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Biomedical subjects

A Fujimura

Publications and source records attributed to A Fujimura.

At least 55 records · Page 3Linked to original sources
PubMed2000

Direct immunization of malaria DNA vaccine into the liver by gene gun protects against lethal challenge of Plasmodium berghei sporozoite.

The liver is the first target organ for malaria parasites immediately after the bite of an infected mosquito. We studied local immunization of malaria DNA vaccines at the site of the liver using a gene gun as a useful tool for in vivo transfection of foreign genes. A malaria DNA vaccine consisting of the Plasmodium berghei circumsporozoite protein (PbCSP) gene plus the mouse IL-12 gene was bombarded directly by a gene gun into mouse liver once or into the skin twice. A marked protective effect was induced by gene bombardment into the liver (more than 71%) compared with that into the skin (less than 33%). A Th1-type immune response and high production of iNOS were observed in the hepatic lymphocytes from mice bombarded into the liver, resulting in more effective protection compared with those bombarded into the skin. These results provide an important implication on the development of efficient malaria vaccine strategies.

Amino Acid Sequence↗
PubMed2000

The functions of circulatory polymorphonuclear leukocytes in diabetic patients with and without diabetic triopathy.

We determined circulatory polymorphonuclear leukocytes (PMN) functions of superoxide anion production, adhesion and aggregation in 38 type 2 diabetic patients with and without diabetic triopathy. Tumor necrosis factor (TNF)-alpha-stimulated superoxide production and N-formyl-methionyl-leucyl-phenylalanine (FMLP)-stimulated aggregation in diabetic patients with triopathy were significantly greater than those in diabetics without triopathy. The more diabetic complications existed, the more TNF-alpha-stimulated superoxide was produced by PMN. These results suggest that the activated PMN contributes to a progression of diabetic triopathy in type 2 diabetic patients.

Cell Adhesion↗
PubMed2000

Ranitidine clearance during hemodialysis with high-flux membrane: comparison of polysulfone and cellulose acetate hemodialyzers.

OBJECTIVE: To compare the effect of hemodialysis using two different types of dialyzer membranes, polysulfone (PS), a high-flux membrane, and cuprophane (CP), a conventional membrane, on blood ranitidine concentration. BACKGROUND: Recent advances in hemodialyzer membranes have improved the removal of small and middle size uremic toxins, while little is known about the change of drug removal by new membranes. METHODS: Eight patients with chronic renal failure who received ranitidine (150 mg/day) on a chronic basis were included. During the dialysis, blood samples were obtained from both the arterial and venous sides (before and after, respectively) of the dialyzer. RESULTS: Serum concentration of ranitidine decreased more on PS [54 +/- 3% (+/- SEM) reduction after 3 h] than on CP (35 +/- 4%). The dialyzer clearance of ranitidine on PS membrane (67.2 +/- 4.4 ml/min/m2) was significantly higher than that on CP (43.1 +/- 3.8 ml/min/m2, P < 0.001). Elimination fraction (EF) of the drug during the dialysis with PS was also significantly higher than that with CP (72 +/- 2% versus 44 +/- 3%). Apparent half-life of ranitidine during dialysis with PS (2.9 +/- 0.4 h) was shorter than that with CP (5.1 +/- 0.7 h). However, the amount of ranitidine removed by a single dialysis with PS membrane was less than 20 mg. CONCLUSION: Ranitidine clearance by hemodialysis is significantly higher with PS than with CP. Although additional dose adjustment may not be needed for ranitidine, the type of dialyzer membrane can affect drug elimination and should be taken into account for consideration of drug removal by hemodialysis.

Cellulose↗
PubMed2000

Improvement of macromolecular clearance via lymph flow in hamster gingiva by topical warming and massage.

The lymphatic system is very important for macromolecular clearance in various tissues, especially in the gingiva. However, the kinetics of macromolecular clearance via the lymph flow in the gingiva are poorly understood. The aim of this study was to investigate whether thermal or mechanical stimulation affects macromolecular clearance via the lymph flow in the gingiva. Carbon black suspension was injected into the mandibular gingiva of anesthetized hamsters and its drainage into cervical lymph nodes was examined. Clearance of 14C-methylated bovine albumin and tritiated water from the gingiva and their drainage into submandibular lymph nodes and blood was quantified. The effect of topical warming or massage on clearance of 14C-methylated albumin from the gingiva during a 15 min period was examined. In addition, the influence of neurochemical antagonists on the stimulatory effect of topical warming on albumin clearance was investigated. Submandibular lymph nodes were clearly delineated by carbon black 10 min after the injection. More radiolabeled albumin appeared in submandibular lymph nodes than in serum, while more tritiated water appeared in serum. Topical warming (45 degrees C, 2 min) and warming plus massage (with a silicon rubber brush, 20 s) decreased the radiolabeled albumin in the gingiva 15 min after the injection. There was less radiolabeled albumin in the gingiva after gingival warming plus massage than after warming. Previous injection of HOE140 or propranolol into the gingiva diminished the stimulatory effect of topical warming on albumin clearance. It was concluded that topical warming plus massage improves macromolecular clearance via the lymph flow in hamster gingiva.

Albumins↗
PubMed2000

Delayed hypotensive effect of the thromboxane A2/prostaglandin H2 receptor antagonist S-1452 in spontaneously hypertensive rats.

1. Several lines of evidence indicate that thromboxane (Tx) A2 may contribute to the development and maintenance of hypertension. The present study was undertaken to evaluate the role of TxA2 in the development of hypertension in spontaneously hypertensive rats (SHR) by using an orally active, highly specific TxA2/prostaglandin H2 receptor antagonist S-1452. 2. Vehicle (1% arabic gum solution) alone was given orally to Wistar-Kyoto (WKY) rats (n = 15) and SHR (n = 14), while S-1452 (10 mg/kg per day, twice daily) was administered orally to SHR (n = 16) for 18 weeks (from 5 to 23 weeks of age). 3. No significant difference was observed in tail-cuff blood pressure (BP) between vehicle- and S-1452-treated SHR before and at 5 and 11 weeks after treatment. Thereafter, BP was further elevated in vehicle-treated SHR, but was significantly blunted in SHR treated with S-1452 at 15 (224+/-8 vs 211+/-13 mmHg; P < 0.01) and 18 weeks (227+/-9 vs 206+/-10 mmHg; P < 0.001); this was associated with reduced proteinuria. 4. Urinary TxB2 in vehicle-treated SHR, especially during the early period, was significantly greater than that in WKY rats, while no significant difference was observed in urinary 6-ketoprostaglandin F1alpha (6-keto-PGF1alpha) between the two groups. Treatment with S-1452 reduced urinary excretion of TxB2 at 18 weeks. 5. The present study shows that S-1452, at the dose used, does not reduce BP during the early period of the development of hypertension. These results suggest that the role of enhanced TxA2 production in the development of hypertension is small, if any, in SHR. Delayed response of BP may be independent of the direct pharmacological effects of S-1452.

6-Ketoprostaglandin F1 alpha↗
PubMed2000

Enhanced responsiveness of circulatory neutrophils after cardiopulmonary bypass: increased aggregability and superoxide producing capacity.

Cardiac surgery with cardiopulmonary bypass (CPB) induces a whole body inflammatory response that sometimes leads to postoperative organ dysfunction, and neutrophil activation plays an important role in this reaction. Neutrophil priming has been described as a change in neutrophil status such that neutrophils show enhanced responsiveness to a second activating stimulus. We hypothesized that neutrophil priming occurs by cardiac surgery with CPB and is temporally related to the neutrophilia after surgery. To evaluate primed circulatory neutrophil status, we measured aggregation activity stimulated by N-formyl-methyl-leucyl-phenyl-alanine (FMLP) and free radical producing activity by tumor necrosing factor (TNF) alpha in peripheral blood samples. Eleven adult patients undergoing elective cardiac surgery with CPB were studied. Blood samples were taken before surgery, at the end of bypass, 12 h after surgery, and 7 days after surgery. Aggregation activity and superoxide generation were significantly elevated 12 h after surgery when compared to presurgery values, indicating that cardiac surgery is associated with circulatory neutrophil priming. The number of neutrophils markedly increased at the end of cardiopulmonary bypass and reached a peak 12 h after surgery. The circulatory neutrophils of cardiac surgical patients become primed after surgery, coincident with the peak neutrophil count. These results suggest that circulatory neutrophils after cardiac surgery with CPB have enhanced responsiveness and are predisposed to systemic inflammation.

Adult↗
PubMed2000

Antagonistic activity of tamsulosin against human vascular alpha1-adrenergic receptors.

OBJECTIVE: To elucidate the vascular effect of tamsulosin hydrochloride (INN, tamsulosin), a selective alpha1A-adrenergic receptor antagonist, in humans, we examined the alpha1-adrenergic receptor antagonistic activity against blood vessels after oral intake of recommended and higher doses of the drug and evaluated the relation between its plasma concentrations and the effect. METHODS: Nine healthy men ranging in age from 21 to 38 years received tamsulosin (0.2 mg or 0.6 mg) or lactate capsule as a control after breakfast in a randomized crossover fashion. Seven hours after administration, their fingertip vasoconstrictor response to contralateral hand cooling and vasoconstrictor response of the dorsal hand vein to phenylephrine were examined, and blood samples for the measurement of plasma drug concentration were obtained. RESULTS: The fingertip vasoconstrictor response was significantly reduced and the infusion rate of phenylephrine producing a half-maximal constriction was significantly increased by 0.6 mg tamsulosin but not by 0.2 mg tamsulosin. There were significant positive correlations between plasma drug concentrations and the changes of these parameters. CONCLUSION: These results suggest that although the alpha1-adrenergic receptor-blocking effect of tamsulosin on blood vessels is relatively small, it is clearly correlated with plasma drug concentration and a higher dose of the drug could cause systemic adverse effects.

Administration, Oral↗
PubMed2000

Polymorphonuclear leukocytes (PMNs) functions in SHR, L-NAME- and DOCA/salt-induced hypertensive rats.

OBJECTIVES: To clarify ex-vivo polymorphonuclear leukocytes (PMNs) functions, we examined superoxide anion (O2-) production and adhesion to a plastic plate of isolated PMNs obtained from spontaneously hypertensive rats (SHR/lzm), NG-nitro-L-arginine methyl ester (L-NAME)- and deoxycorticosterone acetate (DOCA)/salt-induced hypertensive rats. DESIGN: Sixteen week-old male SHR/Izm and Wistar-Kyoto rats (WKY/Izm) were used as a model of hypertension and its control, respectively. L-NAME-hypertension was induced by oral administration of 100 mg/kg per day of L-NAME twice daily for 4 weeks using 4-week-old male Wistar rats. DOCA/salt-hypertension was induced by once daily subcutaneous injection of 1 mg DOCA with 1% NaCl drinking water for 2 weeks using 8-week-old male Wistar rats with heminephrectomy. METHODS: Heparinized whole blood was obtained from abdominal aorta. PMNs were isolated by density gradient following dextran sedimentation. A production of superoxide anion (O2-) by PMNs stimulated with phorbol ester myristate acetate (PMA, 100 ng/ml) was determined by a superoxide dismutase (SOD)-inhibitable cytochrome-C reduction method. Adhesion of PMNs was evaluated by their protein content on a plastic plate measured by Lowry method. RESULTS: SHR/Izm showed a significant enhancement of O2- production by isolated PMNs compared with WKY/Izm. Rats treated with L-NAME showed a lower O2- production by PMNs compared to control animals. In DOCA/salt hypertensive rats, O2- production was not different from that in the control rats. Adherent function of isolated PMNs did not differ significantly among these hypertensive animal models. CONCLUSIONS: These results suggest that O2- production by circulatory PMNs is augmented in SHR, but not in L-NAME and DOCA/salt hypertensive rats. This enhanced function, which is also observed in human essential hypertension, might contribute to the development of cardiovascular damage in genetically determined hypertension.

Animals↗
PubMed2000

Effects of chronic neutral endopeptidase inhibition in rats with cyclosporine-induced hypertension.

OBJECTIVE: Cyclosporine (CysA), a potent immunosuppressant, is associated with hypertension and nephrotoxicity. Neutral endopeptidase (NEP) degrades vasoactive peptides, including the natriuretic peptides and endothelin-1 (ET-1). We conducted the present study to determine whether or not the NEP inhibitor, ecadotril, prevents cyclosporine-induced hypertension and to clarify the mechanisms responsible for the hypotensive effects of ecadotril. DESIGN AND METHODS: We studied the chronic effects of ecadotril (30 mg/kg per day) on blood pressure; the production of ET-1 and C-type natriuretic peptide (CNP); endothelial nitric oxide synthase (eNOS) activity; and the expression of messenger RNA (mRNA), for each substance in blood vessels of CysA-induced hypertensive rats. RESULTS: CysA (25 mg/kg per day) given for 4 weeks increased the blood pressure from 116 +/- 14 mmHg to 159 +/- 15 mmHg, in rats. This increase was blunted by the co-administration of ecadotril (blood pressure: 134 +/- 14 mmHg). CysA increased plasma NEP activity. CysA increased the production of ET-1 and the expression of ET-1 mRNA without affecting CNP synthesis and endothelin converting enzyme (ECE)-1 mRNA expression. CysA decreased the eNOS activity and eNOS mRNA levels. Addition of the NEP inhibitor decreased the synthesis of ET-1 and ET-1 mRNA levels and increased the eNOS activity and the eNOS mRNA levels. Vascular CNP synthesis and ECE-1 mRNA expression in rats treated with ecadotril did not differ from those in rats treated with CysA and ecadotril. CONCLUSION: These results indicate that chronic NEP inhibition may prevent the CysA-induced hypertension by decreasing local ET-1 synthesis and partly increasing vascular nitric oxide production.

Animals↗
PubMed2000

Influence of losartan on alpha-adrenoceptor-mediated vasoconstrictor response in humans.

To evaluate the influence of losartan on alpha-adrenoceptor-mediated vasoconstrictor response, we examined dorsal hand vein constrictor response to phenylephrine (16-8,192 ng/min) and fingertip vasoconstrictor response to cold stimulation with and without pretreatment with losartan (50 mg/day) for 3 days in nine healthy men. The effect of coadministration of angiotensin II (Ang II) (0.3 ng/min) on the venoconstrictor response also was evaluated. Oral pretreatment with losartan alone influenced neither of the responses. The log of the infusion rate of phenylephrine producing half-maximal venoconstriction [log(ED50)] was 2.69 +/- 0.10 (mean +/- SEM) for control and 2.68 +/- 0.09 for losartan, and the reduction ratio of fingertip blood flow was 68.1 +/- 4.0% for control and 66.7 +/- 4.3% for losartan. Coadministration of Ang II, however, significantly enhanced the venoconstrictor response to phenylephrine [log(ED50): 2.43 +/- 0.09, p < 0.05 vs. control], and the pretreatment with losartan attenuated this effect [log(ED50): 2.60 +/- 0.11]. These findings indicate that the alpha-adrenoceptor-mediated vasoconstrictor response is not influenced by losartan; however, it is enhanced by exogenous Ang II, and losartan attenuates the enhanced response, in healthy human subjects.

Adult↗
PubMed2000

Hepatic lymphocyte transplantation in hyperbilirubinemic gunn rats.

Hepatic lymphomyeloid cells (HLCs) are thought to contain liver stem cells. We investigated whether HLCs generated enzyme-producing cells in vivo. HLCs from normal Wistar/Shi rats and rats in which liver ischemia was induced using a portal clamp 4 days previously were studied histopathologically and characterized using flow cytometry. Splenic lymphocytes obtained from these animals were compared as a control. The proliferative activity of HLCs and splenic cells from both groups was also tested by stimulation with concanavalin A. HLCs contained a significantly higher number of NK-T cells and OV6+ cells compared with the splenic cells. The HLCs from rats in which liver ischemia was induced tended to have greater proliferative activity than those from normal rats, while the proliferative activity of splenic lymphocytes was impaired by liver ischemia. The HLCs obtained from Wistar/Shi rats with liver ischemia were then injected into hereditary hyperbilirubinemic Gunn rats to determine whether the HLCs generated enzyme-producing cells. After injection of these stimulated HLCs, the titer of serum bilirubin in the recipient rats was markedly reduced over a long time course (6.80+/-0.93 to 4.87+/-0.22 mg/dl after 1 month and 3.52+/-1.33 mg/dl after 6 months). The results of the present study indicate that HLCs have different populations than splenic cells, and ischemia-reperfusion of the liver increased their proliferative activity. HLC transplantation successfully reduced high bilirubin levels over a long time course.

Animals↗
PubMed2000

Effects of dosing time and schedule on cisplatin-induced nephrotoxicity in rats.

Renal dysfunction induced by a single injection of cisplatin depends on the timing of the dose. However, the effects of repeated administration of cisplatin on time-dependent toxicity have not been evaluated despite the fact that in clinical practice high doses are repeatedly injected at intervals or low doses are administered daily. We studied chrononephrotoxicity in rats after weekly or daily cisplatin injections. Weekly high doses (5 mg kg(-1)) or daily low doses (1.2 mg kg(-1)) of cisplatin were injected at four time points (3, 9, 15 and 21 h after the light was turned on (HALO)) for 3 weeks. Changes in body weight after weekly cisplatin administration were independent of the timing of the doses. In the group that received daily cisplatin, the loss in body weight in the 3 HALO group was smaller than in animals receiving injections at 15 and 21 HALO (P < 0.05 and 0.001, respectively). The blood urea nitrogen and serum creatinine levels in the control rats showed a significant circadian change (peak at 15 HALO and trough at 9 HALO), but these parameters were markedly elevated in both trials and their circadian variations were disturbed. In conclusion, cisplatin-induced nephrotoxicity was the lowest at 3HALO compared with other time points of both dose regimens.

Animals↗
PubMed2000

Time-dependent nephrotoxicity associated with daily administration of cisplatin in mice.

The chronopharmacokinetics and chronopharmacodynamics of cisplatin were studied in a mouse model to reveal the mechanisms of dosing time-dependent nephrotoxicity induced by daily administration. Chronotoxicity was tested by daily intraperitoneal injections of cisplatin (6mg kg(-1)) for 5 days at four time points (04:00, 10:00, 16:00 and 22:00h) in BALB/c mice (n = 6 in each group). After following the changes in body weight, serum concentrations of blood urea nitrogen (BUN) and creatinine obtained on day 6 were compared. The results showed diurnal variations in cisplatin toxicity, with the 04:00 and 16:00h time points the best and the worst, respectively. We then measured platinum concentrations in blood, liver and kidney and compared the results of the 04:00 and 16:00 h groups (n = 4 in each group). Kidney sensitivity to cisplatin alone, lipopolysaccharide (LPS) alone, cisplatin with LPS and saline (control) were also measured using a tissue culture system (a measurement system of interleukin-6 (IL-6) production) between the 04:00 and the 16:00 h groups (n = 4 in each group). These results showed no significant difference in platinum accumulation between the two groups. IL-6 production was higher in the 16:00 h group than in the 04:00 h group after saline injection alone (P < 0.05). Cisplatin treatment alone did not increase IL-6 production. However, IL-6 levels were markedly augmented by cisplatin with LPS. In conclusion, chrononephrotoxicity induced by daily cisplatin administration does not only depend on cisplatin accumulation, but might also depend on kidney sensitivity to diurnal variations in inflammatory reaction without direct cisplatin toxicity.

Animals↗