Search

Lenvatinib (LEN), a multitarget tyrosine kinase inhibitor used in various cancer treatments, is mainly metabolized by cytochrome P450 3A (CYP3A) enzymes. The importance of therapeutic drug monitoring (TDM) in patients administered LEN has been proposed. Although some biomarkers of endogenous CYP3A activity have been reported, their utility in dosage adjustments has not been well evaluated. This study investigated the correlation between plasma LEN concentrations and endogenous urinary CYP3A biomarkers in clinical practice. Concentrations of plasma LEN (N = 225) and CYP3A biomarkers (cortisol, 6β‐hydroxycortisol, deoxycholic acid, and 1β‐hydroxydeoxycholic acid) in urine (N = 214) from 20 patients (hepatocellular carcinoma, N = 6; thyroid cancer, N = 3; endometrial cancer, N = 8; and renal cell carcinoma, N = 3) collected for consultation for up to 1 year were evaluated using liquid chromatography–tandem mass spectrometry. Moreover, plasma trough LEN concentrations were predicted using a three‐compartment model with linear elimination for outpatients administered LEN before sample collection. Moderate correlations were observed between the quantified actual concentrations and the predicted trough concentrations of LEN, whereas there was no correlation with endogenous urinary CYP3A biomarkers. The utility of endogenous urinary CYP3A biomarkers could not be determined. However, TDM for outpatients administered orally available medicines may be predicted using a nonlinear mixed effect model (NONMEM). This study investigated the utility of endogenous urinary CYP3A biomarkers for personalized medicine and NONMEM for predicting plasma trough drug concentrations. These findings will provide important information for further clinical investigation and detailed TDM. [ABSTRACT FROM AUTHOR]

Aim: Nucleos(t)ide analogs do not completely prevent hepatocellular carcinoma (HCC) in chronic hepatitis B virus infection. This study aimed to evaluate the dynamics of a non‐invasive liver fibrosis marker, the Fibrosis‐4 (FIB‐4) index, for predicting HCC development. Methods: Among a total of 882 chronically hepatitis B virus infection‐infected patients who were treated with nucleos(t)ide analogs, 472 patients without HCC history whose FIB‐4 at baseline and 1 year of treatment was obtained were evaluated for the incidence of HCC. Results: The median FIB‐4 was 2.00 at baseline and was significantly reduced to 1.58 at 1 year (P < 0.001), but the reduction was small at 2 years or later. When a receiver operating characteristic analysis of FIB‐4 was performed to predict HCC within 5 years, the area under the curve of FIB‐4 at 1 year was higher than that at baseline (0.676 vs. 0.599). The HCC incidence was significantly higher in patients with FIB‐4 ≥1.58 than in those with FIB‐4 <1.58 (14.8% vs. 3.6% at 10 years, P < 0.001). Additionally, an abnormal alanine aminotransferase (≥31 U/L) at 1 year was an independent risk for HCC. When a fibrosis and alanine aminotransferase‐1 (FAL‐1) score was evaluated as an applicable number of FIB‐4 ≥1.58, and alanine aminotransferase ≥31 as 0, 1, and 2, the HCC risk in patients with score 2 was significantly higher than in those with score 1 or score 0 (24.1% vs. 9.8% vs. 0.7% at 10 years, P < 0.001). Conclusions: FIB‐4 ≥1.58 and alanine aminotransferase ≥31 at 1 year of nucleos(t)ide analog was an independent risk factor for HCC development, and a score using these factors stratified the risk of HCC. [ABSTRACT FROM AUTHOR]

Background and Aim: Stimulant laxatives may cause electrolyte abnormalities, dehydration, and abdominal pain; their long‐term use can lead to tolerance and subsequent refractory constipation. We investigated the effectiveness, safety, and quality of life after switching from stimulant laxatives to lubiprostone in elderly patients with chronic constipation (CC). Methods: This multicenter, interventional, open‐label, single‐arm, before‐and‐after comparison study enrolled 99 Japanese patients aged 65–90 years with CC who took stimulant laxatives for ≥2 weeks prior to switching to lubiprostone monotherapy. Results: The mean ± SD spontaneous defecations at Week 1 of 7.8 ± 6.2 times/week was not significantly different from that at baseline (8.3 ± 4.7). Spontaneous defecations were significantly reduced at Weeks 2 (−1.5 ± 4.0, P < 0.001) and 4 (−1.5 ± 3.7, P < 0.001). The Bristol Stool Form Scale score did not change from baseline (4.7 ± 0.9) at Weeks 1 (4.5 ± 1.3) or 4 (4.3 ± 1.3), but it did at Week 2 (4.3 ± 1.5, P < 0.05). The Patient Assessment of Constipation Quality of Life questionnaire score increased (0.36 ± 0.07, P < 0.001) after 28 days. Nausea was the only symptom that worsened from baseline and was the most frequently reported adverse drug reaction (15.2%). Conclusion: Switching to lubiprostone monotherapy for CC was not associated with significant concerns in short‐term spontaneous defecation frequency and safety, but it might affect the efficacy and patient quality of life over 2 weeks. Careful treatment strategies facilitating gradual switching to lubiprostone monotherapy may be needed in patients using stimulant laxatives. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Whether basal β‐cell proliferation during adulthood is involved in maintaining sufficient β‐cell mass, and if so, the molecular mechanism(s) underlying basal β‐cell proliferation remain unclear. FoxM1 is a critical transcription factor which is known to play roles in 'adaptive' β‐cell proliferation, which facilitates rapid increases in β‐cell mass in response to increased insulin demands. Therefore, herein we focused on the roles of β‐cell FoxM1 in 'basal' β‐cell proliferation under normal conditions and in the maintenance of sufficient β‐cell mass as well as glucose homeostasis during adulthood. Materials and Methods: FoxM1 deficiency was induced specifically in β‐cells of 8‐week‐old mice, followed by analyzing its short‐ (2 weeks) and long‐ (10 months) term effects on β‐cell proliferation, β‐cell mass, and glucose tolerance. Results: FoxM1 deficiency suppressed β‐cell proliferation at both ages, indicating critical roles of FoxM1 in basal β‐cell proliferation throughout adulthood. While short‐term FoxM1 deficiency affected neither β‐cell mass nor glucose tolerance, long‐term FoxM1 deficiency suppressed β‐cell mass increases with impaired insulin secretion, thereby worsening glucose tolerance. In contrast, the insulin secretory function was not impaired in islets isolated from mice subjected to long‐term β‐cell FoxM1 deficiency. Therefore, β‐cell mass reduction is the primary cause of impaired insulin secretion and deterioration of glucose tolerance due to long‐term β‐cell FoxM1 deficiency. Conclusions: Basal low‐level proliferation of β‐cells during adulthood is important for maintaining sufficient β‐cell mass and good glucose tolerance and β‐cell FoxM1 underlies this mechanism. Preserving β‐cell FoxM1 activity may prevent the impairment of glucose tolerance with advancing age. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Many East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in 'super‐aged' populations, such as Japan. This post‐hoc analysis assessed once‐weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups. Materials and Methods: Data were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once‐weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m2). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed. Results: In this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8–73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20–168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups. Reductions from baseline in glycosylated hemoglobin ranged from –1.7 to –2.1 with semaglutide 0.5 mg, –1.8 to –2.4 with semaglutide 1.0 mg and –0.6 to –1.0 with comparators. Corresponding ranges for bodyweight (kg) were –1.0 to –2.5, –2.4 to –4.3 and 1.0 to –1.0 kg, respectively. The safety profile of semaglutide was broadly similar across BMI and age subgroups. Conclusions: In this post‐hoc analysis with modest subgroup numbers, once‐weekly semaglutide appeared consistently more efficacious versus comparators across age and BMI subgroups in Japanese patients, with a similar safety profile. [ABSTRACT FROM AUTHOR]

Recent studies have shown that therapeutic drug monitoring of tyrosine kinase inhibitors (TKIs) could improve treatment efficacy and safety. A simple analytical method using high‐performance LC/electrospray ionization–tandem mass spectrometry has been developed and validated for simultaneous quantification of BCR‐ABL and Bruton's TKIs used for chronic leukemia (imatinib, dasatinib, bosutinib, nilotinib, and ibrutinib) in human plasma. Although these structures and physical properties are similar, owing to their different linear ranges, simultaneously determining the plasma levels of these five TKIs by applying optimal MS parameters remains difficult. A quantitative range exceeding 60,000‐fold was required, and the linear dynamic ranges of imatinib, bosutinib, and nilotinib were limited because of the presence of a saturated detection signal. In this study, we applied the in‐source collision‐induced dissociation technique to control the ion amounts in mass spectrometry. This new method allowed rapid determination within 5 min with simple pretreatment. The method was validated according to the US Food and Drug Administration guidelines. Moreover, all samples of patients with chronic leukemia were successfully measured and their values were within the linear range of measurement. Therefore, our high‐throughput analytical system is useful to measure the plasma concentrations of imatinib, dasatinib, bosutinib, nilotinib, and ibrutinib in clinical practice. [ABSTRACT FROM AUTHOR]

Clozapine (CLZ) is a key drug in treatment‐resistant schizophrenia. Therapeutic drug monitoring (TDM) of CLZ and its metabolites, N‐desmethylclozapine and clozapine N‐oxide, is required to monitor and manage the risks of side effects. Although quantification methods for TDM have been developed for CLZ and its metabolites, they were not sufficiently accurate for the quantification of CLZ owing to the upper limits of the calibration curves. An analytical method using high‐performance liquid chromatography/electrospray ionization tandem mass spectrometry was developed and validated for the simultaneous measurement of CLZ and its metabolites in human plasma. To expand the concentration range of the calibration curves, we used a linear range shift technique using in‐source collision‐induced dissociation (CID). Using our approach, the linearity and quantitative range were improved compared to those reported by previous studies, and were sufficient for TDM in clinical practice. The intra‐ and inter‐assay accuracy was 84.6%–114.8%, and the intra‐ and inter‐assay precisions were ≤9.1% and ≤9.9%, respectively. Moreover, all samples from patients with treatment‐resistant schizophrenia were successfully quantified. Therefore, our novel analytical method using in‐source CID had the appropriate performance to measure the plasma concentrations of CLZ and its metabolites for TDM in clinical practice. [ABSTRACT FROM AUTHOR]

We report a case of a 64‐year‐old woman with a past medical history (PMH) of prosthetic valve replacement 7 months prior to admission, who presented with only right back pain. Physical examination revealed one conjunctival spot hemorrhage and a mild systolic murmur. Blood cultures were positive for methicillin‐resistant Staphylococcus epidermidis. Trans‐esophageal echocardiography revealed aortic valve vegetations; hence, a diagnosis of prosthetic valve endocarditis (PVE) was made. Clinical presentation of infective endocarditis varies and sometimes mimics that of polymyalgia rheumatica. The patient was diagnosed as PVE considering the whole clinical picture including the patient's PMH, physical examination, and blood cultures. [ABSTRACT FROM AUTHOR]

Aim: Hepatitis B virus genotype B (HBV/B) has been reported to have less risk of liver cirrhosis and hepatocellular carcinoma (HCC), but long‐term observation has rarely been reported. We aimed to clarify the characteristics of HBV/B in nucleos(t)ide analog‐treated patients in an area where HBV/B is more prevalent than in other areas of Japan. Methods: A total of 498 chronically HBV‐infected patients treated with nucleos(t)ide analog (lamivudine, entecavir, tenofovir disoproxil fumarate, or tenofovir alafenamide fumarate) for >6 months (mean 70.6 months) were included from nine hospitals in northeast Japan. The frequencies of hepatitis B surface antigen loss and HCC occurrence were analyzed. Results: Among 427 patients whose genotype could be determined, 34.0% and 64.4% were infected with HBV/B and genotype C (HBV/C), respectively. The age of patients with HBV/B was significantly older than those with HBV/C (57.7 vs. 48.1). The cumulative rate of hepatitis B surface antigen loss was significantly higher in HBV/B than in HBV/C (3.6% vs. 0.7% at 10 years). Among 480 patients without HCC history, HCC occurrence was found in 40 patients (13.4% at 10 years). There was no cumulative rate difference of HCC occurrence among the genotypes, but after propensity score matching for age/sex, it was significantly lower in HBV/B than in HBV/C (5.3% vs. 18.5% at 10 years). Conclusions: Although a lower rate of HCC occurrence in HBV/B was shown by an age/sex‐matched analysis than that in HBV/C, patients with HBV/B were significantly older and had a comparative risk of HCC occurrence in nucleos(t)ide analog‐treated patients. [ABSTRACT FROM AUTHOR]

Psoriatic arthritis (PsA) is an inflammatory arthritis with as yet unclear pathophysiology. This retrospective, multicenter, cross‐sectional study was conducted in 19 facilities in western Japan and aimed to identify patients' characteristics and factors that affect the results of treatment with biologic agents. Of 2116 patients with psoriasis, 285 (13.5%) had PsA. Skin manifestations preceded joint manifestations in 69.8%, the onset was simultaneous in 17.2%, whereas PsA preceded skin manifestations in 2.5%. Peripheral arthritis was most common, occurring in 73.7%, compared with axial disease in 21.8%, enthesitis in 23.5% and dactylitis in 35.4%. Patients with severe skin manifestations were significantly younger at onset (P = 0.02) and more frequently had axial disease (P < 0.01). Biologic agents were used in 206 patients (72.3%), anti‐tumor necrosis factor (TNF)‐α antibodies being prescribed first to 157 of them. Anti‐TNF‐α antibodies were continued by 105 participants and discontinued by 47, the remaining five patients being lost to follow up. Patients who discontinued anti‐TNF‐α antibodies were significantly older than those who continued (55 vs 51 years, P = 0.04) and significantly older at onset of joint manifestations (50 vs 44 years, P = 0.01). Multivariate analysis revealed that patients over 50 years significantly more frequently terminated anti‐TNF‐α antibodies (P < 0.01). In conclusion, patients with PsA and severe skin manifestations have earlier onset and axial disease, which seriously impacts on quality of life. Anti‐TNF‐α antibodies were generally effective enough to continue but less so in patients aged over 50 years. Further detailed research is needed. [ABSTRACT FROM AUTHOR]

Many clinically approved protein kinase inhibitors stabilize an inactive conformation of their kinase target. Such inhibitors are generally highly selective compared to active conformation inhibitors, and consequently, general methods to identify inhibitors that stabilize an inactive conformation are much sought after. Here, we have applied a high‐throughput, second‐harmonic generation (SHG)‐based conformational approach to identify small molecule stabilizers of the inactive conformation of interleukin‐2‐inducible T‐cell kinase (ITK). A single‐site cysteine mutant of the ITK kinase domain was created, labeled with an SHG‐active dye, and tethered to a supported lipid bilayer membrane. Fourteen tool compounds, including stabilizers of the inactive and active conformations as well as nonbinders, were first examined for their effect on the conformation of the labeled ITK protein in the SHG assay. As a result, inactive conformation inhibitors were clearly distinguished from active conformation inhibitors by the intensity of SHG signal. Utilizing the SHG assay developed with the tool compounds described above, we identified the mechanism of action of 22 highly selective, inactive conformation inhibitors within a group of 105 small molecule inhibitors previously identified in a high‐throughput biochemical screen. We describe here the first use of SHG for identifying and classifying inhibitors that stabilize an inactive vs. an active conformation of a protein kinase, without the need to determine costructures by X‐ray crystallography. Our results suggest broad applicability to other proteins, particularly with single‐site labels reporting on specific protein movements associated with selectivity. [ABSTRACT FROM AUTHOR]

Background and Aim: Leptin, the product of the obese ( ob) gene, is a circulating peptide mainly synthesized by adipocytes. Leptin inhibits food intake and decreases body weight. A recent report has suggested that the gastric mucosa is also the source of leptin, and that the stomach leptin also contributes to the regulation of the serum leptin level. The aim of the present study was to investigate the effect of water-immersion stress on serum, stomach and adipose tissue leptin levels to understand the relationship between stress and eating behavior. Methods: Male Sprague–Dawley rats were used in this experiment. The leptin level in the serum, gastric mucosa and adipose tissue was measured using ELISA system before and after the initiation of water-immersion stress. Results: The serum leptin level was significantly increased by water-immersion stress. The peak was observed 9 h after the initiation of the stress ( P < 0.01). However, the gastric leptin level significantly decreased 6 and 9 h after the stress. The adipose tissue leptin level significantly increased 3 h after the stress. Conclusions: The results suggest that changes in serum leptin levels could be associated with stimulation of leptin secretion from the gastric mucosa and leptin production in the adipose tissue by systemic stress and that leptin might be regulated by stress-related events. [ABSTRACT FROM AUTHOR]

Rolipram is a specific type IV phosphodiesterase inhibitor that suppresses the activity of immune cells and the production of pro-inflammatory cytokines. In this study, we assessed the effect of rolipram on acute liver injury using thioacetamide (TAA)-induced liver injury in rats as a model.Rats were treated with rolipram (0.5–5 mg/kg, intraperitoneally) or vehicle and injected 30 min later with TAA (100 mg/kg, subcutaneously). Serum transaminase concentrations and tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β) and growth related oncogene/cytokine-induced neutrophil chemoattractant-1 (GRO/CINC-1) levels were measured and livers were examined for microscopic changes. Dose-dependent protection against TAA liver injury was based on transaminase levels and inflammatory cytokine production, and was measured 9 h after TAA when the peak release of cytokines occurred.Rolipram suppressed liver injury based on serum aspartate transaminase (AST), alanine transaminase (ALT) and histology and reduced TNF-α, IL-1β and GRO/CINC-1 levels. Rolipram, at doses of 0.5–5 mg/kg, suppressed serum transaminase and TNF-α production in a dose-dependent manner, and these effects were significant at doses of 2.5 and 5 mg/kg.In our rodent model of acute liver injury, rolipram clearly reduced liver damage and inhibited pro-inflammatory cytokine production. These results suggest that specific type IV phosphodiesterase inhibitors, such as rolipram, have potent hepatoprotective effects that are associated with suppressing inflammatory cytokine production. [ABSTRACT FROM AUTHOR]

Despite the many devices and care, decubitus ulcer is not well managed in elderly nursing home patients. Decubitus ulcers are often infected with methicillin-resistant Staphylococcus aureus (MRSA). Green tea includes catechins, a type of polyphenol, and its antimicrobial and anti-oxidant properties have been documented. Green tea might be effective for decubitus ulcer infected with MRSA. Decubitus ulcer was treated using green tea in the elderly in a nursing home and its effectiveness was compared with conventional debridement with saline. Decubitus ulcer treated with green tea subsided significantly compared with decubitus ulcer treated with conventional saline. The MRSA disappeared in half of the patients in the treated group but did not change in the control group. Green tea should be used for care of decubitus ulcer. [ABSTRACT FROM AUTHOR]

AbstractBackground: Interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) are believed to play a significant role in the pathogenesis of inflammatory bowel disease (IBD). Interleukin-1 and TNF-α possess overlapping and synergetic activities inducing the production in cascade of other cytokines, adhesion molecules, arachidonic acid metabolites, as well as activating immune and non-immune cells. FR167653 (C24H18FN5O2.H2SO4.H2O) is a newly synthesized organic compound with a potent inhibitory effect on IL-1β and TNF-α production. We hypothesized that the suppression of IL-1 and TNF-α induced by FR167653 could effectively attenuate experimentally induced colonic damage. Methods: Colonic lesions were induced in male Sprague–Dawley rats (250–300 g) by intrarectal instillation of 4% acetic acid. The effect of FR167653 administration at 1.0, 1.5, 2.5 mg/kg per 6 h subcutaneously on acetic acid-induced colonic damage was assessed. The lesion area, microscopic findings, colonic and serum levels of TNF-α and IL-1β were also evaluated. Results: Treatment with FR167653 at 1.5 and 2.5 mg/kg per 6 h was able to ameliorate the gross macroscopic appearance of colonic lesions significantly, as well as ameliorate the lesion area induced by acetic acid. Colonic mucosal TNF-α and IL-1β levels of rats treated with FR167653 showed significant decrease in a dose-dependent fashion compared with the control group. In the same manner, serum TNF-α of rats treated with FR167653 was significantly lower than that of respective controls. Conclusions: Subcutaneous administration of FR167653 was able to ameliorate the acute changes induced by acetic acid instillation in a dose-dependent manner. This is the first report to evaluate the dual inhibition of the production of IL-1 and TNF-α, offered by FR167653, in acute experimental colitis.... [ABSTRACT FROM AUTHOR]

A severe case of placental mesenchymal dysplasia occurred in association with intrauterine fetal death (IUFD). The gravida-1, para-1 mother was a 26-year-old Japanese. The first pregnancy was unremarkable and a healthy female infant was delivered. The present pregnancy had been uneventful until 34 weeks of gestation when IUFD was detected. The 1516-g (mean ± SD, 2050 ± 387 g) stillborn infant had no external abnormalities and the karyotype was 46,XX. The placenta was markedly enlarged (1050 g; mean ± SD, 452 ± 202 g), and approximately 80% was occupied by extraordinary enlarged villous structures with a myxoid appearance. Histologically, the dysplastic villi had myxoid stroma and a decreased number of, occasionally obliterated, fetal vessels. There was no abnormal trophoblastic proliferation. Large-sized fetal vessels in the chorionic plate frequently contained organized thrombi. This is the first case of placental mesenchymal dysplasia, which possibly lead to the IUFD. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor on the use of green tea for tinea manuum in bedridden patients.

Presents a letter to the editor on the treatment of epidermal necrolysis with calcium sodium alginate fiber.

AbstractBackground: Interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) are believed to play a significant role in the pathogenesis of inflammatory bowel disease (IBD). Interleukin-1 and TNF-α possess overlapping and synergetic activities inducing the production in cascade of other cytokines, adhesion molecules, arachidonic acid metabolites, as well as activating immune and non-immune cells. FR167653 (C24H18FN5O2.H2SO4.H2O) is a newly synthesized organic compound with a potent inhibitory effect on IL-1β and TNF-α production. We hypothesized that the suppression of IL-1 and TNF-α induced by FR167653 could effectively attenuate experimentally induced colonic damage. Methods: Colonic lesions were induced in male Sprague–Dawley rats (250–300 g) by intrarectal instillation of 4% acetic acid. The effect of FR167653 administration at 1.0, 1.5, 2.5 mg/kg per 6 h subcutaneously on acetic acid-induced colonic damage was assessed. The lesion area, microscopic findings, colonic and serum levels of TNF-α and IL-1β were also evaluated. Results: Treatment with FR167653 at 1.5 and 2.5 mg/kg per 6 h was able to ameliorate the gross macroscopic appearance of colonic lesions significantly, as well as ameliorate the lesion area induced by acetic acid. Colonic mucosal TNF-α and IL-1β levels of rats treated with FR167653 showed significant decrease in a dose-dependent fashion compared with the control group. In the same manner, serum TNF-α of rats treated with FR167653 was significantly lower than that of respective controls. Conclusions: Subcutaneous administration of FR167653 was able to ameliorate the acute changes induced by acetic acid instillation in a dose-dependent manner. This is the first report to evaluate the dual inhibition of the production of IL-1 and TNF-α, offered by FR167653, in acute experimental colitis.... [ABSTRACT FROM AUTHOR]