• YAKHAK HOEJI
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• v.57 no.6
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• pp.432-441
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• 2013

It's been almost 20 years since the adoption of Good Manufacturing Practices (GMP) in Korea since 1994. There have been big progresses in the GMP regulations and its implementations. 'New GMP' in 2008 has adopted validation, pre-approval GMP evaluation, annual quality review, etc.. Upon the submission of PIC/S (Pharmaceutical Inspection Cooperation Scheme) application by Korea's Ministry of Food and Drug Safety in April, 2012, Korea is facing new opportunity to level up Korea GMP regulations. As such, this study suggested GMP revision points by comparing and analyzing the differences between PIC/S GMP and Korea GMP. Those areas which GMP is not required such as radiopharmaceuticals and medical gases should adopt GMP. And independent GMP regulation is needed for Active Pharmaceutical Ingredients and investigational medicinal products. Also, those regulations shall be implemented in the higher level of legal status. Finally, rather than pursuing GMP harmonization only for PIC/S membership, GMP improvement in the long term shall be taken into consideration by reflecting current quality issues such as ICH Q8 (Pharmaceutical development), Q9 (Quality Risk Management) and Q10 (Pharmaceutical Quality System).

• Journal of the Korea Institute of Building Construction
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• v.18 no.3
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• pp.295-303
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• 2018

In the DBB delivery system, the design stage and the construction stage are separated. Because of this, design changes frequently occur, and problems such as construction cost overrun, schedule delay, and quality deterioration happen as well. Recently, in the construction industry CM at Risk(CM@R) delivery system, which can systematically solve the above-mentioned problems of DBB delivery system, meet various demands of clients, and overcome the limited cost and period. In the CM@R delivery system, the contractor negotiates for a maximum guaranteed price(GMP) with the client at the design stage, and the CM performer carries out the construction within the GMP. However, uncertainties are inherent in the GMP calculation because the calculation is based on unfinished drawings and documents. In this study, a Probabilistic Earlier GMP Calculation Method by combining a probabilistic tool of Monte Carlo simulation with a case based reasoning is proposed so that the uncertainty in GMP calculation is reflected. After the earlier GMP is calculated, a process to calculate the $2^{nd}$ GMP at the time of around 80 % of detailed deign and to negotiate with the client to fix the final GMP is proposed. The Probabilistic Earlier GMP Calculation Method is verified through the case study. In this study, researchers set the range of GMP through the proposed probabilistic GMP calculation and tried to reduce the risk through negotiation between the client and the CM performer. The proposed method and process would contribute to the successful introduction of CM@R in Korea.

• The Korean Journal of Physiology and Pharmacology
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• v.2 no.6
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• pp.733-742
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• 1998

Background: We have previously reported that not only cGMP but also 8-Br-cGMP or 8-pCPT-cGMP, specific and potent stimulators of cGMP-dependent protein kinase (cGMP-PK), increased basal L-type calcium current $(I_{Ca})$ in rabbit ventricular myocytes. Our findings in rabbit ventricular myocytes were entirely different from the earlier findings in different species, suggesting that the activation of cGMP-PK is involved in the facilitation of $I_{Ca}}$ by cGMP. However, there is no direct evidence that cGMP-PK can stimulate $I_{Ca}}$ in rabbit ventricular myocytes. In this report, we focused on the direct effect of cGMP-PK on $I_{Ca}}$ in rabbit ventricular myocytes. Methods and Results: We isolated single ventricular myocytes of rabbit hearts by using enzymatic dissociation. Regulation of $I_{Ca}}$ by cGMP-PK was investigated in rabbit ventricular myocytes using whole-cell voltage clamp method. $I_{Ca}}$ was elicited by a depolarizing pulse to +10 mV from a holding potential of -40 mV. Extracellular 8-(4-Chlorophenylthio)-guanosine-3',5'-cyclic monophosphate (8-pCPT-cGMP), potent stimulator of cGMP-dependent protein kinase (cGMP-PK), increased basal $I_{Ca}}$. cGMP-PK also increased basal $I_{Ca}}$. The stimulation of basal $I_{Ca}}$ by cGMP-PK required both 8-Br-cGMP in low concentration and intracellular ATP to be present. The stimulation of basal $I_{Ca}}$ by cGMP-PK was blocked by heat inactivation of the cGMP-PK and by bath application of 8-(4-chlorophenylthio)-guanosine-3',5'-cyclic monophosphate, Rp-isomer (Rp-pCPT-cGMP), a phosphodiesterase-resistant cGMP-PK inhibitor. When $I_{Ca}}$ was increased by internal application of cGMP-PK, IBMX resulted in an additional stimulation of $I_{Ca}}$. In the presence of cGMP-PK, already increased $I_{Ca}}$ was potentiated by bath application of isoprenaline or forskolin or intracellular application of cAMP. Conclusions: We present evidence that cGMP-PK stimulated basal $I_{Ca}}$ by a direct phosphorylation of L-type calcium channel or associated regulatory protein in rabbit ventricular myocytes.

• BMB Reports
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• v.36 no.3
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• pp.299-304
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• 2003

For deciphering the cyclic guanosine monophosphate (cGMP) signaling pathway, we employed chemical proteomics to identify the novel target molecules of cGMP. We used cGMP that was immobilized onto agarose beads with linkers directed at three different positions of cGMP. We performed a pull-down assay using the beads as baits on tissue lysates and identified 9 proteins by MALDI-TOF (Matrix-Assisted Laser Desorption/Ionization Time-of-Flight) mass spectrometry. Some of the identified proteins were previously known cGMP targets, including cGMP-dependent protein kinase and cGMP-stimulated phosphodiesterase. Surprisingly, some of the co-precipitated proteins were never formerly reported to associate with the cGMP signaling pathway. The competition binding assays showed that the interactions are not by nonspecific binding to either the linker or bead itself, but by specific binding to cGMP. Furthermore, we observed that the interactions are highly specific to cGMP against other nucleotides, such as cyclic adenosine monophosphate (cAMP) and 5'-GMP, which are structurally similar to cGMP. As one of the identified targets, MAPK1 was confirmed by immunoblotting with an anti-MAPK1 antibody. For further proof, we observed that the membrane-permeable cGMP (8-bromo cyclic GMP) stimulated mitogen-activated protein kinase 1 signaling in the treated cells. Our present study suggests that chemical proteomics can be a very useful and powerful technique for identifying the target proteins of small bioactive molecules.

• Journal of the Korean Society of Food Science and Nutrition
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• v.24 no.5
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• pp.779-784
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• 1995

The effective production of 5'-GMP(5'-Guanylic acid) by immobilized 5'-GMP producing fusant RC102(intergeneric protoplast fusion between Brevibacterium ammoniagenes ATCC21263 and Corynebacterium glutamicum ATCC21171) was investigated. The Fusant RC102 was immobilized by entrapping in -carrageenan, agar, polyacrylamide or Ca-alginate. 3% k-carrageenan was selected as the most suitable matrix. In the production of 5'-GMP using the immobilized whole cells of fusant RC102, the optimum conditions were $32^{\circ}C$, pH 8.0, $30\mu\textrm{g}/L\;of\;Mn^{2+},\;1{\times}10^{-6}%\;of\;Zn^{2+}$. In order to use fermentation medium containing CSL(Corn Steep Liquor) plentiful in $Mn^{2+}$, the optimum conditions of penicillin G, D-cycloserine and POESA(polyoxyethylene stearylamine) for production of 5'-GMP were 0.8unit/ml, 0.8unit/ml, 0.8unit/ml and 5mg/ml, respectively. Cationic surfactant, POESA was effective and superior to the antibiotics, penicillin G or D-cyloserine in 5'-GMP productivity. The condinuous fermentation using immobilized fusant RC102 showed that 5'-GMP productivity was stable for more than 15 days.

• YAKHAK HOEJI
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• v.59 no.1
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• pp.40-46
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• 2015

The term "GMP" firstly came on the 1962 amendment of the Federal Food, Drug and Cosmetic (FD&C) Act and the US FDA established and officially announced the Good Manufacturing Practice Regulation for the first time in the world in 1963. In 1969, the World Health Organization published the GMP regulation and recommended that member states adopt the GMP regulation and implement the "GMP Certification Scheme" for international commerce of finished pharmaceutical products. As a result, GMP requirements have become important ones that have to be complied with in the manufacture of pharmaceutical products. The Korean GMP regulation was announced as the official notification by the Ministry of Health and Social Affairs in 1977. The KGMP regulation was voluntarily adopted by pharmaceutical companies at the early stage, but it had become mandatory. In addition, various kinds of GMP regulations have been established to cover active pharmaceutical ingredients, biological products and others, in addition to finished pharmaceutical products. Taking account of technological development and changes in the pharmaceutical environments, the KGMP regulation was fully amended and harmonized with GMP requirements of developed countries. In this way, the KGMP has developed to keep up with international trends and standards, leading to accession to the Pharmaceutical Inspection Cooperation Scheme (PIC/S).

• The Korean Journal of Physiology
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• v.27 no.2
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• pp.151-162
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• 1993

In order to investigate the effect of intracellular cyclic GMP on calcium current the whole-cell patch clamp technique with internal perfusion method was used in isolated ventricular myocytes of the rabbit. Cyclic GMP, 8-bromo-cyclic GMP, cyclic AMP, isoprenaline and forskolin were perfused into cells and their effects on calcium current were analysed by applying depolarizing step pulses of + 10 mV in amplitude far 300 msec from holding potential of - 40 mV. Not only cyclic AMP $(100\;{\mu}M)$ but also cyclic GMF $(100\;{\mu}M)$ increased the basal calcium current. 8-Bromo-cyclic GMP $(100\;{\mu}M)$, a good stimulator of the cyclic GMP-dependent protein kinase, also increased the basal calcium current and its peak amplitude of calcium current was larger than that in the presence of cyclic AMP or cyclic GMP alone. In the presence of $100\;{\mu}M$ cyclic GMP or $100\;{\mu}M$ 8-bromo-cyclic GMP, already augmented calcium current was potentiated by intracellular application of $100\;{\mu}M$ cyclic AMP or $1\;{\mu}M$ isoprenaline or $1\;{\mu}M$ forskolin. In the presence of cyclic GMP, acetylcholine reduced the calcium current only when the calcium current was increased by isoprenaline. From the above results it could be concluded that intracellular perfusion with cyclic GMP increases the basal calcium current via a mechanism involving a cyclic GMP-dependent protein kinase.

• The Journal of Korean Society of Virology
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• v.29 no.4
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• pp.261-269
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• 1999

The relationship between second messenger cGMP and human cytomegalovirus (HCMV) replication was investigated. First, the intracellular level of cGMP ([cGMP]i) in HCMV-infected cells was measured. The [cGMP]i increased at early times after HCMV infection, reached maximum level at 12 hr and returned to basal level at 24 hr after virus infection, while [cGMP]i in mock-infected cells remained relatively unchanged. Increasing [cGMP]i resulted in enhanced transcription of HCMV major immediate early gene. For early gene expression, cGMP had varying effect. Expression of 1.2 kb RNA decreased and 2.2 kb RNA increased with increasing cGMP, while 2.7 kb RNA gene expression was not affected. HCMV early genes are regulated by immediate early gene, and the effect of cGMP on the regulatory effect of major immediate early gene on early genes was investigated. In the absence of cGMP, major immediate early gene repressed 2.7 kb RNA gene expression, while 1.2 kb RNA and 2.2 kb RNA early genes were not significantly affected. In the presence of $1\;{\mu}M$ cGMP, however, major immediate early gene stimulated the expression of three early genes.

• Development and Reproduction
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• v.20 no.4
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• pp.359-365
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• 2016

Intact germinal vesicle (GV) arrest and release are essential for maintaining the fertility of mammals inducing human. Intact germinal vesicle release, maturation of oocytes is maintained by very complex procedures along with folliculogenesis and is a critical step for embryonic development. Cyclic guanosine monophosphate (cGMP) has been suggested a key factor for meiotic arrest but so far its mechanisms are controversy. In this study we examine the effects of cGMP on germinal vesicle breakdown in cumulus-enclosed oocytes and denuded oocytes. Spontaneous maturation was inhibited by a cGMP agonist, 8-Br-cGMP with concentration dependent manners both in cumulus-enclosed oocytes and denuded oocytes. The inhibitory effect was more severe in denuded oocytes than cumulus-enclosed oocytes. The Rp-8-Br-cGMP and Rp-pCPT-8-Br-cGMP did not severely block GVB compared to 8-Br-cGMP. The spontaneous GVB inhibitory effects were different by the existence of cumulus. Based on them it is suggested that the cumulus modulates the role of cGMP in GV arrest.

• Proceedings of the Korean Institute of Building Construction Conference
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• 2018.05a
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• pp.122-123
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• 2018

Recently, CM at Risk delivery system(CM@R) that could solve the problems of Design Bid Build delivery(DBB) system has been emerging. In the CM@R delivery system, the contractor negotiates for a maximum guaranteed price(GMP) with the client at the design stage, and the contractor carries out the construction within the GMP. In CM @ R, the construction company with expertise in construction participates from the design stage to reflects the construction know-how in the design. On the other hand, the modification design frequently occurs due to the change of the construction cost when negotiating the GMP. In addition, uncertainties are inherent in the GMP calculation because the calculation is based on unfinished drawings and documents. This study proposes a probabilistic GMP estimation method applying MCS to the BIM - based cost prediction model, in order to extract the accurate quantity information when estimating the GMP and to cope with the change of the construction cost inherent in uncertainty.