Characterization of CYP2C Induction in Cryopreserved Human Hepatocytes and Its Application in the Prediction of the Clinical Consequences of the Induction

CYP2C enzymes play key roles in drug metabolism, and clinical drug-drug interactions caused by CYP2C induction have been reported. The aim of this study was to establish a method to predict the potency of CYP2C inductions considering the mechanism. We first investigated the relations of CYP2C induction with CYP3A4 or CYP2B6 induction in human hepatocytes after 48-h exposure with 19 inducers. The fold-induction values of CYP2C8 and CYP2C9 were well correlated with those of CYP3A4, whereas the inducers were separated into 2 groups showing different correlations with CYP2B6 induction for CYP2C8 and CYP2C9 induction. In the regression models established, the fold-induction values of CYP2C8 and CYP2C9 were well expressed as the functions of those of CYP3A4 and CYP2B6, while no such obvious correlation was observed for CYP2C19 induction. These results suggest that CYP2Cs are not simply coinduced with CYP3A4 and that CYP2C8 and CYP2C9 inductions are regulated by both pregnane X receptor and constitutive androstane receptor with different contributions. Finally, simple correlations were proposed using the experimental E_max values obtained and plasma concentrations of CYP2C9 substrates from the literature, and positive correlations were observed. These data provide methods to estimate the clinical impact of CYP2C9 induction from in vitro data.     

Surgical management of a primary external iliac venous aneurysm causing pulmonary thromboembolism: report of a case

Primary iliac venous aneurysm is an extremely rare clinical entity. We report a case of primary external iliac venous aneurysm containing an intraluminal thrombus that caused pulmonary thromboembolism in a 22-year-old woman. The aneurysm and pulmonary emboli were detected during examination for sudden onset of dyspnea. After receiving anticoagulation and thrombolytic therapy, the patient underwent aneurysm resection. We devised venoplasty using a dual-row saphenous vein patch to cover the large defect of the vessel wall. Primary iliac venous aneurysms associated with pulmonary thromboembolism are uncommon and surgical repair is made difficult by the fragility of the affected vessel. We reviewed the clinical features of this unusual entity.     

Uptake and intracellular activity of AM-1155 in phagocytic cells.

The uptake and intracellular activity of AM-1155 in murine J774.1 macrophages and human polymorphonuclear leukocytes were investigated. AM-1155 penetrated phagocytic cells rapidly and reversibly, although the penetration process was not affected by metabolic inhibitors such as sodium fluoride, cyanide m-chlorophenylhydrazone, or ouabain or by nucleoside transport system inhibitors such as adenosine. The intracellular concentration-to-extracellular concentration ratio of AM-1155 in both cell types of phagocytes ranged from 5 to 7. These ratios were almost equal to those for sparfloxacin. The intracellular activity of AM-1155 in J774.1 macrophages, examined with Staphylococcus aureus 209P as a test bacterium, was dependent on the extracellular concentration. AM-1155 at a concentration of 1 microgram/ml reduced the number of viable cells of S. aureus ingested by more than 90%. The intracellular activity of AM-1155 was more potent than those of sparfloxacin, ofloxacin, ciprofloxacin, flomoxef, and erythromycin. These results suggest that the potent intracellular activity of AM-1155 might mainly be due to the high intracellular concentration and its potent in vitro activity.     

Role of consultation–liaison psychiatry toward shortening of length of stay for medically ill patients with depression

Depression in physically ill patients is often encountered in consultation– liaison psychiatry. First, this investigation examined the relationship between length of stay (LOS) and depression comorbidity. Physically ill patients with depression stayed significantly longer than those without. Second, the change of LOS with and without antidepressant treatment for depression in medically ill patients has been investigated, which showed that LOS in physically ill patients with depression could be shortened by effective antidepressant treatment. This study also revealed that the early detection and antidepressant treatment are important for physically ill patients with depression that could lead to the shortening of LOS.     

Hydroxyapatite Affects the Physicochemical Properties of Contemporary One-Step Self-Etch Adhesives

The study aimed to evaluate the influence of the manipulation surfaces on the physical properties of one-step self-etch adhesives (1-SEAs). Scotchbond Universal (SBU), Clearfil Universal Bond Quick ER (UBQ), and an experimental adhesive (UBQ_exp) were manipulated on different surfaces: manufacturer’s Teflon-based dispensing dish (TD) or hydroxyapatite plate (HA). After manipulation of the adhesives, the pH of each 1-SEA was measured. Samples of each adhesive/manipulation surface were prepared and subjected to water sorption (WS)/solubility (SL) and flexural strength tests. The modulus of elasticity (E) was measured in dry and wet conditions before and after 24 h water storage, and the percentage of variation of E (ΔE) was calculated. Results were analyzed using the t-test with Bonferroni corrections (α = 0.05). When adhesives were manipulated on the HA plate, there was a significant increase in the adhesives’ pH. WS and SL of all 1-SEAs decreased when the HA was used. Only SBU showed higher flexural strength when manipulated on the HA compared to the manipulation on TD under dry and wet conditions. For each 1-SEA, the use of HA resulted in significantly higher E in dry and wet conditions. ΔE of all adhesives was smaller with the manipulation on HA than on TD. It was concluded that the manipulation of 1-SEA on a hydroxyapatite plate considerably affected the adhesives’ properties.     

Differences in cerebral metabolic impairment between early and late onset types of Alzheimer's disease

Hypercortisolemia is thought to be a marker of the stress response following stroke. The aim of this study was to investigate the prevalence and prognostic significance of hypercortisolemia. The circadian variation of cortisol level and the relationship between serum cortisol levels and other stress, inflammatory, and haemostatic markers were also investigated. Seventy consecutive patients with their first ischemic stroke and 24 age- and sex-matched controls were included in the study. Serum cortisol levels (at 6:00 AM, 10:00 AM, 6:00 PM, and 10:00 PM), 24-h urine catecholamine excretion, beta-thromboglobulin levels, and other standard biochemical and haematological parameters were measured on the first day of hospitalisation and in control subjects. Outcome measures used the Barthel Index at Day 30, as well as 30- and 90-day mortality rates. Hypercortisolemia, defined as at least two of the four measurements above the normal range of serum cortisol levels (i.e. >618 nmol/l from the morning samples and >460 nmol/l from the evening samples) was found in 25 (35.7%) of the acute stroke patients and in 3 (12.5%) of the controls (p<0.05). Hypercortisolemia was associated with older age, greater severity of neurological deficit, larger ischemic lesions on CT, and worse prognoses (p<0.05). The study did not find a correlation between serum cortisol levels and other markers of the stress response such as catecholamines excretion and glucose levels. A significant correlation between serum cortisol levels and some markers of the inflammatory response, such as fever, fibrinogen level, white blood cell (WBC) count, and beta-thromboglobulin level, was established in stroke patients. Prognostic significance of hypercortisolemia in acute stroke patients seems to be related to the inflammatory response rather than to the stress response.     

Dissociation of Sleep Stages Between the Two Hemispheres in a Case With Unilateral

A case with an astrocytoma in the right basal ganglia, suspected of having originated from the posterior ventro-lateral part of the thalamus, without any clinical findings indicating severe internal hydrocephalus and cortical damage, showed dissociation of sleep stages between the two hemispheres, i.e., the affected side always fell earlier into deeper stages of sleep and was more difficult to arouse by sonic stimulations than the other side. It is assumed that this bilateral dissociation with ipsilateral deactivation is due to the severe unilateral reduction of EEG activating influences from the brain stem and a possible functional damage to the interthalamic commissures. This finding can be explained sufficiently by recent theories based on experimental results in animals. The clinical value of this finding is also discussed in this paper.     

Phase IIb study of pembrolizumab combined with S‐1 + oxaliplatin or S‐1 + cisplatin as first‐line chemotherapy for gastric cancer

The KEYNOTE‐659 study evaluated the efficacy and safety of first‐line pembrolizumab plus S‐1 and oxaliplatin (SOX) (cohort 1) or S‐1 and cisplatin (SP) (cohort 2) for advanced gastric/gastroesophageal junction (G/GEJ) cancer in Japan. Herein, we update the results of cohort 1 and describe the results of cohort 2. This open‐label phase IIb study enrolled patients with advanced programmed death‐ligand 1 (PD‐L1)‐positive (combined positive score ≥ 1) human epidermal growth factor receptor 2 (HER2)‐negative G/GEJ adenocarcinoma. The primary end‐point was the objective response rate (ORR). Other end‐points were duration of response (DOR), disease control rate (DCR), progression‐free survival (PFS), overall survival (OS), and safety. One hundred patients were enrolled. In cohorts 1 and 2, median follow‐up time was 16.9 and 17.1 months; ORR (central review), 72.2% and 80.4%; DOR, 10.6 and 9.5 months; DCR (central review), 96.3% and 97.8%; median PFS (central review), 9.4 and 8.3 months; and median OS, 16.9 and 17.1 months, respectively. Treatment‐related adverse events (TRAEs) occurred in all patients, including peripheral sensory neuropathy (94.4%, cohort 1), decreased neutrophil count (82.6%, cohort 2), nausea (59.3% and 60.9% in cohorts 1 and 2), and decreased appetite (61.1% and 60.9% in cohorts 1 and 2). Grade 3 or higher TRAEs were reported by 59.3% (cohort 1) and 78.3% (cohort 2), including decreased platelet count (14.8%, cohort 1) and decreased neutrophil count (52.2%, cohort 2). Pembrolizumab in combination with SOX or SP showed favorable efficacy and safety in patients with PD‐L1‐positive, HER2‐negative G/GEJ adenocarcinoma.