Biomedical subjects

Kenji Takagi

Publications and source records attributed to Kenji Takagi.

44 records · Page 3Linked to original sources

PubMed2002

Possible involvement of P-glycoprotein in the biliary excretion of grepafloxacin.

1. In the present study, we have examined the effects of the quinolones norfloxacin (NFLX), enoxacin (ENX), ofloxacin (OFLX), tosufloxacin (TFLX), lomefloxacin (LFLX), sparfloxacin (SPFX) and grepafloxacin (GPFX) on the efflux of doxorubicin from mouse leukaemia P388/ADR cells expressing P-glycoprotein. The relationship between their partition coefficients (hydrophobicity) and effluxing potencies was also elucidated. 2. Both TFLX and SPFX strongly increased the intracellular accumulation of doxorubicin (5 micromol/L) in P388/ADR cells, but had no effect on P388/S cells not expressing P-glycoprotein. The rank of order of the potency of the quinolones (TFLX > SPFX > GPFX > NFLX) was not related directly to their hydrophobicity. These results suggest that some quinolones can reverse anticancer drug resistance. 3. Because GPFX is more highly excreted into the bile than other known quinolones, the effects of doxorubicin (10 mg/kg) or the well-known inhibitors of P-glycoprotein, namely cyclosporine A (10 mg/kg) and erythromycin (100 mg/kg), on the biliary excretion of GPFX at steady state was studied in rats. 4. Doxorubicin, cyclosporine A and erythromycin significantly decreased the biliary clearance of GPFX. Cyclosporine A and erythromycin had a much stronger inhibitory effect on the biliary excretion of GPFX than doxorubicin. These results suggest the possibility that GPFX is, at least in part, excreted into the bile by a P-glycoprotein-mediated transport mechanism.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2002

Amino acid substitutions in the nonstructural region 5A of hepatitis C virus genotypes 2a and 2b and its relation to viral load and response to interferon.

OBJECTIVES: The interferon sensitivity-determining region (ISDR) in nonstructural region 5A (NS5A) of hepatitis C virus genotype 1b has been reported to correlate with response to interferon therapy and viral load. Recently the correlation between NS5A and response to interferon in genotype 2a was also reported. We examined the region of genotypes 2a and 2b corresponding to the ISDR of genotype lb to elucidate its correlation with response to interferon and viral load. METHODS: The sequences of amino acid positions 2213-2248 in NS5A were determined in 39 patients with genotype 2a and 12 patients with genotype 2b. RESULTS: In the patients infected with genotype 2a, the number of amino acid substitutions in the ISDR-corresponding region compared with the consensus sequence of genotype 2a was significantly correlated with viral load (p = -0.541, p < 0.001) and with response to interferon therapy (p < 0.05); 83% of the patients with three or more substitutions obtained sustained responses, whereas only 44% of those with less than three substitutions obtained sustained responses. Multivariate analysis confirmed that the number of substitutions in the ISDR-corresponding region of genotype 2a was one of the independent predictors of response to interferon therapy (discriminant coefficient = 1.35, p < 0.001). CONCLUSIONS: Substitutions in the ISDR-corresponding region in NS5A of hepatitis C virus genotype 2a was confirmed to correlate to viral load and response to interferon therapy. In genotype 2b, further work must be considered because of the small number of patients studied.

5' Flanking Region↗

PubMed2002

Shiga-like toxin II derived from Escherichia coli O157:H7 modifies renal handling of levofloxacin in rats.

The effect of Shiga-like toxin II (SLT-II) (2 microg/animal), which was derived from Escherichia coli O157:H7, on renal handling of levofloxacin (LVX), a model drug for quinolone antimicrobial agents, was investigated in rats 24 h after intravenous injection. In histopathological examination, acute tubular injury was observed in SLT-II-treated rats, but the glomeruli were not injured. SLT-II significantly increased the steady-state concentration of LVX in plasma to 1.5-fold that of control rats. SLT-II induced significant decreases in the glomerular filtration rate (GFR) and renal clearance (CL(R)) of LVX. SLT-II slightly, but significantly, increased the unbound fraction and decreased renal plasma flow with no change in the extraction ratio of p-aminohippurate. SLT-II significantly increased concentrations of tumor necrosis factor alpha (TNF-alpha) and nitrite and nitrate (NOx) in plasma. The TNF-alpha inhibitor pentoxifylline partly, but significantly, inhibited SLT-II-induced decreases in the GFR and CL(R) of LVX; in contrast, S-methylisothiourea, a selective inhibitor of inducible nitric oxide synthase, did not. Western blotting analysis revealed that SLT-II did not alter the levels of multidrug resistance-associated protein 2 (Mrp2) and P-glycoprotein in kidneys 24 h after injection, assuming the lack of involvement of Mrp2 and P-glycoprotein in SLT-II-induced acute renal tubular injury and renal handling of LVX observed 24 h after SLT-II injection. The present study suggests that SLT-II impairs the renal handling of LVX by decreasing GFR and causing decreased renal plasma flow.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2002

Selective phosphodiesterase type 4 inhibitors reduce the prolonged survival of eosinophils stimulated by granulocyte-macrophage colony-stimulating factor.

It is well known that bronchial asthma is defined as chronic eosinophilic inflammation of the respiratory tract and that as one of the various types of inflammatory cells, eosinophils induce the airway inflammation of chronic asthma. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to play an important role in the prolongation of the survival of eosinophils. We investigated the inhibitory effect of the selective phosphodiesterase (PDE) 4 inhibitors, 3,4-dipropyl-4,5,7,8-tetrahydro-3H-imidazo[1,2-i]purin-5-one (XT-611) and rolipram, and the nonselective PDE inhibitor theophylline, against GM-CSF-induced prolongation of the survival of eosinophils isolated from patients with bronchial asthma. Eosinophils (10(6) cells/ml) were incubated in the presence of GM-CSF together with or without theophylline, rolipram or XT-611 at 37 degrees C, and the viable cells were assessed up to 4d using Trypan blue dye exclusion. The presence of theophylline (10(-4) M), rolipram (10(-4)-10(-5) M) or XT-611 (10(-4)-10(-5) M) significantly reduced the GM-CSF (10 pg/ml)-induced prolongation of viability of eosinophils. These findings suggest that selective PDE 4 inhibitors, including XT-611, may effectively reduce the activities of inflammatory cells in the airway of bronchial asthma patients.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMedDate not supplied

Smallest cystic tumor, measuring 5 mm, was identified as an invasive adenocarcinoma among multiple intraductal papillary-mucinous tumors.

We encountered a case of four cysts of intraductal papillary-mucinous tumor in the pancreas, a 25-mm diameter tumor, a 20-mm tumor, and a 10-mm tumor in the pancreatic body and tail, and a 5-mm diameter tumor in the uncinatus process, and the smallest diameter intraductal papillary-mucinous tumor (5 mm) was regarded as an invasive papillary adenocarcinoma, while the other three intraductal papillary-mucinous tumors were adenomas. A 63-year-old asymptomatic male was indicated of the presence of multiple pancreatic tumors by computed tomography during a physical examination. Endoscopic retrograde cholangiopancreatography revealed three cysts (25 mm, 20 mm, 10 mm diameter tumor) in the pancreatic body and tail, and one cyst 5 mm) in the uncinatus process. Cytologic examination of the pancreatic juice determined them as Class V. Based on a diagnosis of malignant intraductal papillary-mucinous tumors, he underwent distal pancreatectomy with removal of the uncinatus process. Pathologically, three cysts in the body and tail of the pancreas were found to be adenomas, but the 5-mm cyst in the uncinatus process was found to be an invasive intraductal papillary-mucinous tumor. The interstitium had been invaded by cancer, and the uncinatus process was the cancer positive surgical margin, and cystological examination of the pancreatic juice through repeated endoscopic retrograde cholangiopancreatography resulted in a class V, so the patient underwent a total pancreatectomy. When diagnosing intraductal papillary-mucinous tumor(s), there is the possibility of incorrectly differentiating between benignancy and malignancy when the diagnosis is based on cyst diameter, as is conventional.

Adenocarcinoma↗

PubMedDate not supplied

Exceptional ultra-late recurrence of papilla Vater carcinoma after pancreaticoduodenectomy: two cases at 17 and 25 years.

Curative resection does not always equate with long-term survival. Cancer of the papilla Vater can remain clinically quiescent for decades prior to regional or distant recurrence. Nevertheless, late and ultra-late recurrence (respectively 10 and 15 years after initial treatment) are exceptional events. This protracted disease-free interval challenges the concept of a "cure" for cancer of the papilla Vater. In the first case reported here, a 74-year-old female underwent pancreaticoduodenectomy in 1985 for cancer of the papilla Vater revealed histologically as a well-differentiated papillotubular adenocarcinoma, stage IA (UICC classification). Multiple hepatic recurrences were found 17 years after the operation; hepatic biopsy showed histologically well to moderately differentiated papillotubular adenocarcinoma. She died about 17.5 years after the original operation. The second case is that of an 82-year-old female who underwent pancreaticoduodenectomy in 1974 for cancer of the papilla Vater, histologically a well-differentiated adenocarcinoma, stage IA. In the 25.5 years after the operation, the cancer recurred at the choledochoduodenal anastomosis and involved the liver hilus. Autopsy showed histologically well to moderately differentiated adenocarcinoma at the locations indicated, together with lung and lymph node metastases. The ultra-late recurrences (>15 years) in these cases are highly exceptional and, to our knowledge, this is the first report of such recurrences in cancer of the papilla Vater. It can occur in any patient, with or without identifiable risk factors. Because cancer of the papilla Vater can recur in many prognostically favorable cases after prolonged disease-free intervals, the possibility of delayed recurrence should not be ignored.

Adenocarcinoma↗

PubMedDate not supplied

MPR-hCT imaging of the pancreatic fluid pathway to Grey-Turner's and Cullen's sign in acute pancreatitis.

Subcutaneous manifestations (Grey Turner's sign and Cullen's sign) of severe acute pancreatitis (SAP) are often discussed but rarely observed in a daily clinic setting. This paper will demonstrate the anatomic pathways followed by the extravasated pancreatic enzymes and how their effects lead to these ecchymoses by multiplanar reformation (MPR) images obtained by helical computed tomography (hCT). A 34-year-old female was admitted with SAP. A hCT scan revealed a swollen pancreas and cholecystolithiasis. The fluid collection around the pancreas extended to the pelvic cavity, infiltrating subcutaneous tissue in the left anterior and lateral abdominal wall. She was treated with interventional endoscopy (IVE) and continuous arterial infusion (CAI) therapy immediately following admission, she survived the SAP and these ecchymoses resolved within 7 days of presentation. MPR images obtained by hCT revealed that, the infiltration of the extra-pancreatic fluid collection between the leaves of the anterior renal fascia through the anterior and posterior pararenal space had reached into a relationship with the subcutaneous tissues in the left flank at the clinical site of discoloration as the pathway of extension to Grey Turner's sign, and also revealed anterior extension from the inflamed gastrohepatic ligament and across the falciform ligament to Cullen's sign.

Abdominal Wall↗

PubMedDate not supplied

The lethal toxicity of pancreatic ascites fluid in severe acute necrotizing pancreatitis.

BACKGROUND/AIMS: The pathogenesis and the molecular mechanisms of the development and progression of the acute pancreatitis (AP) are not clearly understood. Ascites fluid is known to be important in the clinical progression of AP. We present the lethal toxicity of human pancreatic ascites fluid for experimental pancreatitis, with the therapeutic course of severe necrotizing AP. METHODOLOGY: The material was in a 33-year-old male admitted with epigastric pain. An abdominal CT revealed that his pancreas was swollen and contained pancreatic fluid collection extending to the pelvic cavity. He had complicated acute renal failure, sepsis, and DIC, and received hemodialysis, and continuous arterial infusion therapy (CAI). The peripancreatic infection was acquired, and percutaneous interventional radiology (IVR) was performed for the abscess drainage. The drained liquid around the pancreas contained high molecular cytokines, protease, and bacterial contamination. To evaluate the toxicity of the ascites fluid, we gave it intraperitoneally to rats in which pancreatitis had been induced and rats that had undergone a sham operation; these rats died immediately. The consistent irrigation and drainage of the abscess was administered and the patient's general condition improved. At this time, we gave the drained material intraperitoneally to other rats with induced pancreatitis and sham operation, but all these rats survived. RESULTS: These experimental results suggested that pancreatitis-associated ascites fluid contained a lethal toxicity. For curing this disease, elimination of these potential toxic mediators was essential. Our intensive IVR-based therapy improved the patient's prognosis. CONCLUSIONS: Downregulating this inflammatory process leads to a decrease in the mortality of severe acute pancreatitis.

Adult↗