Domain transformation using semi-supervised CycleGAN for improving performance of classifying thyroid tissue images.

PURPOSE: A large number of research has been conducted on the classification of medical images using deep learning. The thyroid tissue images can be also classified by cancer types. Deep learning requires a large amount of data, but every medical institution cannot collect sufficient number of data for deep learning. In that case, we can consider a case where a classifier trained at a certain medical institution that has a sufficient number of data is reused at other institutions. However, when using data from multiple institutions, it is necessary to unify the feature distribution because the feature of the data differs due to differences in data acquisition conditions. METHODS: To unify the feature distribution, the data from Institution T are transformed to have the closer distribution to that from Institution S by applying a domain transformation using semi-supervised CycleGAN. The proposed method enhances CycleGAN considering the feature distribution of classes for making appropriate domain transformation for classification. In addition, to address the problem of imbalanced data with different numbers of data for each cancer type, several methods dealing with imbalanced data are applied to semi-supervised CycleGAN. RESULTS: The experimental results showed that the classification performance was enhanced when the dataset from Institution S was used as training data and the testing dataset from Institution T was classified after applying domain transformation. In addition, focal loss contributed to improving the mean F1 score the best as a method that addresses the class imbalance. CONCLUSION: The proposed method achieved the domain transformation of thyroid tissue images between two domains, where it retained the important features related to the classes across domains and showed the best F1 score with significant differences compared with other methods. In addition, the proposed method was further enhanced by addressing the class imbalance of the dataset.

Liver fibrosis estimated using extracellular volume fraction obtained from dual-energy CT as a risk factor for hepatocellular carcinoma after sustained virologic response: A preliminary case-control study.

PURPOSE: To assess hepatocellular carcinoma (HCC) risk after sustained virologic response (SVR) through clinical data analyses, including evaluation of liver fibrosis using the extracellular volume fraction (ECV) obtained from dual-energy computed tomography (DECT). METHODS: Ninety-two patients (52 men and 40 women; mean age, 69.9 years) with hepatitis C virus infection after SVR underwent DECT of the liver (3-minute equilibrium-phase images) between January 2020 and March 2022. The ECV was calculated by measuring iodine density; fibrous markers, including ECV, fibrosis-4 index, aspartate aminotransferase to platelet ratio index, and platelet count, were statistically analyzed (p < 0.05). The risk factors associated with HCC were analyzed using univariate and multivariate logistic regression analyses. RESULTS: The ECV (26.1 ± 4.6 %) in patients with HCC (n,21) was significantly larger than the ECV (20.7 ± 3.3 %) in patients without HCC (n = 71) (p < 0.001). The cutoff value for the ECV was 24.3 %. The area under the operating characteristic curve of the ECV was 0.857, which was higher than that of the serum fibrosis markers. Older age, SVR achieved with interferon, alpha-fetoprotein level (>5 ng/mL), advanced fibrosis before treatment (>F3), and ECV were associated with HCC according to the univariate analysis. Multivariate analyses showed that ECV was the only factor independently associated with HCC (odds ratio 0.619, 95 % confidence interval 0.482-0.795, p < 0.001). CONCLUSION: Liver fibrosis estimated using ECV can be a predictive marker in patients with HCC after SVR.

A case of focal nodular hyperplasia-like lesion presenting unusual signal intensity on the hepatobiliary phase of gadoxetic acid-enhanced magnetic resonance image.

Focal nodular hyperplasia (FNH) or FNH-like lesions of the liver are benign lesions that can be mostly diagnosed by hepatobiliary phase gadoxetic acid-enhanced magnetic resonance imaging (MRI). Accurate imaging diagnosis is based on the fact that most FNHs or FNH-like lesions show characteristic hyper- or isointensity on hepatobiliary phase images. We report a case of an FNH-like lesion in a 73-year-old woman that mimicked a malignant tumor. Dynamic contrast-enhanced computed tomography (CT) and MRI using gadoxetic-acid revealed an ill-defined nodule showing early enhancement in the arterial phase and gradual and prolonged enhancement in the portal and equilibrium/transitional phases. Hepatobiliary phase imaging revealed inhomogeneous hypointensity, accompanied by a slightly isointense area compared to the background liver. Angiography-assisted CT showed a portal perfusion defect of the nodule, inhomogeneous arterial blood supply in the early phase, and less internal enhancement in the late phase, accompanied by irregularly shaped peritumoral enhancement. No central stellate scar was identified in any of the images. Imaging findings could not exclude the possibility of hepatocellular carcinoma, but the nodule was pathologically diagnosed as an FNH-like lesion by partial hepatectomy. In the present case, an unusual inhomogeneous hypointensity on hepatobiliary phase imaging made it difficult to diagnose the FNH-like lesions.

Exploration of sepsis assisting parameters in hospital autopsied-patients: a prospective study.

Although Sepsis-3 doesn't require evidence of bacteremia to diagnose sepsis, clinicians often want to identify the causative pathogen at autopsy. In principle, if the blood cultures are the same at ante- and postmortem, the cause of death is obvious. However, interpretations of postmortem blood cultures are often difficult due to discordance, negativity, mixed infection, and contamination, of pathogens occupying ≥ 50% of the tests. To increase specificity identifying agonal phase sepsis in the situations where blood cultures are discordant, multiple or negative at postmortem, we established a scoring system using blood cultures, procalcitonin (PCN) showing highest sensitivity and specificity for postmortem serum, and bone marrow polyhemophagocytosis (PHP). Histological sepsis showed significantly higher levels of culture score (2.3 ± 1.5 vs. 0.4 ± 0.5, p < 0.001), PHP score (2.5 ± 0.8 vs. 1.0 ± 1.1, p < 0.001), and PCN score (1.8 ± 0.8 vs. 0.8 ± 0.6, p < 0.01) than non-septic patients. Receiver operating characteristic curve analysis indicated that estimation of three scores was the most reliable indicator for recognizing agonal phase sepsis. These findings suggest that the combination of these three inspections enables to determine the pathological diagnoses of sepsis even it is not obvious by discordant, mixed or negative blood cultures.

Extracellular volume fraction obtained by dual-energy CT depicting the etiological differences of liver fibrosis.

PURPOSE: To assess etiological differences in extracellular volume fraction (ECV) and evaluate its influence on staging performance. METHODS: A total of 166 patients with normal liver (n = 14) and chronic liver disease related to viral hepatitis (n = 71), alcohol (n = 44), and nonalcoholic steatohepatitis (NASH) (n = 37) underwent dual-energy CT (DECT) of the liver (5-min equilibrium-phase images) between January 2020 and July 2022. The iodine densities of the parenchyma and aorta were measured and ECV was calculated. Comparisons of ECV between each etiology and METAVIR fibrosis stage were statistically analyzed (p < 0.05). RESULTS: ECV in each etiology and all patients significantly increased with higher fibrosis stage (p < 0.001) and showed a strong or moderate correlation with fibrosis stage (Spearman's ρ; all patients, 0.701; viral hepatitis, 0.638; alcoholic, 0.885; NASH, 0.791). In stages F2-F4, ECV in alcoholic liver disease was significantly larger than those for viral hepatitis and NASH (p < 0.05); however, no significant difference in stage F1 was found among the three etiologies. The cutoff values and areas under the receiver operating characteristic curve (AUC-ROCs) for discriminating fibrosis stage (≥ F1- ≥ F4) were higher for alcohol (cutoff values and AUC-ROC; 20.1% and 0.708 for ≥ F1, 23.8% and 0.990 for ≥ F2, 24.3% and 0.968 for ≥ F3, and 26.6% and 0.961 for ≥ F4, respectively) compared with those for the others. CONCLUSION: ECV in alcoholic liver disease is higher than that in other etiologies in the advanced stages of fibrosis, and etiological differences in ECV affect the staging performance of fibrosis.

Postoperative Residual Coronal Decompensation Inhibits Self-image Improvement in Adolescent Patients with Idiopathic Scoliosis.

STUDY DESIGN: Retrospective cohort study. PURPOSE: This study aimed to evaluate the relationship between C7 plumb line (C7PL) decompensation and the Scoliosis Research Society (SRS) 22-item patient questionnaire scores, including those related to self-image, preoperatively and 2 years after surgery. OVERVIEW OF LITERATURE: In the surgical treatment of adolescent idiopathic scoliosis (AIS), inferior trunk balance caused by C7PL decompensation can negatively affect patients' quality of life. However, there are few reports in the literature that describe or clarify how postoperative trunk imbalance affects each SRS-22 domain, including self-image domain scores. METHODS: A total of 120 patients with AIS who underwent posterior spinal fusion from August 2006 to March 2017 at our facility and were followed up for 2 years or more were included. Radiological parameters were measured on whole-spine anteroposterior and lateral radiographs. Revised SRS-22 (SRS-22r) values were also recorded. Coronal trunk imbalance was defined as a deviation of ≥2.0 cm between the C7PL and the central sacral vertical line. Patients with and without coronal trunk imbalance at 2 years after surgery were defined as D (+) (decompensation type) and D (-), respectively. Mean SRS-22r values, including function, pain, self-image, mental health, and subtotal were compared between the D (+) and D (-) groups. Logistic regression analysis was performed to detect the preoperative factors related to D (+) using predictors, including curve type, maximum Cobb angle, and coronal trunk imbalance. RESULTS: At 2 years after surgery, the D (+) group had a significantly lower self-image in the domain of SRS-22r scores compared with the D (-) group. Preoperative coronal trunk imbalance was significantly related to D (+) but not to significant changes in the postoperative SRS-22 score in any of the SRS-22 domains. CONCLUSIONS: Postoperative C7PL deviation lowers the self-image in patients with AIS. Patients with preoperative coronal trunk imbalance were significantly more likely to be D (+).

Diagnostic performance of abbreviated gadoxetic acid-enhanced magnetic resonance protocols with contrast-enhanced computed tomography for detection of colorectal liver metastases.

BACKGROUND: Although contrast-enhanced magnetic resonance imaging (MRI) using gadoxetic acid has been shown to have higher accuracy, sensitivity, and specificity for the detection and characterization of hepatic metastases compared with other modalities, the long examination time would limit the broad indication. Several abbreviated enhanced MRI (Ab-MRI) protocols without dynamic phases have been proposed to achieve equivalent diagnostic performance for the detection of colorectal liver metastases. However, an optimal protocol has not been established, and no studies have assessed the diagnostic performance of Ab-MRI combined with contrast-enhanced computed tomography (CE-CT), which is the preoperative imaging of colorectal cancer staging in clinical settings, to determine the best therapeutic strategy. AIM: To compare the diagnostic performance of two kinds of Ab-MRI protocol with the standard MRI protocol and a combination of the Ab-MRI protocol and CE-CT for the detection of colorectal liver metastases. METHODS: Study participants comprised 87 patients (51 males, 36 females; mean age, 67.2 ± 10.8 years) who had undergone gadoxetic acid-enhanced MRI and CE-CT during the initial work-up for colorectal cancer from 2010 to 2021. Each exam was independently reviewed by two readers in three reading sessions: (1) Only single-shot fast spin echo (FSE) T2-weighted or fat-suppressed-FSE-T2-weighted, diffusion-weighted, and hepatobiliary-phase images (Ab-MRI protocol 1 or 2); (2) all acquired MRI sequences (standard protocol); and (3) a combination of an Ab-MRI protocol (1 or 2) and CE-CT. Diagnostic performance was then statistically analyzed. RESULTS: A total of 380 Lesions were analyzed, including 195 metastases (51.4%). Results from the two Ab-MRI protocols were similar. The sensitivity, specificity, and positive and negative predictive values from Ab-MRI were non-inferior to those from standard MRI (P > 0.05), while those from the combination of Ab-MRI protocol and CE-CT tended to be higher than those from Ab-MRI alone, although the difference was not significant (P > 0.05), and were quite similar to those from standard MRI (P > 0.05). CONCLUSION: The diagnostic performances of two Ab-MRI protocols were non-inferior to that of the standard protocol. Combining Ab-MRI with CE-CT provided better diagnostic performance than Ab-MRI alone.

Liver Metastases: Correlation between Imaging Features and Pathomolecular Environments.

A wide range of imaging manifestations of liver metastases can be encountered, as various primary cancers preferably metastasize to the liver (organ-specific metastases), with the imaging characteristics largely depending on various primary tumor-specific factors such as histopathologic category, degree of tumor differentiation, histologic behavior, and intratumor alterations. Characteristic imaging features potentially can help provide a more precise diagnosis in some clinical settings. These settings include those of (a) primary cancers of hollow organs such as gastrointestinal organs, the lungs, and the bladder, owing to the appearance of metastases that cannot be applied to the liver, which is a parenchymal organ; (b) unknown primary tumors; (c) more than one primary tumor; (d) another emergent malignancy; and (e) transformation to a different histopathologic tumor subtype. The characteristic features include the target sign on T2-weighted MR images or during the hepatobiliary phase of hypovascular metastasis, the peripheral rim washout sign on delayed phase images, peritumor hyperintensity during the hepatobiliary phase, hypervascular metastasis, a cystic appearance with marked hyperintensity on T2-weighted images, marked hyperintensity on T1-weighted images, calcification, capsular retraction, absence of the vessel-penetrating sign, distribution of liver metastases, and rare intraductal forms of metastases. In addition to various factors associated with the primary cancer, desmoplastic reactions around the tumor-which can be observed in adenocarcinomas with peripheral and peritumor enhancement, distinct arterioportal shunts with metastases from pancreatic ductal carcinoma, and pseudocirrhosis-also can affect these findings. The authors review the characteristic imaging findings of liver metastases from various primary cancers, with a focus on the mechanisms that underlie organ-specific liver metastases. Online supplemental material is available for this article. ©RSNA, 2022.

Pearls and pitfalls of imaging features of pancreatic cystic lesions: a case-based approach with imaging-pathologic correlation.

A variety of neoplastic and non-neoplastic lesions of the pancreas can present with a predominantly cystic architecture. These lesions are increasingly being detected as incidental findings on routine cross-sectional imaging following technological advances in these techniques and their widespread use. The different histopathological behaviors show various common and uncommon imaging findings, and some cases show similar appearance in spite of different histopathology. Each lesion requires specific management because of the differing risk of progression to malignancy, and an accurate imaging diagnosis is crucial. The typical imaging characteristics that differentiate pancreatic cystic lesions have been well described and fully summarized. However, in addition to a small percentage of cases that shows uncommon imaging findings, a substantial percentage of cystic lesions shows overlapping imaging findings that can lead to radiological misdiagnosis. For appropriate diagnosis and optimal treatment strategy, it is important to know the uncommon and overlapping imaging findings of these lesions, in addition to familiarity with the typical aspects. In this article, we reconfirm the well-known characteristic imaging features of pancreatic cystic lesions and present several diagnostically challenging cases, focusing on the uncommon and overlapping imaging findings.

3D-CT stress test for the assessment of CFL insufficiency.

BACKGROUND: Following ankle sprains, some patients complain of their ankles "giving way," characterized by functional instability with no positive findings in traditional stress tests. The calcaneofibular ligament (CFL) may contribute to the stabilization of the subtalar and talocrural joints, and some functional instability may be due to CFL insufficiency. We aimed to clarify and quantitatively assess CFL insufficiency with three-dimensional stress computer tomography (CT) using the Pronation-External Rotation Stress Test (PERST). METHODS: Ten patients who tested positive under PERST and underwent an isolated CFL reconstruction were included. Using a custom-made loading jig, we used the Supination-Internal Rotation Stress Test (SIRST) and PERST to assess the function of anterior talofibular ligament (ATFL) and CFL, respectively. 3D-CT in neutral position was used as a baseline, and we quantified the distance between the origin and insertion of the CFL and ATFL at 2 years pre- and postoperatively. RESULTS: Postoperative scores improved in all patients with no giving way symptoms. The preoperative length of the CFL increased by 14.0% from baseline under PERST, while the postoperative length only increased by 2.0% and was significantly restricted (P < .01). The pre- and postoperative length of ATFL was increased by 7.5% and 9.0% from baseline under SIRST, respectively, with no significant difference (P = .41). The clinical function improved with significantly less change in distance between the origin and insertion under PERST and showed no difference under SIRST. CONCLUSION: The 3D-CT stress test may be useful for quantifying pre- and postoperative CFL function. CFL insufficiency is one of the main causes of subtalar joint instability; therefore, measuring the distance between the origin and insertion of the CFL could provide the means to quantify the instability of the subtalar joint.

Enhanced Exciton-Exciton Collisions in an Ultraflat Monolayer MoSe2 Prepared through Deterministic Flattening.

Squeezing bubbles and impurities out of interlayer spaces by applying force through a few-layer graphene capping layer leads to van der Waals heterostructures with the ultraflat structure free from random electrostatic potential arising from charged impurities. Without the graphene capping layer, a squeezing process with an AFM tip induces applied-force-dependent charges of Δn ∼ 2 × 1012 cm-2 µN-1, resulting in the significant intensity of trions in photoluminescence spectra of MoSe2 at low temperature. We found that a hBN/MoSe2/hBN prepared with the "graphene-capping-assisted AFM nano-squeezing method" shows a strong excitonic emission with negligible trion peak, and the residual line width of the exciton peak is only 2.2 meV, which is comparable to the homogeneous limit. Furthermore, in this high-quality sample, we found that the formation of biexciton occurs even at extremely low excitation power (Φph ∼ 2.3 × 1019 cm-2 s-1) due to the enhanced collisions between excitons.

Primary hepatic diffuse large B-cell lymphoma presenting unusual imaging features.

Primary hepatic lymphomas are frequently misdiagnosed, due to their rarity and non-specific clinical manifestations. As these tumors can be successfully treated with chemotherapy and/or radiotherapy, early recognition on imaging is essential to avoid unnecessary surgery. We report a case of primary hepatic lymphoma in a 73-year-old woman presenting with a 1-week history of persistent fever and elevated hepatobiliary enzymes. Ultrasound showed a hypoechoic hepatic mass in the anterior segment. Dynamic contrast-enhanced computed tomography (CT) revealed an ill-defined solitary mass showing peripherally dominant slight-to-moderate enhancement contrasting with a hypovascular central area. On magnetic resonance imaging, the mass showed moderate hyperintensity on T2-weighted imaging, hypointensity on T1-weighted imaging, doughnut-like hyperintensity on diffusion-weighted imaging, and an obviously low apparent diffusion coefficient (ADC). The pattern of enhancement resembled that of CT. Neither calcification nor any fat component was observed. Doughnut-like accumulation was seen on 18F-fluorodeoxyglucose (FDG)-positron emission tomography/CT without other FDG-avid lesions. Imaging findings suggested the possibility of cholangiocellular carcinoma, but the low ADC and extremely high FDG accumulation were suggestive of malignant lymphoma, and diffuse large B-cell lymphoma was pathologically confirmed from percutaneous biopsy. The mass disappeared after radiochemotherapy, and no recurrence has been observed for 3 years.

Invasive liver abscess syndrome accompanied by spondylodiscitis: a case report and review of the literature.

A 65-year-old man who had diabetes mellitus was referred to our hospital due to fever and back pain. Laboratory findings showed liver dysfunction and C-reactive protein (CRP) elevation. Enhanced computed tomography (CT) showed multiple liver abscesses, hepatic vein and inferior vena cava thrombosis, and spondylodiscitis in the fourth lumbar vertebrae. Based on several detections of Klebsiella pneumoniae (K. pneumoniae) in blood culture, he was diagnosed as having invasive liver abscess syndrome (ILAS), which is characterized by liver abscess and metastatic infection caused by K. pneumoniae. Despite the prompt improvement of liver abscess and thrombosis, after administering antibiotics and anticoagulant, spondylodiscitis worsened. Additionally, iliopsoas abscess emerged on repeated CT imaging. Lumbar laminectomy was needed as a radical treatment. We reviewed 12 cases of ILAS representing spondylodiscitis, and surgical treatments for spondylodiscitis were required in 7 of these cases (58%). When encountering patients with liver abscess and spondylodiscitis, we should consider the possibility of invasive disseminated K. pneumoniae infection, which is hard to treat with antibiotics alone and sometimes requires surgical treatments for spondylodiscitis.

Preparation and Fluorescence Properties of Perylenediimide Nanodispersions Having a One-Dimensional π-Stacked Structure.

We prepared stable nanodispersions of a fluorescent perylenediimide (PDI) derivative having long alkyl chains by nanosecond laser fragmentation of its microcrystalline powder in acetonitrile (ACN). The nanoparticles had cube-like or rod shapes with a mean size of 100 nm, and they dispersed stably for longer than 1 month. The prepared nanobricks exhibited absorption and fluorescence spectra characteristic of one-dimensional aggregates with cofacial stacking of PDI planes. Single-particle fluorescence measurements demonstrated that nanobricks had a well-aligned structure of one-dimensional columns of PDI. The aqueous dispersions were also fabricated by redispersing the prepared nanobricks, utilizing lipophilic interactions of surfactants having long alkyl chains. We examined the fluorescence properties of nanoparticles dispersed in ACN and in water, and observed amplified fluorescence quenching by the surface-adsorbed dye.

Catalytic roles of CYP2C9 and its variants (CYP2C9*2 and CYP2C9*3) in lornoxicam 5'-hydroxylation.

The effects of allelic variants of CYP2C9 (CYP2C9*2 and CYP2C9*3) on lornoxicam 5'-hydroxylation were studied using the corresponding variant protein expressed in baculovirus-infected insect cells and human liver microsomes of known genotypes of CYP2C9. The results of the baculovirus expression system showed that CYP2C9.3 gives higher K(m) and lower V(max) values for lornoxicam 5'-hydroxylation than does CYP2C9.1. In contrast, K(m) and V(max) values of CYP2C9.1 and CYP2C9.2 for the reaction were comparable. Lornoxicam 5'-hydroxylation was also determined in liver microsomes of 12 humans genotyped for the CYP2C9 gene (*1/*1, n = 7; *1/*2, n = 2; *1/*3, n = 2; *3/*3, n = 1). A sample genotyped as *3/*3 exhibited 8- to 50-fold lower intrinsic clearance for lornoxicam 5'-hydroxylation than did samples genotyped as *1/*1. However, the values for intrinsic clearance for *1/*3 were within the range of values exhibited by samples of *1/*1. In addition, no appreciable differences were observed in kinetic parameters for lornoxicam 5'-hydroxylation between *1/*1 and *1/*2. In conclusion, this study showed that lornoxicam 5'-hydroxylation via CYP2C9 was markedly decreased by the substitution of Ile359Leu (CYP2C9.3), whereas the effect of the substitution of Arg144Cys (CYP2C9.2) was nonexistent or negligible. Additional in vivo studies are required to confirm that individuals with homologous CYP2C9*3 allele exhibit impaired lornoxicam clearance.

CYP isoforms involved in the metabolism of clarithromycin in vitro: comparison between the identification from disappearance rate and that from formation rate of metabolites.

To clarify whether CYP2C19 is involved in the overall metabolism of clarithromycin (CAM) or not, in vitro studies using human liver microsomes and recombinant CYPs were performed by an approach based on the disappearance rate of parent compound from the incubation mixture. In addition, the results of disappearance rate were compared with those obtained from the formation rates of the major metabolites of CAM, 14-(R)-hydroxy-CAM and N-demethyl-CAM. The intrinsic clearance (CL(int)) values determined from the disappearance of CAM in nine different human liver microsomes were highly correlated with the testosterone 6beta-hydroxylation activity (r=0.957, p<0.001). The CL(int) of CAM was markedly reduced by selective inhibitors of CYP3A4 (ketoconazole and troleandomycin) and by polyclonal antibodies raised against CYP3A4/5 in human liver microsomes. Among the 11 isoforms of recombinant human CYP, only CYP3A4 revealed the metabolic activity for the disappearance of CAM. These results were fairly consistent with those obtained from the conventional approach based on the formation of major metabolites of CAM. Comparison of the kinetic parameters estimated from the disappearance rate of CAM and the formation rates of 14-(R)-hydroxy-CAM and N-demethyl-CAM indicates that N-demethylation and 14-(R)-hydroxylation account for 65% of CL(int) derived from the disappearance of CAM in human liver microsomes. The findings suggest that CYP3A4 plays a predominant role in the overall metabolic clearance of CAM as well as in the formation of 14-(R)-hydroxy-CAM and N-demethyl-CAM. CYP2C19 does not appear to be involved in the overall metabolism of CAM at least in human liver microsomes. A combination of the disappearance rate of a parent compound and the formation rate of metabolites appears to be a useful approach for estimating the percentage contribution of the formation of metabolites to the overall metabolic clearance of a parent compound in vitro.

Formation of a disulfide protein conjugate of the SH-group-containing metabolite (M-I) of esonarimod (KE-298) and its elimination in rats.

The reactivity of the thiol moiety of the active main metabolite (M-I) of esonarimod (KE-298), a novel anti-rheumatic agent, was investigated in rats. After repeated oral administration of 14C-KE-298, the radioactivity decreased rapidly and no tendency towards accumulation was found, in marked contrast to other common SH-group-containing drugs. At 30 min after intravenous administration of 14C-M-I to rats, the concentration of the 14C-M-I plasma protein conjugate in plasma was extremely low at 0.143 nmol mL(-1) (0.66% of total plasma radioactivity). The 14C-M-I plasma protein conjugate that formed in rat plasma was mixed disulfide with plasma protein. After intravenous administration of synthetic 14C-M-I plasma protein conjugate to rats, the radioactivity in plasma decreased rapidly, with the terminal half-life at 6.90 h. In-vitro, the 14C-M-I plasma protein conjugate was readily dissociated by the endogenous thiol compounds, cysteine and glutathione. These results suggest that the reactivity of the thiol moiety of M-I is extremely low. Furthermore, the 14C-M-I plasma protein conjugate decreased rapidly in-vivo, which would be related to interaction with endogenous thiol compounds. These properties of M-I are principally responsible for the zero accumulation in rat tissues. KE-298 could therefore be expected to have reduced adverse effects compared with other SH-group-containing anti-rheumatic drugs.

Differentiation between isomeric oxidative metabolites of a piperidine-containing drug by liquid chromatography-tandem mass spectrometry with stable-isotope tracer technique.

This report describes the application of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to differentiation of hydroxylations and N-oxidations and of two different aliphatic hydroxylations in the investigation of the metabolism of pibutidine hydrochloride, a novel H2 antagonist, the structure of which includes a piperidine ring. Pibutidine metabolites in urine samples from adult male volunteers after oral administration of pibutidine hydrochloride were separated by reversed-phase LC and ionized using an electrospray ionization (ESI) interface. A hydroxylated form of pibutidine was distinguished from the N-oxide by comparison of their product ion spectra, although their mass-to-charge ratios of protonated molecules were identical. Further, two hydroxylated compounds were present in rat microsomal incubation mixtures with pibutidine. The distinction between their positions of hydroxylation (beta- and gamma-carbon hydroxylation) on the piperidine ring was studied using [piperidine-2H10] pibutidine as incubation substrate. The production of the beta-hydroxylated form was accompanied by the elimination of three 2H, resulting from a mechanism including the formation of iminium/enamine. The participation of the iminium ion intermediate in the beta-hydroxylation was confirmed by the observation that a cyanide adduct of pibutidine was formed instead of the beta-hydroxylated form when another incubation was performed in the presence of cyanide.