Combined effect of histological findings and diabetes mellitus on liver-related events in patients with metabolic dysfunction-associated steatotic liver disease.

AIM: Advanced fibrosis has a strong influence on the occurrence of liver-related events in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), while diabetes mellitus (DM), which is often complicated by MASLD, is associated with the progression of MASLD. We stratified patients with MASLD according to the severity of liver pathological findings and the presence of DM, aiming to examine whether these indices could be used to accurately assess the risk of developing liver-related events. METHODS: A total of 282 patients with liver biopsy-proven MASLD were included. Liver-related events were defined as the occurrence of hepatocellular carcinoma (HCC) and complications of liver cirrhosis, such as ascites, hepatic encephalopathy, Child-Pugh class B and C, as well as treatment-eligible esophageal and gastric varices. RESULTS: Multivariate analysis adjusted for age, sex, body mass index, alanine aminotransferase, creatinine, hemoglobin A1c, smoking habits, dyslipidemia, hypertension, nonalcoholic fatty liver disease activity score (NAS), or fibrosis stage showed that advanced fibrosis with or without DM was a risk factor for liver-related events. The combined effect of DM and advanced fibrosis increased the risk of HCC onset. However, DM alone or in combination with NAS did not affect the development of liver-related events, including the occurrence of HCC and complications of liver cirrhosis. CONCLUSIONS: While the assessment of fibrosis in patients with MASLD is important for evaluating the risk of developing liver-related events, combining the assessment of DM may be possible to stratify groups at higher risk of developing HCC.

Prediction of combination effect of quinidine on the pharmacokinetics of tipepidine using a physiologically based pharmacokinetic model.

Tipepidine, an antitussive drug, has been reported to have central pharmacological effects and can be expected to be safely repositioned as treatment for psychiatric disorders. Since tipepidine requires three doses per day, development of a once-daily medication would be highly beneficial. Previously, we reported that combination use with quinidine, a CYP2D6 inhibitor, prolongs the half-life of tipepidine in chimeric mice with humanised liver.In this study, to predict this combination effect in humans, a physiologically based pharmacokinetic (PBPK) model was developed, and quantitative simulation was conducted. The simulation results indicated that concomitant administration of tipepidine with quinidine increased the predicted Cmax, AUC, and t1/2 of tipepidine in the Japanese population by 3.4-, 6.6-, and 2.4-fold, respectively.Furthermore, to compare with another approach that aims to prolong the half-life, the PK profile of tipepidine administered in hypothetical extended-release form was simulated. Extended-release form was predicted to be more influenced by CYP2D6 genotype than combination with quinidine, and the predicted plasma exposure was markedly increased in poor metabolizers, potentially leading to adverse effects.In conclusion, quantitative simulation using the PBPK model suggests the feasibility of the safe repositioning of tipepidine as a once-daily medication in combination with quinidine.

Association of oral frailty with medical expenditure in older Japanese adults: The study of late-stage older adults in Tottori (START Tottori).

OBJECTS: This study aimed to determine the association between annual medical expenses and oral frailty in later-stage older adults (aged ≥ 75 years). No studies have investigated the association between medical costs and oral frailty, which would elucidate the association between oral frailty and the deterioration of mental and overall physical function. MATERIALS AND METHODS: In this cross-sectional study, 2190 adults (860 men and 1330 women aged 75-94 years) covered by the Medical System for the Elderly and residing in Tottori Prefecture, Japan, between April 2016 and March 2019, were included. Participants were classified into three groups: healthy, pre-orally frail or orally frail, based on dental health screening findings. The medical and dental expenses over the years, number of days of consultations and comorbidities were obtained from the Japanese Health Insurance Claims Database. RESULTS: The number of days of medical and dental consultations and annual medical expenses for outpatient care differed among the three study groups. A significant association was observed between oral frailty and high annual expenses for outpatient medical and dental care. Oral frailty was associated with higher medical expenses in participants with poor masticatory function. Higher and lower dental expenses were associated with subjective poor masticatory function and subjective impairment of swallowing function respectively. CONCLUSION: Medical and dental expenses for orally frail older adults are high, indicating that oral frailty may be related to the occurrence and severity of diseases other than oral health issues. Future studies should examine the mechanism by which oral weakness affects physical and mental functions.

Spleen stiffness in patients with chronic liver disease evaluated by 2-D shear wave elastography with ultrasound multiparametric imaging.

BACKGROUND: The novel 2-D shear wave elastography (2D-SWE) can measure two ultrasound parameters: shear wave dispersion (SWD) and shear wave speed (SWS). We investigated the ability of 2D-SWE in measuring spleen stiffness using ultrasound multiparametric imaging. METHODS: This cross-sectional study included patients with chronic liver disease who underwent esophagogastroduodenoscopy and ultrasonographic examinations of the spleen between September 2018 and December 2021. In total, 157 patients were enrolled in this study: 81 and 67 patients were included in the pilot set for hepatic venous pressure gradient (HVPG) measurements and validation cohort without HVPG measurements, respectively. To confirm reproducibility between the two examiners, an additional 30 patients were enrolled. RESULTS: The Bland-Altman plots revealed no significant bias in the SWD as measured by two examiners. The splenic SWS (r = 0.752) and SWD (r = 0.444) were correlated with the HVPG. Regarding high-risk varices, as per the Youden index, the cut-off value for splenic SWS was 3.30 m/s, with a sensitivity of 85.7%, specificity of 92.5%, positive predictive value of 85.7%, and negative predictive value of 92.4% in the pilot set. In the validation set, good diagnostic performance by the splenic SWS was observed. However, SWD did not perform as well as SWS. CONCLUSIONS: The splenic SWS, measured using ultrasound multiparametric imaging, was closely correlated with the HVPG. Thus, SWS is a useful predictive marker for high-risk varices.

Association of abnormal glucose tolerance with liver-related disease and cardiovascular diseases in patients with chronic hepatitis C.

AIM: Hepatitis C complicated by diabetes mellitus (DM) is considered a risk factor for the progression of fibrosis and development of hepatocellular carcinoma (HCC) and cardiovascular diseases. However, several studies may have lacked appropriate diagnosis of glucose intolerance. We aimed to examine the risk associated with abnormal glucose intolerance in the development of liver-related diseases, including HCC and complications of liver cirrhosis, such as ascites, esophageal and gastric varices, and hepatic encephalopathy, and cardiovascular diseases in patients with hepatitis C accurately diagnosed with impaired glucose tolerance. METHODS: This longitudinal retrospective study included 365 patients with chronic hepatitis C admitted to Ehime University Hospital for anti-hepatitis C therapy between September 1991 and January 2015. Patients were classified into normal glucose tolerance (NGT), prediabetes, and DM groups based on 75-g oral glucose tolerance test results. RESULTS: Both univariate and multivariate (adjusted for potential confounders) analyses revealed a significantly higher risk of developing HCC and cardiovascular events in the DM group than in the NGT group. However, in multivariate analysis, liver-related events, particularly liver cirrhosis complications, revealed no significant association. In addition, the prediabetes group had no significant risk of any outcome. CONCLUSIONS: Patients with hepatitis C complicated by DM, compared with patients with hepatitis C with NGT or complicated with prediabetes, have a higher risk of HCC and cardiovascular disease events, but not liver-related events, particularly in not developing liver cirrhosis complications. Therefore, appropriate follow-up is required for patients with hepatitis C based on their glucose tolerance status.

Estimation of contribution of CYP2D6 to tipepidine metabolism in humans and prolongation of the half-life of tipepidine by combination use with a CYP2D6 inhibitor in chimeric mice with humanised liver.

Recently, it has been reported that tipepidine has various central pharmacological effects and can be expected to be safely repositioned as a treatment for psychiatric disorders. Since tipepidine has a very short half-life and requires three doses per day, the development of a once-daily medication would be highly beneficial to improve adherence and quality of life in patients with chronic psychiatric disorders. The aim of this study was to identify the enzymes involved in tipepidine metabolism and to verify that combination use with an enzyme inhibitor prolongs the half-life of tipepidine.Metabolism studies using recombinant human cytochrome P450 (P450, CYP) isoforms and inhibition studies using various selective P450 inhibitors and human liver microsomes revealed that CYP2D6 is the main enzyme catalysing tipepidine metabolism, with a metabolic contribution ratio of 85.4%.Furthermore, a pharmacokinetic study using chimeric mice with humanised liver showed that oral coadministration of a CYP2D6 inhibitor, quinidine, increased the Cmax, AUC0-t, and t1/2 of tipepidine by 1.5-, 3.2-, and 3.0-fold, respectively.These results indicated that coadministration of a CYP2D6 inhibitor is effective in increasing plasma exposure and prolonging the half-life of tipepidine and is useful for repositioning tipepidine as a treatment for psychiatric disorders.

Role of B Cell-Activating Factor in Fibrosis Progression in a Murine Model of Non-Alcoholic Steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease all over the world. Therapeutic strategies targeting its multidirectional pathways are required. Particularly, fibrosis is closely associated with its prognosis. We previously found that B cell-activating factor (BAFF) is associated with severity of NAFLD. Here, we determined the direct in vivo role of BAFF in the development of liver fibrosis. Histological and biochemical analyses were performed using wild-type and BAFF-deficient mice. We established a murine model of non-alcoholic steatohepatitis (NASH) using carbon tetrachloride injection accompanied by high-fat/high-cholesterol diet feeding. Additionally, in vitro analysis using mouse macrophage-like cell line RAW264.7 and primary hepatic stellate cells was performed. Hepatic steatosis and inflammation, and most importantly, the progression of liver fibrosis, were ameliorated in BAFF-deficient mice compared to those wild-type mice in our model. Additionally, BAFF deficiency reduced the number of CD11c+ M1-type macrophages in the liver. Moreover, BAFF stimulated RAW264.7 cells to secrete nitric oxide and tumor necrosis factor α, which drove the activation of hepatic stellate cells. This indicates that BAFF plays a crucial role in NASH development and may be a promising therapeutic target for NASH.

Measurement of multiple spleen lengths is not necessary for non-invasive prediction of high-risk esophagogastric varices.

AIM: To validate an appropriate spleen size measurement technique for the prediction of high-risk esophagogastric varices. METHODS: This retrospective cross-sectional study included 369 patients who underwent ultrasonography and computed tomography (CT) of the spleen and esophagogastroduodenoscopy between January 2018 and December 2020. Maximum spleen length, width, and craniocaudal length were measured in a longitudinal view. The two-dimensional (2D) spleen index (maximum length × maximum width in the longitudinal view) was calculated. A three-dimensional (3D) spleen index was then defined as follows: 2D spleen index × maximum length in the transverse view. The similarity in spleen volume measured by CT and ultrasonography (spleen index) was assessed by the correlation coefficient. The diagnostic accuracies of the spleen index, platelet/spleen length, and platelet/spleen index were calculated to determine the overall diagnostic accuracy. RESULTS: Compared to the other spleen indices, our 3D spleen index was significantly better correlated with spleen volume on CT (r = 0.91, 95% confidence interval 0.89-0.92, p < 0.001). Receiver-operating characteristic curve analyses revealed no significant difference between the 3D and 2D indices (p = 0.228) but did show a significant difference between the 3D and one-dimensional indices (p = 0.020). Although the area under the curve for the platelet count combined with the spleen index or length was higher than that for our 3D index, there was no significant difference between platelet count and spleen index or length (p = 0.078). CONCLUSIONS: Platelet/spleen length has a reasonable ability to predict high-risk esophagogastric varices, even though measurement of two or three factors can be correlated with spleen volume.

Facilitators and barriers in implementing the nurse practitioner role in Japan: A cross-sectional descriptive study.

AIM: To investigate the distribution of nurse practitioners (NPs) across Japan and their perceived facilitators and barriers to NP implementation in Japan. BACKGROUND: NP certification examinations have been conducted in Japan since 2011, and by 2020, there were 487 NPs in the country. The momentum of NP implementation is slower in Japan compared with other countries. METHODS: A cross-sectional descriptive study, following the STROBE guidelines, was conducted. Web-based survey questionnaires, developed by the authors, were administered to 248 NPs whose email addresses were maintained by the certification management body. RESULTS: Valid responses were obtained from 101 NPs (response rate: 40.7%), of which 34% were male. The respondents had more than 12 years of registered nurse experience on an average before enrolling in the graduate NP program. 53% were employed as NPs from the beginning, while 25% were initially employed as registered nurses and later advanced to NPs, and 11% still worked as RNs. A majority worked in hospitals with beds. Many NPs perceived the lack of NP national licensure and reimbursement benefits as barriers to NP implementation, whereas recognition from superiors and organizations was considered facilitators. CONCLUSIONS: Despite their small numbers in Japan, NPs take on crucial tasks and contribute to the appropriate distribution of medical resources. The NP licensure system and recognition from superiors and organizations may be necessary to promote NP roles in Japan. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Some certified NPs still work as registered nurses. Recognition from nursing and organization administrators is critical to implementing NPs. To this end, a reimbursement system benefiting the organizations and a legislation facilitating NP employment are required.

AFP and eGFR are related to early and late recurrence of HCC following antiviral therapy.

BACKGROUND: An unexpected recurrence of hepatocellular carcinoma (HCC) sometimes occurs in patients with hepatitis C virus (HCV) after treatment with direct-acting antivirals (DAAs). However, the characteristics of patients with HCC recurrence may differ depending on time after DAA treatment. We aimed to identify risk factors related to HCC recurrence according to time after DAA treatment. METHODS: Of 1663 patients with HCV treated with a DAA, 199 patients had a previous history of HCC. We defined HCC recurrence within 1 year after DAA treatment as 'early recurrence', and recurrence more than 1 year after as 'late recurrence'. The different risk factors between the early and late phases of HCC recurrence after the end of DAA therapy were investigated. RESULTS: Ninety-seven patients experienced HCC recurrence during the study period. Incidences of recurrence were 29.8, 41.0, and 53.4% at 1, 2, and 3 years, respectively, after the end of DAA therapy. Multivariate analysis identified post-treatment α-fetoprotein (AFP) as an independent factor contributing to HCC recurrence in the early phase (hazard ratio, 1.056; 95% confidence interval, 1.026-1.087, p < 0.001) and post-treatment estimated glomerular filtration rate (eGFR) (hazard ratio, 0.98; 95% confidence interval, 0.96-0.99, p = 0.032) as a predictor of HCC recurrence in the late phase. CONCLUSION: Patients with higher post-treatment AFP in the early phase and those with lower post-treatment eGFR in the late phase had a high risk of HCC recurrence. The risk factors associated with HCC recurrence after DAA treatment were different between the early and late phases.

Relationship between body composition and the histology of non-alcoholic fatty liver disease: a cross-sectional study.

BACKGROUND: Causes of non-alcoholic fatty liver disease and its progression include visceral fat accumulation and loss of muscle mass; however, which of the two phenomena is more critical is unclear. Therefore, we intended to examine the relationship between body composition and non-alcoholic fatty liver disease progression as indicated by fibrosis and the non-alcoholic fatty liver disease activity score. METHODS: This cross-sectional study comprised 149 patients (55 men; age, 20-76 years) treated for non-alcoholic fatty liver disease between December 2010 and January 2020. Body composition measurements, histological examinations of liver samples, and comprehensive blood chemistry tests were performed. The relationship between body composition and non-alcoholic fatty liver disease histology findings was analyzed using the logistic regression model. RESULTS: Fibrosis was significantly and inversely correlated with muscle mass and appendicular skeletal muscle mass and significantly and positively correlated with fat mass, fat mass/height squared, visceral fat area, and waist-hip ratio (P < 0.05). After adjustment for sex, blood chemistry measurements, and body composition indices, fibrosis remained associated with appendicular skeletal muscle mass, fat mass, fat mass/height squared, and visceral fat area (P < 0.05). Non-alcoholic fatty liver disease activity score ≥ 5 significantly correlated with fat mass and fat mass/height squared in a univariate but not multivariate analysis. CONCLUSIONS: Fibrosis in non-alcoholic fatty liver disease, an indicator of unfavorable long-term outcomes, is associated with more indices of fat mass than of those of muscle mass. Hence, fat mass should be controlled to prevent non-alcoholic fatty liver disease progression.

Dilatation of lymphatic vessels increases liver stiffness on transient elastography irrespective of fibrosis.

AIM: Liver stiffness measured using transient elastography (TE) is affected by tissue viscosity. The role of intrahepatic lymphatic fluid in liver stiffness is unclear. The present study aimed to investigate the effects of lymphatic vessel dilatation on liver stiffness. METHODS: Patients with chronic liver disease (n = 116) were enrolled from June 2018 to March 2020. All specimens were acquired by laparoscopic liver biopsy. Biopsy samples were stained with D2-40 for lymphatic vessel quantification based on a five-point scale for each specimen. Independent associations of liver stiffness measured by TE, strain elasticity (liver fibrosis index), and controlled attenuation parameter with fibrosis, lymphatic vessels, alanine aminotransferase, bilirubin, and steatosis were evaluated. RESULTS: Fibrosis, splenic stiffness measurement, and splenic volume were significantly correlated with the area of lymphatic vessels. Fibrosis, lymphatic vessels, and alanine aminotransferase were independent factors significantly associated with liver stiffness measurement (LSM; standardized coefficient [ß] = 0.375, P < 0.001; ß = 0.342, P < 0.001; and ß = 0.359, P < 0.001, respectively). Fibrosis was the only independent factor significantly associated with liver fibrosis index (ß = 0.360, P < 0.001), whereas the fat deposit area was the only independent factor significantly associated with controlled attenuation parameter (ß = 0.455, P < 0.001). The areas under the receiver operating characteristic curves for diagnosing controlled ascites based on LSM, liver fibrosis index, splenic stiffness measurement, collagen proportionate area, and area of lymphatic vessels were 0.94, 0.66, 0.76, 0.64, and 0.79, respectively. CONCLUSIONS: Lymphatic vessel dilatation can affect liver stiffness measured using TE. Liver stiffness measurement is a predictive factor for ascites.

Validation of the FibroScan-aspartate aminotransferase score by vibration-controlled transient and B-mode ultrasound elastography.

AIM: The FibroScan-aspartate aminotransferase (FAST) score comprises an easy and feasible method for identifying advanced non-alcoholic steatohepatitis. Recently, shear-wave elastography and attenuation coefficient measurement on B-mode ultrasound (US) have become widely utilized. We investigated the diagnostic accuracy of the FAST score as calculated using US-elastography compared with that using vibration-controlled transient elastography (VCTE). METHODS: Patients with chronic liver disease who underwent VCTE, point-shear-wave elastography with attenuation coefficient measurement, and liver biopsy on the same day between January 2015 and September 2020 were retrospectively reviewed. RESULTS: Of 189 patients, 94 underwent VCTE using both M and XL probes. The C-statistics were similar for VCTE (0.846) and US-elastography (0.814; p = 0.251), and for M (0.857) and XL probes (0.833; p = 0.412). Scatter and Bland-Altman plots showed good reproducibility for the FAST score. For VCTE, a cut-off of ≤0.35 had a sensitivity of 92.3%, negative predictive value of 85.5%, and negative likelihood ratio of 0.14, and a cut-off of ≥0.67 had a specificity of 90.6%, positive predictive value of 88.1%, and positive likelihood ratio of 6.03, for ruling out and in advanced non-alcoholic steatohepatitis, respectively. For US-elastography, a cut-off of ≤0.35 had a sensitivity of 90.4%, negative predictive value of 83.3%, and negative likelihood ratio of 0.16, and a cutoff of ≥0.67 had a specificity of 91.8%, positive predictive value of 85.1%, and positive likelihood ratio of 4.67, for ruling out and in advanced non-alcoholic steatohepatitis, respectively. CONCLUSIONS: The FAST score is highly reproducible, even when different echo equipment or probes are used.

[Ectopic Adrenocorticotropic Hormone-Producing Pulmonary Carcinoid Presenting as Cushing's Syndrome after Intrapleural Hyperthermic Chemotherapy].

The patient was a woman in her 70's was referred to our hospital because of an abnormal shadow on chest roentgenogram at an annual medical checkup. Since preoperative examinations suggested lung cancer in the right middle lobe, thoracoscopic right middle lobectomy was planned. However, pleural dissemination was detected at surgery and we changed the treatment plan to the intrapleural hyperthermic chemotherapy. During the postoperative course, facial edema, hypokalemia, and hyperglycemia developed, and the diagnosis of Cushing's syndrome was suggested based on an increase in serum level of adrenocorticotropic hormone (ACTH) and cortisol, and was confirmed by a dexamethasone suppression test. Intrapleural hyperthermic chemotherapy was likely to collapse the ACTH-producing tumor leading Cushing's syndrome.

Sex difference in the development of hepatocellular carcinoma after direct-acting antiviral therapy in patients with HCV infection.

Sex differences in the predictors for hepatocellular carcinoma (HCC) development after direct-acting antiviral (DAA) therapy was investigated. DAA therapy was given to 1438 (663 male, 775 female) patients. Sex differences in the HCC development rate and the factors contributing to HCC development after DAA therapy were investigated. Male patients had a significantly higher cumulative HCC incidence (log-rank test, P = .007). On multivariate analysis, the fibrosis-4 index (HR = 1.11; 95%CI, 1.042-1.202, P = .002) and posttreatment α-fetoprotein (AFP) (HR = 1.11; 95%CI, 1.046-1.197, P = .001) were found to be independent factors that contributed to HCC development following DAA therapy in female patients, whereas only posttreatment AFP (HR = 1.090; 95%CI, 1.024-1.160, P = .007) was an independent factor in male patients. The optimal posttreatment AFP cut-off values were set based on receiver operating characteristic curve analyses. The optimal posttreatment AFP cut-off value was much higher in females (6.0 ng/mL) than in male (3.5 ng/mL) patients. In conclusion both in male and female patients, posttreatment AFP was an independent predictor of HCC development after DAA therapy. However, the cut-off values differed between the sexes. In male patients, HCC could be seen in patients with relatively low posttreatment AFP levels; more careful observation might be needed in such patients.

Role of severe thrombocytopenia in preventing platelet count recovery in thrombocytopenic patients with chronic liver disease.

BACKGROUND AND AIM: Certain thrombocytopenic patients with chronic liver disease have inadequate platelet count recovery after platelet transfusion or lusutrombopag administration. We aimed to identify the reasons for this phenomenon. METHODS: We investigated 58 and 86 thrombocytopenic patients with chronic liver disease who received lusutrombopag (3 mg orally for up to 7 days) or underwent blood transfusions, respectively. Thirty patients underwent simultaneous hepatic surgery and splenectomy. Factors preventing platelet count recovery above 50 × 103 /µL were identified. RESULTS: The median patient age was 64 years. Eleven, 78, and 55 patients had hepatitis B, hepatitis C, or another etiology, respectively; 59, 69, and 16 had Child-Pugh classes A, B, and C, respectively. The median spleen volume was 432 mL, and a median of 10 blood units were transfused per patient. The median platelet count rose significantly (from 41.5 × 103 /µL to 81.0 × 103 /µL) after lusutrombopag administration but not after blood transfusion before invasive procedures. However, maximum platelet counts in patients who underwent splenectomy before platelet transfusion were markedly improved over those who did not. Increasing platelet counts above 50 × 103 /µL required baseline platelets > 30 × 103 /µL and lusutrombopag administration for all patients. Platelet count recovery was dependent on a spleen volume of < 300 mL and baseline platelets of > 40 × 103 /µL in patients who underwent platelet transfusions, while a baseline platelet count of > 30 × 103 /µL was required for patients administered with lusutrombopag. CONCLUSION: Neither blood transfusion nor lusutrombopag improves thrombocytopenia in patients with severe conditions; however, the degree of platelet count elevation following lusutrombopag administration is higher than that following blood transfusion.

Applicability of the Øie-Tozer model to predict three types of distribution volume (Vd) in humans: Vd in central compartment, Vd at steady state, and Vd at beta phase.

This study aimed to investigate the applicability of the Øie-Tozer model to predict human distribution volume (Vd) in the central compartment (V1 ), Vd at steady state (Vdss ), and Vd at beta phase (Vdß ) based on animal Vd. Twenty compounds that have a human V1 /Vdss of 0.053-0.66 were selected from the literature. After intravenous administration of the compounds at 0.1 mg/kg to rats, dogs, and monkeys, plasma concentrations were determined, and pharmacokinetic parameters were obtained by one/two-compartmental analyses. The human V1 , Vdss , and Vdß were predicted from animal Vd using the Øie-Tozer model, and the predictability was compared with that using proportionality and simple allometry. The Øie-Tozer model was the most reliable method for the overall prediction of Vd and applicable for accurately predicting human V1 , Vdss , and Vdß (89%, 85%, and 68% of the compounds within a 3-fold error, respectively) when data of monkey for V1 and data of three animal species for Vdss and Vdß were used. Additionally, the predicted human Vd with the two-compartment model was applicable for predicting pharmacokinetic profiles/parameters in humans after intravenous administration of 18 compounds [except for valproic acid (monophasic elimination profile) and chlorpromazine (deviation: Vdss < V1 )]. The prediction was more accurate than that using the predicted Vdss with the one-compartment model (e.g., underestimation of maximum plasma concentrations: 2 vs 8 compounds within a 3-fold error, respectively). In summary, the Øie-Tozer model was applicable for predicting human V1 , Vdss , and Vdß , and their predicted Vd with the two-compartment model can lead to accurate pharmacokinetic prediction of compounds that show biphasic elimination.

Predictors of hepatocellular carcinoma occurrence after direct-acting antiviral therapy in patients with hepatitis C virus infection.

AIM: The predictors for the development of hepatocellular carcinoma (HCC) after direct-acting antiviral (DAA) treatment were investigated. METHODS: A total of 1174 patients with chronic hepatitis C virus infection were treated with DAA therapy (sofosbuvir and ledipasvir [n = 615], sofosbuvir and ribavirin [n = 380], and daclatasvir and asunaprevir [n = 179]) and achieved sustained virologic response (SVR). The HCC development rate and the factors that might contribute to the development of HCC after the end of DAA treatment were analyzed. RESULTS: During the median observation period of 537 days, HCC developed in 33 cases. The incidence of HCC was 1.9%, 3.2%, and 4.1% at 1, 1.5, and 2 years after the end of DAA therapy, respectively. Multivariate analysis with pre- and post-treatment factors identified the Fibrosis-4 (FIB-4) index (hazard ratio [HR] = 1.09; 95% confidence interval [CI], 1.021-1.178; P = 0.011) and post-treatment α-fetoprotein (AFP) (HR = 1.11; 95% CI, 1.054-1.172; P < 0.001) as independent factors that contributed to the development of HCC after DAA therapy. Using these identified parameters, a new scoring system (0 to 2 points) was established. Patients in the high-score group (2 points) could be identified as having a significantly higher risk of HCC development, and the respective 1- and 2-year cumulative incidence rates of HCC were 6.1% and 14.4%. CONCLUSIONS: A high FIB-4 index and a high post-treatment AFP at the end of DAA treatment were the independent predictors for developing HCC after DAA treatment. For patients with these risk factors, extra attention to the possibility of HCC development is needed.

Using ALBI score at the start of sorafenib treatment to predict regorafenib treatment candidates in patients with hepatocellular carcinoma.

BACKGROUND: Although sorafenib-regorafenib sequential therapy improves the prognosis of patients with hepatocellular carcinoma (HCC), many patients abandon sequential therapy due to worsening hepatic reserve function. Thus, it is important to clarify which patients can be treated using regorafenib. The albumin-bilirubin score is a good biomarker for hepatic reserve function. The aim of this study was to determine whether patient albumin-bilirubin scores at the start of sorafenib treatment could be used to identify candidates for subsequent regorafenib therapy. METHODS: This is a retrospective cohort study. From 2009 to 2017, 267 hepatocellular carcinoma patients treated with sorafenib were enrolled. After sorafenib therapy, 138 progressive disease patients were analyzed. The patients were divided in two groups: (i) regorafenib candidate group (Child-Pugh class A, Eastern Cooperative Oncology Group Performance Status ≤1, and maintained sorafenib tolerance); and (ii) regorafenib non-candidate group. The primary endpoint was the albumin-bilirubin score. We assessed retrospectively whether albumin-bilirubin scores were useful for predicting regorafenib treatment regimen candidacy. RESULTS: For the 138 analyzed patients, the median overall survival duration was 15.6 months in the regorafenib candidate group and 6.8 months in the regorafenib non-candidate group (P < 0.01). Using univariate analysis, etiology, aspartate aminotransferase ≥40 IU/L, prothrombin time ≥85% and albumin-bilirubin score <-2.53 at the start of sorafenib treatment were identified as predictors. Using multivariate analysis, albumin-bilirubin score <-2.53 was the only significant predictor. CONCLUSIONS: Based on the multivariate analysis results, albumin-bilirubin score at the start of sorafenib therapy is a useful marker for identifying candidate patients for starting regorafenib therapy.

Time-dependent inhibition (TDI) of CYP1A2 by a CYP3A4-mediated reactive metabolite: proposal for a novel mechanism of irreversible TDI by a non-suicide substrate.

1. The purpose of this study was to clarify the mechanism of DSP-1053 time-dependent inhibition (TDI) for CYP1A2. 2. DSP-1053 inhibited time- and concentration-dependently CYP1A2 activity in human liver microsomes even in a dilution assay. However, DSP-1053 was not metabolized by recombinant human CYP1A2. These findings indicate that the inhibitory effect of DSP-1053 on CYP1A2 does not follow a general mechanism-based inhibition (MBI) because it did not seem to be a suicide substrate. 3. In fact, CYP1A2 was not inhibited with DSP-1053 pre-incubation in recombinant human CYP1A2. On the other hand, CYP1A2 was potently inhibited after pre-incubation with DSP-1053 in a mixture of human recombinant CYP1A2 and CYP3A4. In addition, DSP-1053 TDI of CYP1A2 in human liver microsomes was drastically reduced not only by addition of a CYP3A4 inhibitor, but also by addition of potassium cyanide (KCN), which is a trapping agent for iminium ions. We also confirmed in this study that CYP1A2 suicide inhibition by DSP-1053 metabolites generated by CYP3A4 had only minimal role in DSP-1053 TDI of CYP1A2. 4. In conclusion, a possible mechanism for DSP-1053 TDI of CYP1A2 is that DSP-1053 iminium ion, which is generated by CYP3A4, departs from CYP3A4 without inhibiting it and covalently binds to CYP1A2.