Biomedical subjects

Takashi Ueda

Publications and source records attributed to Takashi Ueda.

At least 19 recordsLinked to original sources

PubMed2026

Activation of ASIC3 in nociceptors induces itch without overt pain in a novel mouse model of acid-evoked itch.

OBJECTIVE: Acid-sensing ion channel 3 (ASIC3), a proton-gated cation channel predominantly expressed in primary afferent nociceptors, is an acidosis-related pain generator. Previous experiments suggested that ASIC3 is also involved in the generation of itch. However, mechanistic links between ASIC3 and itch, including the expression of ASIC3 in itch-mediating primary sensory neurons, remain unclear. We examined ASIC3 expression in these sensory neurons and then investigated whether mild acid stimulation could induce ASIC3-dependent itch without overt pain in mice. METHODS: Immunohistochemical analyses were performed using ASIC3-FLAG-enhanced green fluorescent protein-FLAG (FEF) expressing mice. Citric acid was applied with a brush to shaved skin of the nape of the neck or cheek in wild-type and ASIC3 knockout (ASIC3 -/- ) mice. Hindlimb scratching and, in the cheek model, forelimb facial wiping were recorded. RESULTS: ASIC3-expressing neurons and plexin C1-positive/tachykinin 1-negative itch-mediating neurons essentially belonged to distinct subpopulations in dorsal root and trigeminal ganglia. Application of 0.2 M citric acid to the nape induced hindlimb scratching directed toward the citric acid-applied area in wild-type mice, and this response was significantly attenuated in ASIC3 -/- mice. Application of 0.5 M citric acid to the cheek induced ASIC3-dependent itch behavior (hindlimb scratching), accompanied by minimal or no pain behavior (forelimb wiping). CONCLUSION: Given the absence of ASIC3 in typical itch-mediating primary sensory neurons, citric acid-induced ASIC3 activation in nociceptive skin afferents primarily involved in pain likely underlies the observed itch behavior. As 0.5 M citric acid likely represents a weak noxious stimulus, weak activation of these pain-mediating afferents can evoke itch, supporting the intensity theory of itch.

Animals↗

PubMed2006

Blockade of high mobility group box-1 protein attenuates experimental severe acute pancreatitis.

AIM: To examine the effects of anti-high mobility group box 1 (HMGB1) neutralizing antibody in experimental severe acute pancreatitis (SAP). METHODS: SAP was induced by creating closed duodenal loop in C3H/HeN mice. SAP was induced immediately after intraperitoneal injection of anti-HMGB1 neutralizing antibody (200 microg). Severity of pancreatitis, organ injury (liver, kidney and lung), and bacterial translocation to pancreas was examined 12 h after induction of SAP. RESULTS: Anti-HMGB1 neutralizing antibody significantly improved the elevation of the serum amylase level and the histological alterations of pancreas and lung in SAP. Anti-HMGB1 antibody also significantly ameliorated the elevations of serum alanine aminotransferase and creatinine in SAP. However, anti-HMGB1 antibody worsened the bacterial translocation to pancreas. CONCLUSION: Blockade of HMGB1 attenuated the development of SAP and associated organ dysfunction, suggesting that HMGB1 may act as a key mediator for inflammatory response and organ injury in SAP.

Animals↗

PubMed2006

[Evaluation of irradiation position in respiratory-gated radiotherapy using a phantom system simulating patient respiration].

Respiratory-gated (RG) radiotherapy is useful for minimizing the irradiated volume of normal tissues resulting from the shifting of internal structures caused by respiratory movement. The present study was conducted to evaluate the treatment field in RG radiotherapy using a phantom system simulating patient respiration. A phantom system consisting of a 3-cm ball-shaped dummy tumor and film placed in a cork lung phantom was used (THK Co., Ltd.). RG radiotherapy was employed in the expiratory phase. The phantom movement distance was set to 2 cm, and the gating signals from a respiratory-gating system (AZ-733V, Anzai Medical) were varied. The settings used for irradiation were an X-ray energy of 6 MV (PRIMUS, Toshiba Medical Systems), treatment field of 5 cm x 7 cm, and X-ray dose of 100 MU. Images were acquired using an electric portal-imaging device (EPID, OPTIVUE 500), and the X-ray dose distribution was measured by the film method. In images acquired using the EPID, the tumor margins became less clear when the gating signals were increased, and the ITVs were determined to be 3.6 cm, 3.7 cm, 4.2 cm, and 5.1 cm at gating rates of 10%, 25%, 50%, and no gate, respectively. With regard to the X-ray dose distribution measured by the film method, the dose profile in the cephalocaudal direction was shifted toward the expiratory phase, and the degree of shift became greater when the gating signals were increased. In addition, the optimal treatment fields in the cephalocaudal direction were determined to be 5.2 cm, 5.2 cm, 5.6 cm, and 7.0 cm at gating rates of 10%, 25%, 50%, and no gating, respectively. Although RG radiotherapy is useful for improving the accuracy of radiotherapy, the characteristics of the RG radiotherapy technique and the radiotherapy system must be clearly understood when this method is to be employed in clinical practice. Image-guided radiotherapy (IGRT) is now assuming a central role in radiotherapy, and properly identifying internal margins is an important issue for ensuring optimal treatment. The results of this study confirmed that it is necessary to ensure the optimal treatment field in radiotherapy of the trunk and that it is essential to confirm tumor position on the basis of image evaluation.

Humans↗

PubMed2006

The assembly pathway of the 19S regulatory particle of the yeast 26S proteasome.

The 26S proteasome consists of the 20S proteasome (core particle) and the 19S regulatory particle made of the base and lid substructures, and it is mainly localized in the nucleus in yeast. To examine how and where this huge enzyme complex is assembled, we performed biochemical and microscopic characterization of proteasomes produced in two lid mutants, rpn5-1 and rpn7-3, and a base mutant DeltaN rpn2, of the yeast Saccharomyces cerevisiae. We found that, although lid formation was abolished in rpn5-1 mutant cells at the restrictive temperature, an apparently intact base was produced and localized in the nucleus. In contrast, in DeltaN rpn2 cells, a free lid was formed and localized in the nucleus even at the restrictive temperature. These results indicate that the modules of the 26S proteasome, namely, the core particle, base, and lid, can be formed and imported into the nucleus independently of each other. Based on these observations, we propose a model for the assembly process of the yeast 26S proteasome.

Active Transport, Cell Nucleus↗

PubMed2006

Primary hepatic lymphoma with spindle cell components: a case report.

Diffuse large B-cell lymphoma (DLBCL) with spindle cell components is extremely rare and often misdiagnosed as carcinoma or sarcoma. Here, we present a case of primary DLBCL with spindle cell components arising in the liver, for which a preoperative diagnosis by needle biopsies was unsuccessful. The patient was a 70-year-old man with a continuous cough. Thoracic computed tomography incidentally detected a mass of 5 cm in diameter in his liver. The initial and second needle biopsies from the liver mass were pathologically diagnosed as suspicious for sarcomatoid hepatocellular carcinoma. He underwent an extended left hepatectomy. Histological examination revealed a diffuse or epithelioid arrangement of round and polygonal cells, mixed with the fascicles of spindle-shaped cells. Immunohistochemically, all the morphological types of tumor cells showed positive reactions for a lymphocytic marker (CD45RB) and B-cell markers (CD20 and CD79a). Double-immunostaining revealed that the spindle-shaped tumor cells expressed CD20, but never expressed alpha-smooth muscle actin. Malignant lymphoma with a spindle cell morphology is quite uncommon, and this variant can be a diagnostic pitfall, especially in tiny biopsy specimens. We emphasize that pathologists should be reminded of lymphoma as a differential diagnosis of spindle cell tumors.

Aged↗

PubMed2006

Simple scoring system for the prediction of the prognosis of severe acute pancreatitis.

BACKGROUND: In severe acute pancreatitis (SAP), it is important clinically to predict the prognosis at the time of admission. Most scoring systems for severity of acute pancreatitis consist of multiple factors and are complicated. This investigation aimed to propose a simple scoring system for the prediction of the prognosis of SAP. METHODS: Prognostic factors were evaluated by receiver operator characteristic curve analyses and multivariate analysis from data that were obtained on admission of 137 patients with SAP. A simple scoring system with 3 most useful factors was made, and its usefulness was investigated in comparison with conventional scoring systems. RESULTS: Three prognostic factors were selected: serum blood urea nitrogen > or = 25 mg/dL, serum lactate dehydrogenase > or = 900 IU/L, and contrast-enhanced computed tomography finding with pancreatic necrosis. On admission, 137 patients were classified from 0 to 3 by the number of positive items (simple prognostic score [SPS]). Mortality rates for patients whose SPS was 0, 1, 2, and 3 were 2% (1/42 patients), 18% (7/40 patients), 48% (12/25 patients), and 67% (20/30 patients), respectively. Furthermore, when usefulness of SPS was compared with conventional scoring systems, the area under the curve by receiver operator characteristic curve analyses in SPS was 0.83; the Ranson score was 0.83; the Japanese severity score was 0.83; the Acute Physiology and Chronic Health Evaluation II score was 0.81, and the Glasgow score was 0.75. After onset, SPS kept almost same levels from day 2 to day 6, and a significant difference was observed between survivors and nonsurvivors from day 1 to day 6. CONCLUSION: This scoring system that comprised 3 items is simple, is feasible for the prediction of prognosis and conventional scoring systems, and is useful for the selection of the extremely severe patients with SAP on admission.

Blood Glucose↗

PubMed2006

Acid-sensing ion channel-1b in the stereocilia of mammalian cochlear hair cells.

We investigated whether amiloride-blockable proton-gated cation channels ASIC1a (acid-sensing ion channel-1a) and ASIC1b are expressed in the stereocilia of mouse cochlear hair cells. In-situ hybridization studies showed that ASIC1b transcripts, but not ASIC1a transcripts, were expressed in the inner and outer hair cells. Fluorescent immunohistochemical and immunogold electron microscopic analyses revealed that the ASIC1b channels were located at the insertions of the stereocilia into the hair cells. Our findings provide a novel molecular key to the understanding of cochlear physiology and pathophysiology.

Acid Sensing Ion Channels↗

PubMed2006

A novel spliced variant of the epithelial Na+ channel delta-subunit in the human brain.

The amiloride-sensitive epithelial Na+ channel regulates Na+ homeostasis in cells. Recently, we described that the delta-subunit is a candidate molecule for a pH sensor in the human brain. Here, an N-terminal spliced variant of the delta-subunit is cloned from human brain, and designated as the delta2-subunit, which is expressed with the original delta-subunit (delta1-subunit) at the same level in the human brain. Functional analyses revealed that the physiological and pharmacological properties (interaction with accessory betagamma-subunits, activation by acidic pH, amiloride sensitivity) of the delta2-subunit were similar to those of the delta1-subunit. In conclusion, the activities of both subunits may be involved in the mechanism underlying pH sensing in the human brain.

Alternative Splicing↗

PubMed2006

Adenosine A2a blockade prevents synergy between mu-opiate and cannabinoid CB1 receptors and eliminates heroin-seeking behavior in addicted rats.

Relapse is the most serious limitation of effective medical treatment of opiate addiction. Opiate-related behaviors appear to be modulated by cannabinoid CB1 receptors (CB1) through poorly understood cross-talk mechanisms. Opiate and CB1 receptors are coexpressed in the nucleus accumbens (NAc) and dorsal striatum. These regions also have the highest density of adenosine A2a receptors (A2a) in the brain. We have been investigating the postsynaptic signaling mechanisms of mu-opiate receptors (MORs) and CB1 receptors in primary NAc/striatal neurons. In this article, we present evidence that MOR and CB1 act synergistically on cAMP/PKA signaling in NAc/striatal neurons. In addition, we find that synergy requires adenosine and A2a. Importantly, an A2a antagonist administered either directly into the NAc or indirectly by i.p. injection eliminates heroin-induced reinstatement in rats trained to self-administer heroin, a model of human craving and relapse. These findings suggest that A2a antagonists might be effective therapeutic agents in the management of abstinent heroin addicts.

Adenosine A2 Receptor Antagonists↗

PubMed2006

Vascular endothelial growth factor increases in serum and protects against the organ injuries in severe acute pancreatitis.

BACKGROUND: We have demonstrated that apoptosis was detected in liver and kidney cells in severe acute pancreatitis and that cellular injury because of apoptosis may be involved in the mechanism of multiple organ dysfunction syndrome. Vascular endothelial growth factor (VEGF) is a glycoprotein with potent angiogenic, mitogenic, and vascular permeability-enhancing activities specific for endothelial cells. It has been reported that VEGF is implicated in many diseases such as cancer and inflammation. METHODS: Serum VEGF concentrations were determined in patients with acute pancreatitis at the time of admission, and the relationships with severity, blood biochemical parameters on admission, organ dysfunction during the clinical course, and prognosis were analyzed. Moreover, to clarify the role of VEGF in acute pancreatitis, effects of VEGF were investigated in experimental severe acute pancreatitis. RESULTS: Serum VEGF levels were significantly elevated in patients with acute pancreatitis. Serum VEGF levels were not related to severity or prognosis. In male patients, among the various blood biochemical parameters, serum lactate dehydrogenase, and blood urea nitrogen levels were positively correlated with serum VEGF levels. Serum VEGF levels with organ dysfunction (liver and kidney) were higher than those without organ dysfunction. In rat experimental severe acute pancreatitis, serum VEGF levels were significantly elevated. Recombinant VEGF did not affect the lung water content, volume of ascitic fluid, hematocrit, or serum amylase, but improved the hepatic and renal dysfunctions. Apoptosis of liver and kidney was significantly inhibited by the administration of VEGF. CONCLUSIONS: These results suggest that VEGF is closely related to organ dysfunction in severe acute pancreatitis, and that VEGF may function as not a vascular permeability factor, but a protective factor via the anti-apoptotic effect against the organ injuries in this disease.

Acute Disease↗

PubMed2006

Outcomes of surgery for intraductal papillary mucinous neoplasms of the pancreas.

BACKGROUND: Our objective was to evaluate outcomes of surgery for intraductal papillary mucinous neoplasms of the pancreas (IPMN) in terms of the clinicopathological features. METHODS: Fifty-seven patients with IPMN were examined using clinicopathological analyses to evaluate appropriate surgical treatment, including total pancreatectomy (TP). IPMN was classified into two types: main-duct type (MD, n = 33) and branch-duct type (BD, n = 24). RESULTS: Ultrasound (US) and computed tomography (CT) examinations easily revealed the main site of the lesions. Intraoperative US was the most useful device for diagnosis of lateral spreading, and accuracy rates were 74% for MD and 96% for BD. TP was performed on 16 patients and was appropriate for removing neoplastic lesions with malignancy or malignant potential in 12. Three patients who underwent partial pancreatectomy with involved cancer died of progressive disease. MD is a strong predictive factor in malignancy and indicative of TP. Concerning long-term outcomes, 5 of 16 patients suffered from severe hypoglycemia, and 2 of 16 died from this condition. CONCLUSION: Partial resection with cancer clearance was applied for BD-type IPMN. TP should be performed on selected patients with MD-type IPMN.

Adult↗

PubMed2006

Significant elevation of serum interleukin-18 levels in patients with acute pancreatitis.

BACKGROUND: We have reported that peripheral lymphocyte reduction due to apoptosis is linked to the development of subsequent infectious complications in patients with severe acute pancreatitis and that Th1 (helper T cell type 1)/Th2 (helper T cell type 2) balance tends to cause Th1 suppression in experimental severe acute pancreatitis. It has been reported that interleukin (IL)-18 is a cytokine produced from Kupffer cells and activated macrophages, and that IL-18 acts on Th1 cells and in combination with IL-12 strongly induces production of interferon-gamma. However, the role of IL-18 in acute pancreatitis has not yet been fully understood. METHODS: Serum IL-18 concentrations were determined by an enzyme-linked immunosorbent assay in 43 patients with acute pancreatitis at the time of admission. The relationships with etiology, pancreatic necrosis, severity, blood biochemical parameters on admission, infection, and organ dysfunction during the clinical course and prognosis were analyzed. RESULTS: Serum IL-18 levels in patients with acute pancreatitis (656+/- 11pg/ml) were significantly higher than those in healthy volunteers (126+/- pg/ml). Serum IL-18 levels were significantly positively correlated with the Ranson score and Japanese severity score. Among the blood biochemical parameters on admission, base excess and total protein were significantly negatively correlated with serum IL-18 levels. Moreover, the CD4/CD8 rate of lymphocytes, serum IL-6 levels, and serum IL-8 levels were significantly positively correlated with serum IL-18 levels. On day 7 after admission, the CD4/CD8 rate of lymphocytes and the rate of CD4-positive lymphocytes were significantly positively correlated with serum IL-18 levels. Furthermore, serum IL-18 levels in patients with hepatic dysfunction (980+/- 25pg/ml) were significantly higher than those without hepatic dysfunction (464+/- 8pg/ml). Serum IL-18 levels were not related to infection or prognosis. Elevation of serum IL-18 levels continued during 4 weeks after admission. CONCLUSIONS: These results suggest that serum IL-18 levels are significantly elevated and are correlated with severity in patients with acute pancreatitis and that IL-18 may be closely related to helper T cell response and hepatic dysfunction in this disease.

Acute Disease↗

PubMed2006

Elevation of plasma tissue factor levels in patients with severe acute pancreatitis.

BACKGROUND: Coagulative disorders are known to occur in severe acute pancreatitis (SAP), and they are related to its severity and organ dysfunctions. Tissue factor (TF) is a transmembrane glycoprotein that activates the extrinsic pathway of the blood coagulation cascade. Plasma TF levels increase in patients with sepsis and acute coronary syndrome. However, plasma TF levels in SAP have not yet been reported. METHODS: We measured plasma TF antigen levels by enzyme-linked immunosorbent assay in 36 patients with acute pancreatitis at the time of admission. The relationships between their plasma TF levels and various factors (severity, etiology, pancreatic necrosis, organ dysfunction, and prognosis) were analyzed. The utility of plasma TF as a clinical marker was evaluated. RESULTS: Plasma TF levels significantly increased in patients with SAP compared with healthy volunteers and drinkers, respectively. Plasma TF level in alcoholic SAP with pancreatic necrosis was significantly higher than that in alcoholic SAP without pancreatic necrosis or that in nonalcoholic SAP with pancreatic necrosis. The incidence of an abnormally high level of plasma TF was 63.6% in alcoholic SAP with pancreatic necrosis. The area under the ROC curve of plasma TF for detection of pancreatic necrosis in alcoholic SAP was 0.773 and was superior to those of Japanese severity score and lactate dehydrogenase. CONCLUSIONS: Plasma TF levels were elevated in patients with SAP, particularly in those with alcoholic SAP with pancreatic necrosis, suggesting that TF may be closely related to the development of pancreatic necrosis in alcoholic SAP and that the plasma TF level may be a useful marker for it.

Acute Disease↗

PubMed2006

Immunosuppression in patients with severe acute pancreatitis.

BACKGROUND: In severe acute pancreatitis (SAP), immunologic impairment in the early phase may be linked to subsequent infectious complications. In this study, immunologic alterations in patients with SAP were analyzed, and immunologic parameters related to infectious complications were clarified. METHODS: A total of 101 patients with SAP were analyzed retrospectively. Various immunologic parameters on admission were analyzed and compared between the infection group and noninfection group during SAP. Furthermore, chronologic change in the lymphocyte count was investigated, and its utility for predicting infection was compared with conventional scoring systems. RESULTS: Serum immunoglobulin G (IgG), serum IgM, lymphokine-activated killer cell activity, and natural killer cell activity were low, and the incidence of abnormally low values was 50.0%, 65.0%, 45.5%, and 42.4%, respectively. Serum complement factor 3 was significantly negatively correlated with the APACHE II score. The lymphocyte count was decreased below the normal range, and was significantly negatively correlated with the APACHE II score. CD4-, CD8-, and CD20-positive lymphocyte counts were below the normal range, and CD4- and CD8-positive lymphocyte counts were significantly lower in the infection group. The lymphocyte count on day 14 after admission was significantly lower in the infection group and was more useful for predicting infection than conventional scoring systems. CONCLUSIONS: Immunosuppression occurs from the early phase in SAP, and quantitative impairment of lymphocytes, mainly T lymphocytes, may be closely related to infectious complications during SAP. CD4- and CD8-positive lymphocyte counts on admission and the lymphocyte count on day 14 after admission may be useful for predicting infection.

APACHE↗

PubMed2006

Breakdown of intestinal mucosa via accelerated apoptosis increases intestinal permeability in experimental severe acute pancreatitis.

BACKGROUND: Bacterial translocation plays an important role for infectious complications in severe acute pancreatitis (SAP). Breakdown of intestinal mucosal integrity may increase intestinal permeability and may be implicated in bacterial translocation. It is suggested that increase in intestinal permeability is correlated with the changes of tight junction and/or apoptosis in intestinal epithelial cells. The aim of this study was to investigate the changes of intestinal mucosa and its permeability in SAP. METHODS: SAP was induced by injection of 3% sodium deoxycholate into the biliopancreatic ducts in rats. Permeability of intestinal wall was assayed ex vivo by measuring the leaked amount of FITC-dextran from the ileum pouch. Alteration of tight junction proteins such as zonula occludens (ZO)-1 and Occludin was evaluated by Western blotting and immunofluorescence staining. Apoptotic change of intestinal mucosa was detected by TUNEL staining and DNA fragmentation ELISA. In vitro, apoptosis-inducing effect of pancreatitis-associated ascitic fluid (PAAF) was examined using T84 cells. Integrity of monolayer cells was assessed by transepithelial electric resistance (TEER). RESULTS: Permeability of ileum was significantly increased 6 h after induction of SAP. Blood endotoxin level was significantly elevated and bacterial translocation occurred 18 h after induction of SAP. Six hours after induction of SAP, expressions of ZO-1 and Occludin were not altered, but apoptosis of ileum mucosa was significantly accelerated. Addition of PAAF to T84 cells did not affect expressions of ZO-1 or Occludin, but significantly increased the apoptosis and significantly decreased TEER. CONCLUSIONS: These results suggest that breakdown of intestinal mucosa via accelerated apoptosis may increase in intestinal permeability in SAP and that PAAF contains factor(s) that accelerates the apoptosis of intestinal epithelial cells.

Animals↗

PubMed2006

Significant increase of serum high-mobility group box chromosomal protein 1 levels in patients with severe acute pancreatitis.

OBJECTIVE: Multiple organ failure because of systemic inflammatory response in the early phase and sepsis in the late phase is the main contributor to high mortality in severe acute pancreatitis (SAP). High-mobility group box chromosomal protein 1 (HMGB1) was recently identified as a potent proinflammatory mediator and increases in various pathological conditions such as sepsis. The aim of this study was to investigate contributions of HMGB1 in SAP. METHODS: We measured serum HMGB1 concentrations by an enzyme-linked immunosorbent assay in 45 patients with SAP at the time of admission. Furthermore, relationship between their serum HMGB1 levels and clinical factors was analyzed. RESULTS: The mean value of serum HMGB1 levels was significantly higher in patients with SAP (5.4 +/- 1.3 ng/mL) than that in healthy volunteers (1.7 +/- 0.3 ng/mL). Serum HMGB1 levels were significantly positively correlated with the Japanese severity score and Glasgow score. Serum HMGB1 levels were significantly positively correlated with lactate dehydrogenase, C-reactive protein, and total bilirubin. The HMGB1 levels were higher in patients with organ dysfunction and infection during the clinical course. The HMGB1 levels in nonsurvivors were higher than those in survivors. Serum HMGB1 levels gradually declined after the admission. CONCLUSIONS: Serum HMGB1 levels were significantly increased in patients with SAP and were correlated with disease severity. These results suggest that HMGB1 may act as a key mediator for inflammation and organ failure in SAP.

Bacterial Infections↗

PubMed2006

Pharmacokinetic study and limited sampling strategy of cyclosporine in Japanese heart transplant recipients.

BACKGROUND: The purpose of this study was to characterize the pharmacokinetics of cyclosporine (CsA) in Japanese heart transplant patients, and to optimise the monitoring strategy based on measurements of the area under the curve of plasma concentration absorption phase or 2 h post-dose concentrations (C(2)). METHODS AND RESULTS: At defined time periods during the first year after transplantation, the area under the curve for the CsA serum concentration from 0 to 4 h (AUC(0-4 h)) was evaluated. Pharmacokinetic parameters and renal function at 1 month and 12 months after transplantation were compared in 7 Japanese patients. The highest coefficient of determination between CsA AUC(0-4 h) and a single concentration was observed using C2 (r2 =0.838). For CsA pharmacokinetics, the mean measurement of whole blood trough levels value at 12 months was significantly lower than at 1 month after transplantation (p=0.026). The mean serum creatinine level at 12 months was significantly higher than at 1 month (1.00 mg/dl vs 0.73 p=0.0194). CONCLUSION: A single-time-point model that includes C2 is useful for predicting CsA AUC(0-4 h) in Japanese heart transplant patients. Mean C2 values >1,000 ng/ml were obtained in patients with no rejection at 1 month and 12 months after transplantation; however, renal impairment may occur.

Adolescent↗

PubMed2006

The effects of olprinone, a phosphodiesterase 3 inhibitor, on systemic and cerebral circulation.

Olprinone, a phosphodiesterase (PDE) 3 inhibitor, is used to treat heart failure due to its positive inotropic and vasodilative effects. Selective inhibition of the PDE 3 isozyme increases intracellular adenosine 3;5;-cyclic monophosphate and enhances Ca(2+) influx into cardiac muscle cells. The most significant advantage of PDE 3 inhibitors is their ability not only to enhance myocardial contraction, but to reduce, through vasodilatory action, the stress to which the heart is subjected. In peripheral vessels, the decrease of cytosolic free Ca(2+) induces the vasorelaxation of vascular smooth muscle cells. In this way, olprinone reduces mean aortic and pulmonary artery pressures. Additionally, olprinone exerts differential vasodilatory effects on peripheral vessels in each organ, based on the differences in the distribution of PDE 3 among the organs. With respect to the cerebral circulation, olprinone augments blood flow in the cerebral cortex through direct vasodilatory effects on small cerebral arteries or arterioles. Olprinone increases hepatosplanchnic blood flow and improves oxygen supply. While long-term therapy with PDE 3 inhibitors in patients with chronic heart failure may accelerate the progress of the underlying disease and provoke serious ventricular arrhythmia, olprinone shows good potential for short-term treatment in patients who have experienced severe heart failure or patients who have undergone cardiac surgery.

Adult↗