• Journal of Pharmaceutical Investigation
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• 제28권2호
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• pp.73-80
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• 1998

In order to elucidate the effect of N-demethylation on the in vivo metabolite kinetics, especially hepatic first-pass effect of trimebutine(TMB), the N-demethylation of TMB to N-monodesmethyl trimebutine(N-TMB) was studied in rats. TMB(10 mg/kg) and N-TMB(10 mg/kg) were injected into the femoral and the portal vein, respectively. And the pharmacokinetic parameters were obtained from the plasma concentration-time profiles of TMB and N-TMB determined by the simultaneous analysis using high-performance liquid chromatography. It was supposed that these drugs were almost metabolized in vivo because the urinary and biliary excreated amounts of TMB and N-TMB were lower than 0.1% of the administered dose. According to the hepatic biotransformation model and metabolic pathways of TMB proposed, it was found that the fraction of systemic clearance of TMB which formed N-TMB in liver$(G_{mi})$ was 0.826, that of TMB which furnishes the available N-TMB to the systemic circulation$(F_{mi})$ was 0.083, and the absolute hepatic bioavailability of N-TMB formed trom TMB$(F_{mi.p})$ was 0.1. These results showed that TMB was suspected of the sequential hepatic first-pass metabolism and N-demethylated by 82.6%. Therefore, the residue would be hydrolyzed by the esterase in the liver. That is, the ability of N-demethylation of TMB was 4.75-fold larger than that of hydrolysis by the esterase in rats.

• Mass Spectrometry Letters
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• 제1권1호
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• pp.9-12
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• 2010

Trimethylboroxine (TMB) is a six-membered ring compound containing Lewis acidic boron and Lewis basic oxygen atoms that can bind halide anion and alkali metal cation, respectively. We employed Fourier transform ion cyclotron resonance spectroscopy to study the gas-phase binding of $LiBrLi^+$ and $F^-(KF)_2$ to TMB. TMB forms association complexes with both $LiBrLi^+$ and $F^-(KF)_2$ at room temperature, providing direct evidence for the ditopic binding. Interestingly, the $TMB{\cdot}F^-(KF)_2$ anion complex is formed 33 times faster than the $TMB{\cdot}Li^+BrLi$ cation complex. To gain insight into the ditopic binding of an ion pair, we examined the structures and energetics of $TMB{\cdot}Li^+$, $TMB{\cdot}F^-$, $TMB{\cdot}LiF$ (the contact ion pair), and $Li^+{\cdot}TMB{\cdot}F^-$ (the separated ion pair) using Hartree-Fock and density functional theory. Theory suggests that $F^-$ binds more strongly to TMB than $Li^+$ and the contact ion-pair binding ($TMB{\cdot}LiF$) is more stable than the separated ion-pair binding ($Li^+{\cdot}TMB{\cdot}F^-$).

• Journal of Gastric Cancer
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• 제23권3호
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• pp.476-486
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• 2023

Purpose: The optimal tumor mutational burden (TMB) value for predicting treatment response to programmed cell death-1 (PD-1) checkpoint inhibitors in advanced gastric cancer (AGC) remains unclear. We aimed to investigate the optimal TMB cutoff value that could predict the efficacy of PD-1 checkpoint inhibitors in AGC. Materials and Methods: Patients with AGC who received pembrolizumab or nivolumab between October 1, 2020, and July 27, 2021, at Samsung Medical Center in Korea were retrospectively analyzed. The TMB levels were measured using a next-generation sequencing assay. Based on receiver operating characteristic curve analysis, the TMB cutoff value was determined. Results: A total 53 patients were analyzed. The TMB cutoff value for predicting the overall response rate (ORR) to PD-1 checkpoint inhibitors was defined as 13.31 mutations per megabase (mt/Mb) with 56% sensitivity and 95% specificity. Based on this definition, 7 (13.2%) patients were TMB-high (TMB-H). The ORR differed between the TMB-low (TMB-L) and TMB-H (8.7% vs. 71.4%, P=0.001). The progression-free survival and overall survival (OS) for 53 patients were 1.93 (95% confidence interval [CI], 1.600-2.268) and 4.26 months (95% CI, 2.992-5.532). The median OS was longer in the TMB-H (20.8 months; 95% CI, 2.292-39.281) than in the TMB-L (3.31 months; 95% CI, 1.604-5.019; P=0.049). Conclusions: The TMB cutoff value for predicting treatment response in AGC patients who received PD-1 checkpoint inhibitor monotherapy as salvage treatment was 13.31 mt/Mb. When applying the programmed death ligand-1 status to TMB-H, patients who would benefit from PD-1 checkpoint inhibitors can be selected.

• BMB Reports
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• 제54권7호
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• pp.386-391
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• 2021

Owing to rapid advancements in NGS (next generation sequencing), genomic alteration is now considered an essential predictive biomarkers that impact the treatment decision in many cases of cancer. Among the various predictive biomarkers, tumor mutation burden (TMB) was identified by NGS and was considered to be useful in predicting a clinical response in cancer cases treated by immunotherapy. In this study, we directly compared the lab-developed-test (LDT) results by target sequencing panel, K-MASTER panel v3.0 and whole-exome sequencing (WES) to evaluate the concordance of TMB. As an initial step, the reference materials (n = 3) with known TMB status were used as an exploratory test. To validate and evaluate TMB, we used one hundred samples that were acquired from surgically resected tissues of non-small cell lung cancer (NSCLC) patients. The TMB of each sample was tested by using both LDT and WES methods, which extracted the DNA from samples at the same time. In addition, we evaluated the impact of capture region, which might lead to different values of TMB; the evaluation of capture region was based on the size of NGS and target sequencing panels. In this pilot study, TMB was evaluated by LDT and WES by using duplicated reference samples; the results of TMB showed high concordance rate (R² = 0.887). This was also reflected in clinical samples (n = 100), which showed R² of 0.71. The difference between the coding sequence ratio (3.49%) and the ratio of mutations (4.8%) indicated that the LDT panel identified a relatively higher number of mutations. It was feasible to calculate TMB with LDT panel, which can be useful in clinical practice. Furthermore, a customized approach must be developed for calculating TMB, which differs according to cancer types and specific clinical settings.

• Archives of Pharmacal Research
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• 제15권2호
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• pp.115-125
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• 1992

An attempt was made to investigate the effect of TMB-8[3, 4, 5-trimethoxybenzoate-8 (N, N-diethylamino) octyl ester], which is known to be an inhibitor of intracellular $Ca^{2+}$ release, on catecholamines (CA) secretion evoked by Ach, excess $K^+$, DMPP, McN-A-343 and caffeine from the isolated perfused rat adrenal glands and to cleaify its mechanism of action. The pretreatment with a low dose of TMB-8 $(10 \mu{M)}$ for 20 min led to marked inhibition in CA secretion evoked by Ach (5.32 mM), excess K^+$ (56 mM), DMPP $(100\;\mu{M)}$, McN-A-343 $(100 \mu{M)}$ and BAY-K 8644 $(10^{-5}M)$. Caffeine-induced CA secretion was simimlar to that of control only during the first periods (0-3 min) but thereafter maked inhibition in CA secretion evoked by caffeine was observed during the rest periods up to 30 min. The increased moderate concentration of TMB-8 $(30 \;\mu{M)}$ caused the result similar to that of $10 \;\mu{M}$ TMB-8. However, in adrenal glands preloaded with a high dose of TMB-8 $(100\;\mu{M)}$, CA releases evoked by Ach, excess $K^+$, DMPP, McN-A-343 and caffeine were almost completely blocked by the drug. These experimental data demonstrate that TMB-8 may inhibit cholinergic receptor-mediated and also depolarization-dependent Ca secretion, suggenesting that these TMB-8 effects seem to be mediated through inhibiting influx of extracellular calcium into the rat adrenal medullary chromaffin cells as well as reducing the release of calcium from intracellular sources.

• Tuberculosis and Respiratory Diseases
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• 제39권1호
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• pp.7-14
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• 1992

연구배경 : 동맥혈가스 변화에 따른 호흡곤란 및 의식장애는 만성 폐쇄성 폐질환 환자들을 포함한 여러 호흡기 질환 환자들에게서 비교적 흔히 관찰할 수 있다. 그러나 실제로는 같은 질환이라 할지라도 동맥혈가스 변화에 따른 호흡곤란 및 의식장애의 정도는 환자에 따라 매우 다양하다. 한편 만성 폐쇄성 폐질환은 폐기종 우세형과 기관지염 우세형의 두가지 임상군으로 구분할 수 있는데, 이에 저자들은 만성 폐쇄성 폐질환에서 호흡곤란을 느낄 당시의 중추신경계의 반응과 의식장애에 많은영향을 미치는 동액혈가스 소견이 임상군에 따라 차이가 있는지를 규명하고자 본 연구를 시행하였다. 방법 : 16명의 만성 폐쇄성 폐질환 환자들을 대상으로 동맥혈가스 및 인지기능의 척도로 이용되고 있는 trail-making B test를 실시한 후, 다시 이들을 폐기종 우세형군과 기관지염 우세형군으로 분류하고, 각 환자군에서의 인지기능 및 인지기능과 동맥혈가스와의 상관관계를 서로 비교하였다. 결과 : 1) 평균 TMB score는 폐기종 우세형군이 $266.33{\pm}171.62$초, 기관지염 우세형군이 $200.29{\pm}123.13$초로서, 폐기종 우세행군이 기관지염 우세형군에 비해 호흡 곤란을 느낄 당시의 인지기능장애가 다소 심한 경향이 있었다. 2) 두 환자군 모두 저산소혈증, 과탄산혈중 및 산혈증이 심할수록 인지기능장애가 심해지는 경향을 보였다. 3) 폐기종 우세형군에서 TMB score와 동맥혈가스와의 상관계수(r)는 각각 TMB $PaO_2$: -0.477, TMB $-PaCO_2$ : 0.693, TMB-pH : -0.375, TMB-$HCO_3$ : 0.665로서, 폐기종 우세형군에서는 $PaCO_2$가 인지기능의 변화에 가장 많은 영향을 미치는 것으로 나타났다. 4) 기관지염 우세형군에서의 TMB score와 동맥혈 가스와의 상관계수(r)는 각각 TMB-$PaO_2$ : -0.306, TMB-$PaCO_2$ : 0.347, TMB-pH: -0.526, TMB-$HCO_3$ : 0.366으로서, 기관지염 우세형 환자군에서는 pH가 인지가능 변화에 가장 많은 영향을 주는 것으로 나타났다. 5) 저산소혈증, 과탄산혈증시의 인지기능장애는 폐기종 우세형군이 기관지염 우세형군에 비해 다소 심한 경향을 보였으며, 산혈증시의 인지기능장애는 오히려 기관지염 우세형군이 폐기종 우세형군에 비해 다소 심한 경향을 보였다. 결론 : 이상의 연구 결과 만성 폐쇄성 폐질환 환자들에서 호흡곤란을 느낄 당시의 중추신경계의 반응은 페기종 우세형군이나 기관지염 우세형군간에 근본적인 차이는 없지만, 인지기능에 많은 영향을 미치는 동맥혈가스 소견은 서로 다르다는 것을 알았다.

• 기술표준
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• 통권117호
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• pp.4-7
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• 2011

우리나라가 국제표준화기구(ISO) 기술관리이사회(TMB)에 재진출했다. 3년 임기가 만료되는 선출직 다섯 자리를 놓고 열한 개 국가가 경합을 벌인 가운데, 중국, 브라질, 인도네시아, 남아프리카공화국과 함께 이사국으로 선출된 것이다. ISO TMB 재진출의 가장 중요한 의의는 모든 국가와 국민들의 이익에 보탬이 되도록 기존 표준 선진국들의 표준화활동을 감시하고 견제하는 것이다.

• The Korean Journal of Physiology
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• 제29권1호
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• pp.29-37
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• 1995

Gastric smooth muscle of guinea pigs was used to investigate whether the inhibitory effect of calcium antagonists on tonic contraction was accompanied by inhibition of phospholipase C activity. Tonic contraction and $[^{3}H]$ inositol phosphate (IP) formation in response to acetylcholine were measured after pretreatment with verapamil, nifedipine, 8-(N,N-diethylamino)octyl 3,4,5-trimethoxy-benzoate (TMB-8) or EGTA. Verapamil $(10\;{\mu}M)$, TMB-8 $(10\;{\mu}M)$ or EGTA (2 mM) significantly inhibited acetylcholine $(1\;{\mu}M)$-stimulated tonic contraction but nifedipine (100 nM) did not. Acetylcholine dose-dependently increased the formation of $[^{3}H]IP$. This effect was not observed in the presence of 2 mM EGTA. Both verapamil and TMB-8 significantly inhibited $[^{3}H]IP$ formation induced by $10\;{\mu}M$ acetylcholine, whereas nifedipine did not. In a subsequent study, we measured phospholipase C activity in gastric muscle cell homogenate and in permeabilized cells to determine whether calcium antagonists could inhibit the activity directly. The calcium antagonists did not change the phospholipase C activity of the cell homogenate or the permeabilized cells. But EGTA decreased phospholipase C activity by 50%. These results suggest that the inhibitory effects of verapamil and TMB-8 on acetylcholine-stimulated tonic contraction may be accompanied by inhibition of phospholipase C activity.

• 분석과학
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• 제12권4호
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• pp.326-331
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• 1999

방향족 탄화수소인 trimethylbenzene (TMB)은 그 사용량이 늘어갈 뿐 아니라 직업적으로 폭로되는 양도 증가하고 있으므로 생물학적 모니터링 및 흡수, 대사, 배설에 관한 연구가 중요시되고 있다. 일반적으로 TMB는 간의 산화효소에 의해 하나의 메틸기가 산화되고 이것이 glycine과 포합되어 배설되는 것으로 알려져 있다. 본 연구에서는 1,2,4-TMB의 대사체를 합성하고, 모세관 전기영동법으로 분석할 수 있는 방법을 개발하였다. 모세관 전기영동법으로 흰쥐의 뇨 중에서 1,2,4-TMB의 대사체인 3,4-, 2,4-, 2,5-dimethylbenzoic acid 및 3,4-, 2,4-, 2,5-dimethylhippuric acid를 분석하기 위하여 내경 $75{\mu}m$, 총길이 36cm (검출기까지 29cm)인 용융실리카 모세관을 $15^{\circ}C$로 유지하면서 양단에 10㎸의 전압을 걸어주고, 전해질로는 15mM ${\beta}-CD$, 3% 2-프로판올을 포함하는 0.1M 인산완충액 (pH 7)을 사용하였으며, 검출신호는 UV 210nm와 254nm에서 동시에 모니터링하였다. 뇨 시료의 분석 결과 배설된 1,2,4-TMB의 대사체의 상대량은 3,4-이성질체가 56.7%, 2,4-이성질체가 30.5%, 2,5-이성질체가 12.8%였다. 이 방법은 노동자의 뇨 분석에도 적용될 수 있을 것으로 생각된다.

• The Plant Pathology Journal
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• 제36권4호
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• pp.378-383
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• 2020

The objective of this research was introduction of chit42 to tuber mustard plants through Agrobacteriummediated transformation against white mold caused by Sclerotinia sclerotiorum. The binary plasmid pGisPEC1 was used in this study. Polymerase chain reaction analysis detected the transgene in 27 transformants with a transformation efficiency of 6.9%. Southern blot test was used to assess the copy number of transgene in tuber mustard plants. One, two, two, and two chit42-related bands were observed in the transformed lines TMB4, TMB7, TMB12, and TMB18, respectively. Enzymatic tests showed a significant increase in the activity of endochitinase in protein isolated from leaf tissues of chit42 transgenic 75-day tuber mustard lines. The pathogenicity of three pathogen isolates was tested on the leaves of transformed plans. The results of current study showed that expression of the gene chit42 in tuber mustard plants markedly reduced infection radius on the leaves 7 days after inoculation with the fungus.