentiation factor, TNF-related activation-induced cytokine (TRANCE, identical to RANKL, ODF, and OPGL). Northern blot analysis revealed the effect of rolipram to be associated with the increased expression of TRANCE mRNA in mouse calvarial osteoblasts. Collectively, these data indicate that PDE4 inhibitor up-regulates the TRANCE mRNA expression in osteoblasts, which in turn controls osteoclast formation.

• Journal of Korean Neurosurgical Society
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• v.50 no.2
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• pp.109-113
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• 2011

Objective : Peripheral neuropathy is characterized by hyperalgesia, spontaneous burning pain, and allodynia. The purpose of this study was to investigate the effect of rolipram, a phosphodiesterase-4-specific inhibitor, in a segmental spinal nerve ligation model in rats. Methods : Both the L5 and L6 spinal nerves of the left side of the rats were ligated. Phosphodiesterase-4 inhibitor (rolipram) and saline (vehicle) were administered intraperitoneally. We measured mechanical allodynia using von Frey filaments and a nerve conduction study. Results : The mechanical allodynia, which began to manifest on the first day, peaked within 2 days. Multiple intraperitoneal injections of rolipram ameliorated the mechanical allodynia. Furthermore, an intraperitoneal administration of rolipram improved the development of pain behavior and nerve conduction velocity. Conclusion : This study suggests that the phosphodiesterase-4 inhibitor, rolipram, alleviates mechanical allodynia induced by segmental spinal nerve ligation in rats. This finding may have clinical implications.

• Korean Journal of Pharmacognosy
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• v.45 no.3
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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.

• Biomolecules & Therapeutics
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• v.11 no.4
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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.

• Biomolecules & Therapeutics
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• v.10 no.2
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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.

• Applied Biological Chemistry
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• v.13 no.2
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• pp.111-129
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• 1970

As a series of studies on the nucleic acids and their related substances 210 samples were collected from 76 places such as farm soil, compost of heap, nuruk and meju to obtain microbial strains which produce 5'-phosphodiesterase. From these samples total of 758 strains were isolated by the use of dilution pour plate method. For all isolated strains primary screening of the productivity of RNA depolymerase was performed and useful strains with regard to 5'-phosphodiesterase productivities were identified. For these useful strains optimum condition, the effect of various compounds on the activity of 5'-phosphodiesterase, and the optimum condition for enzyme reaction were discussed. The quantitative of 5'-mononucleotides produced by the action of 5'-phosphodiesterase was performed using anion-exchange column chromatography and their identified was done by paper chromatography, thinlayer chromatography, ultra violet spectrophotometry, and characteristic color reaction using carbazole and schiff's reagent. (1) Penicillium citreo-viride PO 2-11 and Streptomyces aureus SOA 4-21 from soil were identified as a potent 5'-phosphodiesterase producing strains. (2) Optimum culture conditions for Penicillium citreo-viride PO 2-11 strain isolated were found to be pH 5.0 and $30^{\circ}C$, and the optimum conditions for enzyme action of 5'-phosphodiesterase were pH 4.2 and $60^{\circ}C$. Best carbon source for the production of 5'-phosphodiesterase was found to be sucrose and ammonium nitrate for nitrogen source. Addition of 0.01% corn steep liquor or yeast extract exhibited 20% increase in the amount of 5'-phosphodiesterase production compared to the control. 5'-phosphodiesterase produced by this strain was activated by $Mg^{++},\;Ca^{++},\;Zn^{++},\;Mn^{++}$ and was inhibited by EDTA, citrate, $Cu^{++},\;CO^{++}$. 5'-phosphodiesterase produced 5'-mononucleotide from RNA at a rate of 65.81%, and among the 5'-mononucleotides accumulated 5'-GMP only was found to have flavorous and the strain was also found lack of 5'-AMP deaminase. Productivity of flavorous 5'-GMP was found to be 186.7mg per gram of RNA. (3) Optimum culture canditions for the isolated Streptomyces aureus SOA 4-21 strain were pH 7.0 and $28^{\circ}C$, and the optimum conditions for the action of 5'-phosphodiesterase were pH 7.3 and $50^{\circ}C$. The best carbon source for 5'-phosphodiesterase production was found to be glucose and that of nitrogen was asparagine. Addition of 0.01% yeast extract exhibited increased productivity of 5'-phosphodiesterase by 40% compared to the non-added control. 5'-phosphodiesterase produced by this strain was activated by $Ca^{++},\;Zn^{++},\;Mn^{++}$ and was inhibited by citrate, EDTA, $Cu^{++}$. It was also found that the strain produce 5'-AMP deaminase in addition to 5'-phosphodiesterase. For this reason although decomposition rate was 63.58% the accumulation of 5'-AMP, 5'-CMP, 5'-GMP and 5'-UMP occurred by the breakdown of RNA. In the course of these reaction 5'-AMP deaminase converted 60% of 5'-AMP thus produced into 5'-IMP and flavorous 5'-mono nucleotide production was significantly increased by this strain over the above mentioned one. Production rates were found to be 171.8mg per grain of RNA for 5'-IMP and 148.2mg per gram of RNA for 5'-GMP, respectively.

• Proceedings of the Korean Society of Toxicology Conference
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• 2003.05a
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• pp.43-44
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• 2003

The subacute toxicity and toxicokinetics of a type IV phosphodiesterase inhibitor, CJ-10882, were evaluated after single (on the 1st day) and 4-week (on the 27th day) oral administration of the drug, in doses of 0 (to serve as a control), 2, 10 and 50 mg/kg/d, to male and female dogs (n = 3 for male and female dogs for each dose). During the test period, clinical signs, mortality, body weight, food consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross findings, organ weight and histopathology were examined.(omitted)

• YAKHAK HOEJI
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• v.52 no.1
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• pp.43-47
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• 2008

To determine the regulatory roles of PDE4 inhibitor on LPS-induced osteoclastogenesis, we investigated the effect of a PDE4 inhibitor on osteoclast formation in the presence of LPS. A specific PDE4 inhibitor, rolipram, increased LPS-induced osteoclast formation in cocultures. To verify that whether rolipram acts indirectly on osteoblasts, we investigated the TRANCE and COX-2 mRNA expression levels in osteoblasts. Treatment of rolipram increased the expression of TRANCE and COX-2 mRNA in osteoblasts stimulated by LPS. On the contrary, rolipram did not augment the number of osteoclasts differentiated from bone marrow cells by LPS. In conclusion, the stimulation of LPS-induced osteoclast formation by the PDE4 inhibitor are attributable to its indirect effect on osteoblasts, not to their direct effect on bone marrow-derived osteoclast precursors.

• Journal of Korean Neurosurgical Society
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• v.52 no.1
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• pp.32-36
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• 2012

Objective : Alcoholic neuropathy is characterized by allodynia (a discomfort evoked by normally innocuous stimuli), hyperalgesia (an exaggerated pain in response to painful stimuli) and spontaneous burning pain. The aim of the present study is to investigate the effect of rolipram, a phosphodiesterase 4 inhibitor, against alcohol-induced neuropathy in rats. Methods : Allodynia was induced by administering 35% v/v ethanol (10 g/kg; oral gavage) to Spraue-Dawley rats for 8 weeks. Rolipram and saline (vehicle) were administered intraperitoneally. Mechanical allodynia was measured by using von Frey filaments. Somatosensory evoked potential (SEP) was proposed as complementary measure to assess the integrity of nerve pathway. Results : The ethanol-induced mechanical allodynia began to manifest from 3 week, and then peaked within 1 week. Beginning from 3 week, latency significantly started to increased in control group. In rolipram treated rats, the shorter latency was sustained until 8 weeks (p<0.05). The mechanical allodynia, which began to manifest on the 3 weeks, intraperitoneal injections of rolipram sustained statistical difference until 8 weeks, the final week of the study (p<0.05). Conclusion : This study suggests that rolipram might alleviate mechanical allodynia induced by alcohol in rats, which clearly has clinical implication.

• Clinical and Experimental Reproductive Medicine
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• v.43 no.1
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• pp.26-30
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• 2016

Objective: We aimed to investigate the prevalence of erectile dysfunction (ED) and the usage of phosphodiesterase type 5 (PDE5) inhibitors for ED treatment in infertile couples. Methods: A total of 260 male partners in couples reporting infertility lasting at least 1 year were included in this study. In addition to an evaluation of infertility, all participants completed the International Index of Erectile Function (IIEF)-5 questionnaire to evaluate their sexual function. The participants were asked about their use of PDE5 inhibitors while trying to conceive during their partner's ovulatory period and about their concerns regarding the risks of PDE5 inhibitor use to any eventual pregnancy and/or the fetus. Results: Based on the IIEF-5 questionnaire, 41.5% of the participants (108/260) were classified as having mild ED (an IIEF-5 score of 17-21), while 10.4% of the participants (27/260) had greater than mild ED (an IIEF-5 score of 16 or less). The majority (74.2%, 193/260) of male partners of infertile couples had a negative perception of the safety of using a PDE5 inhibitor while trying to conceive. Only 11.1% of men (15/135) with ED in infertile couples had used a PDE5 inhibitor when attempting conception. Conclusion: ED was found to be common in the male partners of infertile couples, but the use of PDE5 inhibitors among these men was found to be very low. The majority of male partners were concerned about the risks of using PDE5 inhibitors when attempting to conceive. Appropriate counseling about this topic and treatment when necessary would likely be beneficial to infertile couples in which the male partner has ED.