• Journal of Pharmaceutical Investigation
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• v.28 no.2
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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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• v.1 no.1
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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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• v.23 no.3
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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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• v.54 no.7
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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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• v.15 no.2
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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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• v.39 no.1
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• pp.7-14
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• 1992

Background: Cognitive deficit by hypoxia and/or hypercapnia is one of neuropsychological impairments frequently observed in patients with chronic obstructive pulmonary disease (COPD). The degree of cognitive deficit is variable among patients with similar level of hypoxia and/or hypercapnia, although a cause of this individual difference is well not known. COPD can be divided into two characteristic clinical entities including predominant emphysema and predominant bronchitis. This study was designed to evaluate the individual difference in cognitive deficit respond to hypoxia and/or hypercapnia in patients with COPD. Method: Sixteen patients with COPD (9 emphysema-dominant and 7 bronchitis-dominant) participated in this study. On admission arterial blood gas analysis and trail-making B (TMB) test for the evaluation of cognitive function were done in all patients. Mean TMB scores and the correlations between TMB scores and arterial blood gases were compared between two clinical groups. Results: 1) Mean TMB scores and arterial blood gases between two clinical groups were not different. 2) There was a tendency to be higher TMB score in hypoxemia, acidemia, and hypercapnia. However these findings were not statistically significant. 3) In emphysema-dominant group, $PaCO_2$ was mostly well correlated with TMB score (r=0.693). 4) In bronchitis-dominant group, arterial pH was mostly well correlated with TMB score (r=-0.526). Conclusion: Our data suggest that the individual difference in cognitive deficit respond to hypoxia and/or hypercapnia in patients with COPD may be dependent on their clinical entities, and arterial blood gases mostly well correlated with cognitive function that may be different according to their clinical entities.

• The Monthly Technology and Standards
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• s.117
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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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• v.29 no.1
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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.

• Analytical Science and Technology
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• v.12 no.4
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• pp.326-331
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• 1999

The metabolites of 1,2,4-trimethylbenzene (TMB) were synthesized and determined by capillary electrophoresis (CE). The optimum conditions of CE for the separation and determination of 3,4-, 2,4-, 2,5-dimethylbenzoic acid and 3,4-, 2,4-, 2,5-dimethylhippuric acid from the rat urine were as following: the fused silica capillary($75{\mu}m$ i.d. ${\times}$ 36 cm length, 29 cm to detector) was used and kept at $15^{\circ}C$. The applied voltage was 10㎸ and compounds were detected at UV 210 mnm and 254 nm. The running electrolyte was 0.1 M phosphate buffer (pH 7) containing 15 mM of ${\beta}-CD$ and 3% of 2-propanol. The relative amount of the metabolite of 1,2,4-TMB in the rat urine was 56.7% of 3,4-isomer, 30.5% of 2,4-isomer and 12.8% of 2,5-isomer. This method can be applied to the analysis of TMB-metabolites in human urine.

• The Plant Pathology Journal
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• v.36 no.4
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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.