• Applied Chemistry for Engineering
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• v.33 no.4
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• pp.440-443
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• 2022

A key step in the synthesis of camostat mesylate, which is most widely used as a treatment for chronic pancreatitis, was conducted. Camostat mesylate was synthesized through the esterification reaction of two intermediates, GBA (4-guanidinobenzoic acid hydrochloride) and DOHA [2-(dimethylamino)-2-oxoethyl-2-(4-hydroxyphenyl)acetate]. In order to overcome the problem raised due to the low yield and expensive reagents, a new economical synthesis method was developed that can produce camostat mesylate with a high yield of 80% by activating the acid functional group of GBA using the Vilsmeier-Haack reaction and coupling it with DOHA.

• The Korean Journal of Pharmacology
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• v.30 no.2
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• pp.205-215
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• 1994

It is well known that chronic stimulation with CCK gives rise to growth of exocrine pancreas and to increased content of enzyme proteins in pancreas. However, littls Is known about changes of the secretory function of exocrine pancreas which has been chronically stimulated with CCK, especially about the responsiveness to secretagogues such as CCK, caerulein and carbachol. The present study was performed to investigate the effect of camostat on secretory profiles and the responsiveness to secretagogues of exocrine pancreas by observing in vitro amylase release stimulated by cholecystokinin-octapeptide(CCK-8) and carbachol in dispersed isolated pancreatic acini from camostat-treated rats for 4 or 10 days. The results summarized as follows : 1) The maximal effective concentration of CCK-8 in amylase release in the camostat treated group was greater than control group, but that of carbachol was not different between groups. 2) Analysis of the stimulated amylase release as the percentage of the maximal response revealed that camostat treatment caused right-shift of the dose-response curve of CCK-8. Camostat did not cause significant changes in the dose-response curve of carbachol. 3) There were considerable increases in the amylase release in the camostat-treated group, compared to the control when acini were stimulated with CCK-8 $10^{-9}\;M$ and carbaochol $10^{-6}\;M$, and higher concentrations. 4) There was a reverse correlation between the tissue content and the maximal release(percent of the total content) of amylase. These results suggest that chronic exposure of exocrine pancreas to increased endogenous CCK can enhance the responsiveness of exocrine enzyme secretion to secretagogues, especially at higher concentrations of CCK and carbachol.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1993.04a
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• pp.84-84
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• 1993

취장 외분비 기능 부전은 임상적으로 영양결핍, 발육부전, 지방변동을 유발하나 이의 치료로는 결려된 소화효소 보충 등 보존적 요법만 시행될 뿐 근본적인 치료법은 없는 실정이다. 지난해 과제는 합성 단백분해 억제물질인 Camostat이 취장의 비대와 중식을 일으키며 또한 단백분해 효소분비를 증가시킴을 보고한 바 있다. 이를 토대로 최근 보고된 실험적 취장 외분비기능 부전 모델을 이용하여 camostat의 효과를 검색하고자 하였으며 아울러 이를 CCK효과와 비교하였다. 실험동물로는 몸무게 200 g 안팎의 수컷 Sprague-Dawley계 흰쥐를 사용하였으며 취장기능 부전은 oleic acid (25 $\mu$/100 g bw)를 취관내 주입하여 유발하였다. Camostat은 200 mg/kg씩 위내 투여(i.g.)하였으며 CCK(CCK-8)는 5 $\mu\textrm{g}$/kg씩 하루 2회 피하주사하였고 투여기간은 각각 3, 7, 14 일간으로 하였다. 각 약물 투여 후 취장 외분비 기능과 조직학적 검색을 실시하여 다음과 같온 결과를 얻었다. 1. Oleic acid의 취관내 주입으로 흰쥐의 취장 무게, 조직내 효소단백 함량 및 효소분비량이 현저히 감소되었고 조직학적으로 심한 위축과 섬유화를 관찰할 수 있었으며 이는 주입 후 기간이 지남에 따라 계속 진행하였다. 2. 취장기능 부전 유발 흰쥐에서 camostat 처치로 조직내 효소단백 함량 및 효소분비가 증가 되었으며 이는 14일간 처치군에서 뚜렷하였다. 3. 취장 기능부전 유발 횐쥐에서 camostat 처치는 조직학적으로 기능적인 외분비 조직이 유지되었으며 이는 3일군에서 특히 뚜fut하였다. 4. 취장기능부전 유발 횐쥐에서 CCK 처치효과는 camostat 처치효과와 비슷하였다. 이상의 결과로 보아 oleic acid 주입은 취장기능부전 연구에 유용한 실험모델로 생각되며 합성 단백 분해 효소 억제제인 Camostat은 취장외분비 기능 부전의 진행을 억제하고 어느정도 그 기능을 호전시킬 수 있으며 이는 CCK유리에 기인한다고 생각한다.

• The Korean Journal of Pharmacology
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• v.32 no.2
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• pp.243-257
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• 1996

CCK and cholinergic agonist stimulate enzyme release from the pancreatic acini via G-protein-mediated activation of phospholipase C, In contrast secretin and related peptides increase the level of cAMP and activate cAMP-dependent protein kinase. Camostat, a synthetic protease inhibitor, causes pancreatic hypertrophy and hyperplasia by increasing the CCK release. In this study, the secretagogue-induced changes of intracellular proteins were examined in the dispersed pancreatic acini of rats with or without camostat treatment. Camostat(FOY-305, 200 mg/kg, p.o.) was given for 4 days twice daily and the dispersed acini were prepared at 12 bouts after last treatment. The profiles of Intracellular phosphoproteins were analyzed by two-dimensional gel electrophoresis after incubating the acini with $^{32}P$. The amylase release from the dispersed acini was measured. The pancreatic weight was increased to 126% of control, while amylase activity per mg acinar protein decreased to 41% of control, The maximum response of amylase release from dispersed acini to CCK-8 or carbachol was markedly decreased(65% or 46% of control, respectively). The group of intracellular proteins(24 kD, pI $4.5{\sim}8.5$) was increased in quantity by camostat. CCK-8 or secretin increased phosphorylation of a protein(34 kD, pI 4.7) in camostat-treated as well as control rats. CCK-8 increased tyrosine phosphoryiation in the acini of control rats. However, in camostat-treated rats, the basal level of tyrosine phosphorylation was increased and it was rather decreased by CCK-8. Secretin had no effect on the level of tyrosine phosphorylation in acini. These results indicate that both phospholipase C and adenylate cyclase induce phosphorylation of an intracellular acinar protein(34 kD, pI 4.7) and camostat treatment increases the basal level of tyrosine phosphorylation in acinar cells. And these results suggest that not only serine/threonine protein kinase but also protein tyrosine kinase/phosphatase are involved in the process of CCK receptor mediated stimulation-secrelion coupling.

• Analytical Science and Technology
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• v.24 no.2
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• pp.78-84
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• 2011

The fragmentation patterns of a serine protease inhibitor, camostat, and its degradation product, 4-(4-guanidinobenzoyloxy)phenylacetic acid (GBPA), were for the first time investigated by a triple quadrupole tandem mass spectrometry equipped with an electrospray source (ESI-MS/MS) in positive and/or negative ion mode under collision-induced dissociation (CID). The positive CID spectrum of camostat showed distinctly that the single bond (C-O) cleavage between carbonyl group and oxygen atom of the ester bonds of the compound favorably occurred and then the loss of N,N-dimethylcarbamoylmethyl group was more susceptible than that of guanidine moiety. In the positive ion CID spectrum of GBPA, the initial cleavage between the carbonyl group and oxygen atom of 4-guanidinobenzoyloxy group also occurred, yielding the most abundant fragment ion at m/z 145. On the other hand, the negative CID spectrum of GBPA characteristically showed the occurrence of the most abundant peak at m/z 226 resulting from the sequential neutral losses of $CO_2$ and HN=C=NH from the parent ion at m/z 312.