Safety and effectiveness of denosumab in Japanese patients with rheumatoid arthritis: a 2-year post-marketing surveillance study.

OBJECTIVES: To investigate the 2-year safety and effectiveness of denosumab 60 mg in patients with rheumatoid arthritis (RA) in clinical practice in Japan. METHODS: This 2-year, prospective, observational cohort study included patients who initiated treatment with denosumab 60 mg for the progression of bone erosion associated with RA. Key endpoints were adverse drug reactions (ADRs), progression of bone erosion, and 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP) or erythrocyte sedimentation rate (DAS28-ESR). Univariate and multivariate analyses were conducted to determine the risk factors for ADRs and the progression of bone erosion. RESULTS: In the safety analysis set (N=1,239), the incidence of ADRs was 3.0%; the most common ADRs were hypocalcaemia (1.2%) and osteonecrosis of jaw-related events (0.6%). A history of any drug allergy was a statistically significant risk factor associated with the occurrence of ADRs. In the effectiveness analysis set (N=815), the incidence of progression of bone erosion was 8.7%. Steinbrocker stage and initial steroid dose were statistically significant risk factors associated with the progression of bone erosion. CONCLUSION: Denosumab demonstrated safety and effectiveness over a 2-year period in RA patients without any new safety concerns.

Structural Characterization of Zinc(II)/Cobalt(II) Complexes of Chiral N-(Anthracen-9-yl)methyl-N,N-bis(2-picolyl)amine and Evaluation of DNA Photocleavage Activity.

We designed and synthesized a chiral ligand N-(anthracen-9-ylmethyl)-1-(pyridin-2-yl)-N-(pyridin-2-ylmethyl)ethanamine (APPE) DNA photocleavage agent to investigate the effects of chirality of bis(2-picolyl)amine on the DNA photocleavage activity of metal complexes. The structures of ZnII and CoII complexes in APPE were analyzed via X-ray crystallography and fluorometric titration. APPE formed metal complexes with a 1 : 1 stoichiometry in both the crystalline and solution states. Fluorometric titration was used to show that the ZnII and CoII association constants of these complexes (log Kas) were 4.95 and 5.39, respectively. The synthesized complexes were found to cleave pUC19 plasmid DNA when irradiated at 370 nm. The DNA photocleavage activity of the ZnII complex was higher than that of the CoII complex. The absolute configuration of the methyl-attached carbon did not affect DNA cleavage activity and, unfortunately, an achiral APPE derivative without the methyl group (ABPM) was found to perform DNA photocleavage more effectively than APPE. One reason for this may be that the methyl group suppressed the structural flexibility of the photosensitizer. These results will be useful for the design of new photoreactive reagents.

Docosahexaenoic acid contributes to increased CaMKII protein expression and a tendency to increase nNOS protein expression in differentiated NG108-15 cells.

Docosahexaenoic acid (DHA; 22:6n-3), an n-3 polyunsaturated fatty acid, has various important roles in brain functions. Nitric oxide (NO) produced by neuronal NO synthase (nNOS) and Ca2+/calmodulindependent protein kinase II (CaMKII) is also involved in brain functions. We investigated the influence of DHA on nNOS and CaMKII protein expression in differentiated NG108-15 cells. NG108-15 cells were seeded in 12-well plates, and after 24 h, the medium was replaced with Dulbecco's modified Eagle's medium containing 1% fetal bovine serum, 0.2 mM dibutyryl cyclic adenosine monophosphate and 100 nM dexamethasone as differentiation-inducing medium. When cells were cultured in differentiation-inducing medium, neurite-like outgrowths were observed on days 5 and 6. However, no significant difference in morphology was observed in cells with or without DHA treatment. With or without DHA addition, nNOS protein expression was increased on days 5 and 6 compared with day 0. This increase tended to be enhanced by DHA. CaMKII protein expression did not change after differentiation without DHA, but was significantly increased on day 6 compared with day 0 with DHA addition. These data indicate that DHA is involved in brain functions by regulating CaMKII and nNOS protein expression.

Docosahexaenoic Acid Increases Vesicular Glutamate Transporter 2 Protein Levels in Differentiated NG108-15 Cells.

Docosahexaenoic acid (DHA; 22:6n-3), which is enriched in the neuronal membrane, plays a variety of roles in the brain. Vesicular glutamate transporters (VGLUTs) are responsible for incorporating glutamine into synaptic vesicles. We investigated the influence of DHA on the fatty acid profile and the levels of VGLUT1 and VGLUT2 proteins in differentiated NG108-15 cells, a neuroblastoma-glioma hybrid cell line. NG108-15 cells were plated and 24 h later the medium was replaced with Dulbecco's modified Eagle's medium supplemented with 1% fetal bovine serum, 0.2 mM dibutyryl cAMP, and 100 nM dexamethasone, which was added to induce differentiation. After 6 d, the amount of DHA in the cells was increased by addition of DHA to the medium. VGLUT2 levels were increased by the addition of DHA. These data indicate that DHA affected the levels of VGLUT2 in NG108-15 cells under differentiation-promoting conditions, suggesting that DHA affects brain functions involving VGLUT2.

Long-term safety and effectiveness of denosumab in Japanese patients with osteoporosis: 3-year post-marketing surveillance study.

INTRODUCTION: Denosumab is a humanized IgG2 monoclonal antibody that was approved for the treatment of osteoporosis in Japan in 2013. This study aimed to investigate the long-term safety and effectiveness of denosumab in Japanese patients with osteoporosis in daily clinical practice. MATERIALS AND METHODS: This 3-year, prospective, observational, post-marketing study included patients who initiated treatment with denosumab (60 mg/6 months) for osteoporosis. Data were assessed at baseline, 3, 6, 12, 24 and 36 months. Key endpoints were adverse events (AEs), adverse drug reactions (ADRs), occurrence of osteoporotic fractures, bone mineral density (BMD), and bone turnover markers. Multivariate analyses were conducted to identify predictors of hypocalcaemia and percent change in BMD. RESULTS: Overall, 3534 patients were assessed (mean 75.7 years; 89.8% women). In total, 298 patients (8.4%) developed ADRs; the most common was hypocalcaemia (3.9%). Hypocalcaemia risk was significantly increased in patients with creatinine clearance < 30 mL/min, no prior use of bisphosphonates, prior use of calcium and vitamin D preparations, baseline serum calcium < 8.5 mg/dL, and no concomitant use of calcium or vitamin D preparations. Six patients had adjudicated osteonecrosis of the jaw. Lumbar spine BMD increased significantly from baseline (mean percent change: 11.4% at 36 months). All bone turnover markers decreased significantly from baseline. Over 3 years, 3.3% of patients developed a new osteoporotic fracture. CONCLUSIONS: This study confirmed the long-term safety and effectiveness of denosumab in Japanese patients with osteoporosis in daily clinical practice. No new safety signals were identified.

Idarubicin, an Anthracycline, Induces Oxidative DNA Damage in the Presence of Copper (II).

BACKGROUND/AIM: The aim of the present study was to investigate whether idarubicin (IDR) induces oxidative DNA damage in the presence of copper (II). MATERIALS AND METHODS: DNA damage was evaluated by pBR322 plasmid DNA cleavage. The formation of oxidative stress markers [O2 •- and 8-hydroxy-2'-deoxyguanosine (8-OHdG)] was analysed. RESULTS: IDR induced DNA damage and O2 •- and 8-OHdG generation in the presence of copper (II). CONCLUSION: IDR induced oxidative DNA damage in the presence of copper (II). Since it has been reported that the concentration of copper in the serum of cancer patients is higher than that in healthy groups, IDR-induced oxidative DNA damage in the presence of copper (II) may play an important role in anticancer therapeutic strategies.

Oxidative DNA Damage and Apoptosis Induced by Aclarubicin, an Anthracycline: Role of Hydrogen Peroxide and Copper.

BACKGROUND/AIM: This study aimed to investigate aclarubicin (ACR)-induced oxidative DNA damage and apoptosis. MATERIALS AND METHODS: ACR-induced apoptosis was analyzed using HL-60 leukemia cells and HP100 cells, hydrogen peroxide (H2O2)-resistant cells derived from HL-60 cells. ACR-induced DNA damage was analyzed using plasmid DNA. RESULTS: HL-60 cells were more sensitive to ACR than HP100 cells. In HP100 cells, DNA ladder formation and caspase-3/7 activity induced by ACR were suppressed or delayed in comparison to those in HL-60 cells. ACR-induced DNA damage occurred in the presence of Cu(II), and scavenger experiments showed that the reactive species causing DNA damage appeared to be generated from H2O2 and Cu(I). Moreover, we detected intracellular Cu(I) induced by ACR in HL-60 cells, using CopperGREEN™, a fluorescent probe for detection of Cu(I) ion specifically. CONCLUSION: ACR-induced DNA damage and apoptosis can be accounted for by the involvement of H2O2 and Cu(I).

Study on Redox Properties and Cytotoxicity of Anthraquinone Derivatives to Understand Antitumor Active Anthracycline Substances.

This study demonstrates the relation between the redox properties and cytotoxicity of anthraquinone derivatives with a hydroxyl and methoxy group. The redox behavior of the anthraquinone derivatives was initially observed via cyclic voltammetry and their characteristics were investigated using molecular orbital calculations. The cytotoxicity of the anthraquinone derivatives was then evaluated using human leukemia HL-60 and H2O2 resistant HP100 cells, and its correlation with the redox properties of these compounds was investigated. Therefore, it was suggested that the anthraquinone derivatives express cytotoxicity through H2O2 production, and that generation of the oxidized radical form influences their cytotoxicity.

A Facile and Convenient Synthesis of Trisubstituted (E)-α,ß-Unsaturated Esters by Tandem Acetylation-E1cB Reaction.

A facile and convenient synthesis of trisubstituted (E)-α,ß-unsaturated esters was developed by improving our previously established method. The new method circumvented the separation of the intermediates, which have an activating group of the hydroxyl group in ß-hydroxy esters, furnishing α,ß-unsaturated esters in shorter steps than the previous method: an acetylation of ß-hydroxy group and subsequent E1cB reaction proceeded in tandem. In addition, the new method can not only employ a diastereomeric mixture of the substrate for the E1cB reaction, it has a wide substrate scope as well, which would enable the synthesis of various trisubstituted (E)-α,ß-unsaturated esters.

Post-Marketing Surveillance of Silodosin in Patients with Benign Prostatic Hyperplasia and Poor Response to Existing Alpha-1 Blockers: The SPLASH Study.

OBJECTIVES: Our objective was to investigate the effectiveness and safety of silodosin in patients with benign prostatic hyperplasia (BPH) who switched to silodosin from another α1 blocker because of inadequate response. METHODS: This was a prospective observational study conducted at 715 medical facilities in Japan in patients with BPH who received an α1 blocker other than silodosin for at least 3 months but had experienced unsatisfactory treatment outcomes. Patients completed questionnaires, including the International Prostate Symptom Score (IPSS), quality of life (QOL) score and Overactive Bladder Symptom Score (OABSS) at baseline (time of switching) and after 3 months of treatment with silodosin. RESULTS: Overall, 3355 patients were assessed for safety and 3144 patients for effectiveness. Mean ± standard deviation age was 73.1 ± 8.2 years, and most patients had been receiving tamsulosin (53.6%) or naftopidil (45.5%) before silodosin. Silodosin was well tolerated, with an overall incidence of adverse drug reactions of 8.1% and no unexpected safety signals. Significant improvements were observed after switching to silodosin in all effectiveness outcome measures, including total IPSS, all IPSS subscale scores, QOL score, total OABSS, all OABSS subscale scores and residual urine volume. Significant improvements in total IPSS were seen in patients who had been receiving tamsulosin or naftopidil before switching and in almost all other patient subgroups, with the exception of patients with mild symptoms (total IPSS ≤ 7) at baseline. CONCLUSIONS: This post-marketing analysis indicates that switching to silodosin from tamsulosin or naftopidil significantly improved symptoms associated with BPH, and silodosin was well tolerated in Japanese patients.

Oxidative DNA Damage Induced by Pirarubicin, an Anthracycline Anticancer Agent, in the Presence of Copper(II).

BACKGROUND/AIM: One mechanism of the anticancer action of anthracyclines is believed to be oxidative DNA damage. Previously, we reported that doxorubicin induced oxidative DNA damage in the presence of Cu(II). However, the mechanism of pirarubicin-induced oxidative DNA damage has not been well clarified. MATERIALS AND METHODS: DNA damage by pirarubicin in the presence of Cu(II) was analyzed using pBR322 plasmid DNA. O2•- derived from pirarubicin in the presence of Cu(II) was detected by cytochrome c reduction. RESULTS: Pirarubicin induced DNA damage in the presence of Cu(II). Scavenger experiments suggest that reactive species are generated from H2O2 and Cu(I). Pirarubicin induced O2•- production in the presence of Cu(II). CONCLUSION: These findings suggest that pirarubicin plus Cu(II) induces oxidative DNA damage in a similar manner to doxorubicin, and Cu(II)-mediated oxidative DNA damage may serve as a common mechanism for antitumor effects of anthracyclines.

Pirarubicin, an Anthracycline Anticancer Agent, Induces Apoptosis Through Generation of Hydrogen Peroxide.

BACKGROUND/AIM: Pirarubicin (THP) has shown equal or superior cytotoxicity compared to doxorubicin. One of the main anticancer actions of doxorubicin is believed to be involved in ROS (reactive oxygen species) generation. Therefore, the anticancer mechanisms of THP may involve ROS generation. The aim of this study was to clarify the mechanisms of THP-induced apoptosis through ROS generation. MATERIALS AND METHODS: We analyzed the apoptotic events induced by THP in HL-60 cells and HP100 cells, hydrogen peroxide (H2O2)-resistant cells derived from HL-60. RESULTS: The apparent cytotoxicity could be detected at above 0.1 µM in HL-60 cells after 24-h incubation, whereas it was suppressed under these conditions in HP100 cells. In HP100 cells, THP-induced apoptosis, evaluated by DNA ladder formation, H2O2 generation, mitochondrial membrane potential decrease and caspase-3/7 activity, was suppressed or delayed compared to those of HL-60 cells. CONCLUSION: These findings can be explained by the involvement of H2O2 generation in the THP apoptotic pathway. This is the first report on THP-induced apoptosis through the H2O2 generation.

The enhancement of oxidative DNA damage by anti-diabetic metformin, buformin, and phenformin, via nitrogen-centered radicals.

Metformin (N,N-dimethylbiguanide), buformin (1-butylbiguanide), and phenformin (1-phenethylbiguanide) are anti-diabetic biguanide drugs, expected to having anti-cancer effect. The mechanism of anti-cancer effect by these drugs is not completely understood. In this study, we demonstrated that these drugs dramatically enhanced oxidative DNA damage under oxidative condition. Metformin, buformin, and phenformin enhanced generation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in isolated DNA reacted with hydrogen peroxide (H2O2) and Cu(II), although these drugs did not form 8-oxodG in the absence of H2O2 or Cu(II). An electron paramagnetic resonance (EPR) study, utilizing alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone and 3,3,5,5-tetramethyl-1-pyrroline-N-oxide as spin trapping agents, showed that nitrogen-centered radicals were generated from biguanides in the presence of Cu(II) and H2O2, and that these radicals were decreased by the addition of DNA. These results suggest that biguanides enhance Cu(II)/H2O2-mediated 8-oxodG generation via nitrogen-centered radical formation. The enhancing effect on oxidative DNA damage may play a role on anti-cancer activity.

Osteogenesis Imperfecta Diagnosed from Mandibular and Lower Limb Fractures: A Case Report.

Osteogenesis imperfecta (OI) is a congenital disease characterized by bone fragility and low bone mass. Despite the variety of its manifestation and severity, facial fractures occur very infrequently. Here, we report a case of an infant diagnosed with OI after mandibular and lower limb fractures. A boy aged 1 year and 3 months was brought to his neighboring hospital with a complaint of facial injury. He was transferred to our hospital to undergo operation 3 days later. Computed tomography images revealed multiple mandibular fractures including complete fracture in the symphysis and dislocated condylar fracture on the right side. Open reduction and internal fixation with absorbable implants was performed 7 days after injury. He fractured his right lower limb 2 months later. He was diagnosed with OI type IA by an orthopedist. He will be administered bone-modifying agents if he suffers from frequent fractures.

Appropriate Tongue Blade Length of the Dingman Mouth Gag for Japanese Pediatric Patients With Cleft Palate and Mandibular Micrognathia.

Objective Our objective is to determine appropriate specifications for smaller tongue blade for Japanese pediatric patients with cleft palate (CP) and mandibular micrognathia. Patients We investigated 59 patients who underwent palatoplasty. Patients were divided into two groups: the micrognathia (MG) group consisted of 11 patients and the normognathia (NG) group consisted of 48 patients. Interventions The following five items were investigated retrospectively: (1) gender, (2) cleft type, (3) age at the time of surgery, (4) weight at the time of surgery, and (5) distance from the tongue blade base to the posterior pharyngeal wall (Dis). Results There was a significant difference (P < .01) in age at the time of surgery and in Dis between groups, but not in weight. The minimum values were 55 mm for the MG group. As for correlations between age and weight at the time of surgery, the P values for the MG and NG groups were .993 and .052, respectively. As for correlations between weight at the time of surgery and Dis, the P values for the MG and NG groups were .987 and .099, respectively. Conclusions It was difficult to predict Dis on the basis of the patient's age and weight measured preoperatively. The minimum Dis was 55 mm, equal to the length from the base to the tip of the Dingman Mouth Gag tongue blade currently in use, suggesting that a tongue blade of approximately 50 mm in length, shorter than the current minimum specifications, may be appropriate.

Local recurrence of sclerosing mucoepidermoid carcinoma with eosinophilia in the upper lip: a case report.

INTRODUCTION: Sclerosing mucoepidermoid carcinoma with eosinophilia is a rare morphological variant of thyroid carcinoma associated with Hashimoto's disease. To date, only three such tumors have been reported in the minor salivary glands. We describe the first case, to the best of our knowledge, of recurrent sclerosing mucoepidermoid carcinoma with eosinophilia in the minor salivary glands of the upper lip. CASE PRESENTATION: A 61-year-old Japanese man was referred to our hospital with a mass in his median upper lip of four years' duration. An examination of his median upper lip revealed a well-defined tumor measuring 9 × 12 mm in diameter, which was subsequently resected. Three years after the first surgery, the tumor recurred and was resected. Both tumors were confirmed by histopathology to be sclerosing mucoepidermoid carcinoma with eosinophilia. Neither recurrence nor metastasis was observed in three and a half years of follow-up after the second surgery. CONCLUSION: Our findings indicate that sclerosing mucoepidermoid carcinoma with eosinophilia can originate in the minor salivary glands and may be clinically or pathologically misdiagnosed as other conditions.

The effectiveness of a mouth guard to protect against strong occlusion caused by modified electroconvulsive therapy.

Modified electroconvulsive therapy (m-ECT) is a treatment for mental disease such as depressive disorder. Although a muscle relaxant is used during current application, strong occlusion occurs due to the proximity of the electrode to the temporal and masseter muscles. Although a feedback mechanism to avoid excessive occlusion occurs unconsciously, the mechanism does not work under general anesthesia. Strong occlusion may cause complications such as tooth injury, pain of the jaw, lip laceration, and bleeding of the gums. Although there was a report that the insertion of shock-absorbing materials such as gauze reduces complications, there has been no study on the effectiveness of a mouth guard (MG) for alleviating the occlusal force during m-ECT. The present study investigated the effectiveness of MG for alleviation of the occlusal force and complications during m-ECT. An ethyl-vinyl-acetate (EVA) MG was used as a shock absorbing material to mitigate the strong occlusion during m-ECT to investigate the influence of MG on the occlusal force and its effectiveness. The results showed that the occlusal force was alleviated by 58 ± 22% on average using MG during m-ECT. It also helped reduce intra-oral problems such as pain and bleeding. The results suggest the effectiveness of MG for alleviating the occlusal force during m-ECT and avoiding complications due to strong occlusion.

Protective effects of fluvoxamine against ischemia/reperfusion injury in isolated, perfused guinea-pig hearts.

Serotonin (5-hydroxytryptamine; 5-HT) is known to be activated during ischemia-reperfusion and triggers contractile dysfunction and pathological apoptosis. Here, the beneficial effects of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine was demonstrated on ischemia-reperfusion injury in guinea-pig hearts perfused using the Langendorff technique. The recovery (%) of left ventricular developed pressure (LVDP) by fluvoxamine (5×10(-8) M) was 95.4% (control: 32%), which was consistent with the inhibition of mitochondrial Ca(2+)([Ca(2+)]m) uptake induced by changes in the Ca(2+) content and acidification of the perfusate, and similar to reperfusion following global ischemia in Langendorff-perfused hearts. Fluvoxamine inhibited the increase in [Ca(2+)]m induced by changes in the Ca(2+) content of the perfusate in perfused preparations of mitochondria, which was similar to the results obtained with the mitochondrial permeability transition pore (MPTP) opener atractyroside. The terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL)-positive cells were significantly less in fluvoxamine-treated hearts than in control hearts, with decreases in caspase-3 activity. These results suggest that SSRI inhibits opening of the MPTP by preventing [Ca(2+)]m overload-induced apoptosis related to the endogenous accumulation of 5-HT in ischemia-reperfusion hearts.

MicroRNA-145 post-transcriptionally regulates the expression and function of P-glycoprotein in intestinal epithelial cells.

P-glycoprotein (P-gp/MDR1) is a multispecific efflux transporter regulating the pharmacokinetics of various drugs. Although P-gp expression in the small intestine is elevated after liver ischemia-reperfusion (I/R) injury, the regulatory mechanism remains to be clarified. MicroRNAs (miRNAs) play an important role in the post-transcriptional regulation of the expression of drug transporters. Here, we investigated the intestinal expression profile of miRNAs after liver I/R and the role of miRNAs in the post-transcriptional regulation of P-gp in intestinal epithelial cells. Microarray analysis showed that microRNA-145 (miR-145) level was decreased in the small intestine of I/R rats. This downregulation of miR-145 was further confirmed by real-time polymerase chain reaction. In silico analysis revealed that 3'-untranslated regions (UTRs) of rat Mdr1a, mouse Mdr1a, and human MDR1 mRNA retain binding sites for miR-145. Luciferase assays using MDR1 3'-UTR reporter plasmid in HEK293 cells showed that luciferase activity was decreased by the overexpression of miR-145, and the deletion of miR-145 binding site within MDR1 3'-UTR abolished this decreased luciferase activity. The downregulation of miR-145 in Caco-2 cells, an epithelial cell line derived from human colon, increased P-gp expression and efflux activity of rhodamine 123, but not MDR1 mRNA level. These findings demonstrated that miR-145 negatively regulates the expression and function of P-gp through the repression of mRNA by direct interaction on the 3'-UTR of MDR1 mRNA. In addition, the downregulation of miR-145 should significantly contribute to the elevated intestinal P-gp expression after liver I/R. Our results provide new insight into the post-transcriptional regulation of intestinal P-gp.

An antioxidant Trolox restores decreased oral absorption of cyclosporine A after liver ischemia-reperfusion through distinct mechanisms between CYP3A and P-glycoprotein in the small intestine.

Oxidative stress is a critical mediator of various injuries following ischemia-reperfusion (I/R) associated with organ transplantation. Although oral bioavailability of cyclosporine A (CsA) was decreased by increased first-pass metabolism through CYP3A and P-glycoprotein (P-gp) specifically in the upper small intestine after liver I/R, the mechanism responsible for them remained to be clarified. In the present study, the effect of Trolox (an α-tocopherol analogue) on the decreased oral absorption of CsA through elevated intestinal CYP3A and P-gp after liver I/R and their regulations were investigated. Rats were subjected to 60 min of liver ischemia followed by 12h of reperfusion. Trolox was administered intravenously 5 min before reperfusion. Trolox diminished the increased malondialdehyde and total glutathione levels in plasma by liver I/R and concomitantly prevented the decreased area under the blood concentration-time curve of orally administered CsA as well as initial absorption rate of CsA from upper small intestine. The elevated CYP3A mRNA and activity in the upper small intestine as well as expression levels of P-gp in upper, middle, and lower small intestines after liver I/R were attenuated by Trolox administration. The elevations of CYP3A levels specifically in the upper small intestine of I/R rats were correlated with the lithocholic acid levels in the bile. These results demonstrate that Trolox ameliorates the decreased oral absorption of CsA through elevated intestinal CYP3A and P-gp by preventing oxidative stress, where the biliary lithocholic acid may be responsible for the elevated transcription of CYP3A specifically in the upper small intestine after liver I/R.