Search PubMed⌕ Search

Biomedical subjects

A Fujimura

Publications and source records attributed to A Fujimura.

At least 37 records · Page 2Linked to original sources
PubMed2001

Effect of enalapril on diabetic nephropathy in OLETF rats: the role of an anti-oxidative action in its protective properties.

1. We have evaluated the effects of the angiotensin-converting enzyme inhibitor enalapril on renal function and oxidative status in the kidney of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of spontaneous onset of type 2 diabetes mellitus. 2. Enalapril (5 mg/kg) or vehicle (distilled water) was given once daily by gavage to 22-week-old male OLETF rats for 32 weeks. Long-Evans Tokushima Otsuka (LETO) rats, the control animals for OLETF rats, received vehicle alone (n = 10 in each group). 3. Enalapril attenuated the rise in blood pressure mildly, but significantly. Enalapril significantly blunted the development of proteinuria without a significant effect on creatinine clearance. At the end of the study period, the lipid peroxide content in the renal cortex was significantly increased in OLETF compared with LETO rats, in which enalapril had no effect on lipid peroxide content. Enalapril enhanced the activity of catalase in the renal cortex of OLETF rats, but had no effect on the activity of either superoxide dismutase or glutathione peroxidase. 4. These results suggest that oxidative stress may be involved in the development of nephropathy in type 2 diabetes. Enalapril exhibited renoprotective effects without changing lipid peroxides in the kidney, suggesting that the beneficial effects of the compound on diabetic renal damage in OLETF rats may not be mediated through an anti-oxidative action.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

Effect of angiotensin II on venodilator response to nitroglycerin.

OBJECTIVE: An enhanced circulatory angiotensin II level that results from the administration of nitroglycerin may contribute to the development of nitrate tolerance. Using human hand veins, we investigated whether a subconstricting dose of angiotensin II attenuates the venodilator effect of nitroglycerin, whether pretreatment with losartan influences this effect, and whether angiotensin II also attenuates the venodilator effect of diltiazem. METHODS: In 9 healthy male subjects, increasing doses (0.5-128 ng/min) of nitroglycerin were infused into the dorsal hand vein pretreated with 0 (control), 0.3, or 1 ng/min of angiotensin II. In 8 healthy male subjects, angiotensin II (0.3 and 1 ng/min) was infused into the vein dilated by nitroglycerin with and without pretreatment with losartan and with diltiazem. The diameter of the vein was measured with a linear variable differential transformer. RESULTS: The venodilator response of nitroglycerin was significantly suppressed by the pretreatment with angiotensin II; The maximum venodilator effect was dose-dependently decreased, and the infusion rate producing half-maximum response was dose-dependently increased. The venodilation caused by nitroglycerin was decreased by angiotensin II, and this effect was attenuated by pretreatment with losartan. The venodilation caused by diltiazem was also attenuated by angiotensin II, but this attenuating effect was smaller compared with that caused by nitroglycerin. CONCLUSIONS: These findings suggest that an enhanced angiotensin II level might attenuate the venodilation caused by nitroglycerin and diltiazem, and pretreatment with losartan might decrease the attenuating effect of angiotensin II.

Adult↗
PubMed2001

Furosemide-probenecid interaction as a laboratory exercise for undergraduate education in clinical pharmacology.

OBJECTIVE: The aim of this study was to determine the easiness, reproducibility, and safety of a laboratory exercise for a drug interaction between furosemide and probenecid. METHODS: From 1995 to 1999 approximately 100 medical students participated in the exercise each year after they gave written informed consent. The students were randomly assigned to one of the three groups in a double-blind fashion: group 1, placebo plus 20 mg of furosemide; group 2, 250 mg of probenecid plus 20 mg of furosemide; and group 3, 1000 mg of probenecid plus 20 mg of furosemide. The students took probenecid or its placebo 1 hour before furosemide. Urine volume and urinary sodium excretion were measured for 3 hours after furosemide. At the end of the exercise in 1999, students responded to several questionnaires concerning the utility of furosemide. RESULTS: The entire course of the exercise was completed within half a day. The following findings were obtained every year. (1) Probenecid dose dependently blunted the diuretic effects of furosemide. (2) Time courses of the diuretic effects were altered by probenecid. Ten to twenty percent of the students had slight complaints but completed the exercise without any medications. Finally, more than 80% of the students considered the exercise to be useful. CONCLUSIONS: The data suggest that the exercise of the drug interaction between furosemide and probenecid is easy to perform, reproducible, and safe. Through the experience of the laboratory exercise, students will develop an attitude to assess and estimate potential drug interactions before they prescribe drugs.

Diuresis↗
PubMed2001

Removal of digoxin by column for specific adsorption of beta(2)-microglobulin: a potential use for digoxin intoxication.

BACKGROUND: A beta(2)-microglobulin adsorption column used for the treatment of dialysis-related amyloidosis removes serum beta(2)-microglobulin by recognition of lipophilic residue in the protein. No data are available for the adsorption of the highly lipophilic drug digoxin. METHODS: In vivo clearance of digoxin with the beta(2)-microglobulin column was measured by a single use of the column in 8 patients receiving hemodialysis with a therapeutic level of digoxin. In vitro adsorption was evaluated by use of incubation with adsorbent of the column and digoxin or ranitidine, a hydrophilic drug. Clearance with the beta(2)-microglobulin column was further compared with that obtained by use of activated charcoal in the dogs intoxicated with digoxin. RESULTS: Digoxin concentration was reduced from 1.11 +/- 0.25 ng/mL to 0.57 +/- 0.15 ng/mL at 240 minutes after initiation of hemoperfusion with the column in the patients. Digoxin clearance with the beta(2)-microglobulin column was about 145 +/- 20 mL/min, with a blood flow rate of 160 to 220 mL/min (80% of plasma flow rate). Eighty-five percent of digoxin was adsorbed in vitro, and the capacity of the beta(2)-microglobulin column was not saturated until a toxic level was reached (50 ng/mL). This value was higher than that obtained with use of charcoal. In dogs with digoxin intoxication, digoxin clearance was 38.9 +/- 1.5 mL/min, with a blood flow rate of 50 mL/min (95% of plasma flow rate), which was almost twice as that achieved with charcoal. The degree of thrombocytopenia and leukopenia was small with use of the beta(2)-microglobulin column. CONCLUSION: These data suggested that the beta(2)-microglobulin column selectively adsorbs digoxin. This column is a promising tool for the treatment of digoxin intoxication, especially in patients undergoing hemodialysis.

Adsorption↗
PubMed2001

Different effects of St John's wort on the pharmacokinetics of simvastatin and pravastatin.

OBJECTIVE: St John's Wort, a widely used herbal product, is an inducer of CYP3A4 and it decreases blood concentrations of CYP3A4 substrates. The effects of St John's Wort on the pharmacokinetics of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors simvastatin (an inactive lactone pro-drug) and pravastatin were determined in this study. METHODS: Sixteen healthy male subjects (n = 8 in group 1 and n = 8 in group 2) took a St John's Wort caplet (300 mg) or matching placebo three times a day for 14 days in a double-blind, crossover study. On day 14, a single oral dose of 10 mg simvastatin and 20 mg pravastatin was given to subjects in group 1 and group 2, respectively. Blood samples were obtained during a 24-hour period after the administration of each drug. RESULTS: Repeated St John's Wort treatment tended to lower plasma simvastatin concentration and significantly (P <.05) lowered concentrations of simvastatin hydroxy acid, its active metabolite. The peak concentration in plasma (ratio, 0.72 of placebo) of simvastatin hydroxy acid tended to be decreased and its area under the plasma concentration-time curve between time zero and 24 hours after administration (ratio, 0.48 of placebo) was significantly decreased (P <.05) by St John's Wort. On the other hand, St John's Wort did not influence plasma pravastatin concentration. No significant differences were observed in the elimination half-life of simvastatin or pravastatin between the placebo and St John's Wort trials. CONCLUSIONS: This study showed that St John's Wort decreases plasma concentrations of simvastatin but not of pravastatin. Because simvastatin is extensively metabolized by CYP3A4 in the intestinal wall and liver, which are induced by St John's Wort, it is likely that this interaction is partly caused by the enhancement of the CYP3A4-mediated first-pass metabolism of simvastatin in the small intestine and liver.

Adult↗
PubMed2001

Cisplatin-induced vomiting depends on circadian timing.

We examined whether the clock time of cisplatin plus antiemetic and diuretic administration affects the amount of cisplatin-associated emesis and severity of renal toxicity. We treated 22 patients with urogenital cancer with two courses of chemotherapy containing 70 mg/m2 of cisplatin. Cisplatin together with furosemide was administered in the morning (05:00) or evening (17:00) during two courses 1 month apart in a crossover fashion. Ondansetron was given either before or after cisplatin to control nausea and vomiting. The number of vomiting episodes, serum creatinine, serum urea nitrogen (BUN), creatinine clearance, and urinary beta-N-acetyl glucosamidase (NAG) concentration were evaluated before and after each treatment course. Regardless of the timing of ondansetron, morning compared to evening cisplatin was always associated with greater vomiting in the first treatment course. However, prophylactic administration of ondansetron markedly diminished the impact of the clock time of cisplatin administration. Serum creatinine transiently decreased rather than increased 14 days after cisplatin and furosemide administration, while NAG excretion increased 3 days after cisplatin and furosemide administration. In the first course, serum creatinine levels were similar regardless of the clock time of cisplatin and furosemide administration. However, in the second course, serum creatinine rose in patients given evening cisplatin and furosemide, while it remained unchanged in those given morning cisplatin and furosemide. Moreover, the first course morning cisplatin and furosemide treatment was associated with less change in NAG excretion (less kidney toxicity) than the first course of evening cisplatin and furosemide treatment. The second course evening cisplatin and furosemide treatment was associated with an increase in NAG excretion compared to the first course of treatment, while morning cisplatin and furosemide treatment in the second course showed less change in NAG excretion compared to the first course. The clock time of cisplatin administration had an impact on the frequency of emesis. Prophylactic ondansetron, however, diminished the time-of-day dependency of cisplatin-induced vomiting. Administration of cisplatin and furosemide in the morning rather than evening appears to cause less renal damage, and this damage may be further reduced with aggressive hydration and routine administration of furosemide.

Acetylglucosaminidase↗
PubMed2001

Role of basolateral carbonic anhydrase in proximal tubular fluid and bicarbonate absorption.

Membrane-bound carbonic anhydrase (CA) is critical to renal acidification. The role of CA activity on the basolateral membrane of the proximal tubule has not been defined clearly. To investigate this issue in microperfused rabbit proximal straight tubules in vitro, we measured fluid and HCO(3)(-) absorption and cell pH before and after the extracellular CA inhibitor p-fluorobenzyl-aminobenzolamide was applied in the bath to inhibit only basolateral CA. This inhibitor was 1% as permeant as acetazolamide. Neutral dextran (2 g/dl, molecular mass 70,000) was used as a colloid to support fluid absorption because albumin could affect CO(2) diffusion and rheogenic HCO(3)(-) efflux. Indeed, dextran in the bath stimulated fluid absorption by 55% over albumin. Basolateral CA inhibition reduced fluid absorption ( approximately 30%) and markedly decreased HCO(3)(-) absorption ( approximately 60%), both reversible when CA was added to the bathing solution. In the presence of luminal CA inhibition, which reduced fluid ( approximately 16%) and HCO(3)(-) ( approximately 66%) absorption, inhibition of basolateral CA further decreased the absorption of fluid (to 74% of baseline) and HCO(3)(-) (to 22% of baseline). CA inhibition also alkalinized cell pH by approximately 0.2 units, suggesting the presence of an alkaline disequilibrium pH in the interspace, which would secondarily block HCO(3)(-) exit from the cell and thereby decrease luminal proton secretion (HCO(3)(-) absorption). These data clearly indicate that basolateral CA has an important role in mediating fluid and especially HCO(3)(-) absorption in the proximal straight tubule.

Absorption↗
PubMed2001

Effect of prolonged nitric oxide synthesis inhibition on plasma fibrinogen concentration in rats.

We examined whether nitro-L-arginine-methyl ester (L-NAME) causes a sustained elevation in plasma fibrinogen concentration in rats. Oral dosing of L-NAME (100 mg/kg per day) for 7 days significantly raised plasma fibrinogen concentration in rats. The increase in plasma fibrinogen, however, returned to control levels by the treatment for more than 7 days, in spite of progressive hypertension. Candesartan failed to reverse the transient hyperfibrinogenemia, indicating that the rise in plasma fibrinogen may occur through the mechanisms other than angiotensin II receptor activation. These data suggest that a prolonged L-NAME treatment does not cause chronic hyperfibrinogenemia in rats.

Animals↗
PubMed2001

Dosing time-dependent effect of trandolapril on the prevention of cardiac hypertrophy in rats with aortic banding.

Trandolapril was given to male Wistar rats with aortic banding at 10 AM or 10 PM for 6 weeks to examine the influence of dosing time on the development of left ventricular mass (LVM). Aortic banding increased the LVM compared with the sham-operated animals (P<0.01). Trandolapril (1 mg/kg) at 10 AM reduced LVM (1.74+/-0.04 [S.E.M.] mg/g) more than the dosing at 10 PM (1.92+/-0.04 mg/g, P<0.05), suggesting that trandolapril has a dosing time-dependent effect in the prevention of cardiac hypertrophy in rats with aortic banding.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

Shoulder stiffness: a common adverse effect of HMG-CoA reductase inhibitors in women?

Muscle symptoms are known as adverse effects of HMG-CoA reductase inhibitors but their incidence is reported to be low. We treated a case of shoulder stiffness related to such a drug, which prompted us to preliminarily survey its incidence. We found that nearly one-tenth of women (6/66) taking such drugs reported drug-related shoulder stiffness. Shoulder stiffness is a very common symptom, while drug-induced shoulder stiffness is generally unknown. Many cases involving such an adverse effect may thus be overlooked. We present 2 typical cases here.

Aged↗
PubMed2001

Chronopharmacology of oral prednisolone in rats.

The chronopharmacology of oral prednisolone (PSL) was studied in rat models. Differences in the dosing-time-dependent toxicity were evaluated at four time points (3, 9, 15 and 21 HALO) in adult male Wistar rats and confirmed in an inbred strain of Lewis rats (MHC haplotype; RTIl) at two time points (9 and 21 HALO). The total body weight and that of the immunologic-related organs were maximally reduced when PSL was repeatedly administered during the late active phase (21 HALO). This chronotoxicity was independent of plasma concentrations of PSL, adrenocorticotropic hormone, and corticosterone. Repeated administration of PSL prolonged cardiac allograft survival in a DA (RTIa) -to-Lewis combination, and there was a tendency to be more effective in the 21 HALO trial. These results suggested that single dose therapy of PSL at the selected point of the day may be less harmful, protecting against allograft rejection.

Administration, Oral↗
PubMed2001

Fluoroquinolone concentrations in plasma, urine, and bile after oral administration in rats with renal failure: useful technique for long-term bile collection.

Using a previously reported technique for bile collection, we studied the pharmacokinetics of levofloxacin (LVFX) and grepafloxacin (GPFX) in normal rats and in animals with renal failure. Continuous bile drainage was performed using normal and renal-failure Wistar rats. Oral GPFX or LVFX (40 mg/Kg) was administered. The drug concentrations in plasma, urine, and bile were determined by high-performance liquid chromatography. The area under the blood concentration-time curve (AUC) in each renal-failure rat was calculated. There were no significant differences in GPFX concentrations in the serum, urine, and bile between the renal-failure and normal rats, but the LVFX level in the urine of the renal-failure group was statistically significantly lower than in the normal group. The AUC of GPFX had an opposite correlation with the degree of renal failure, but that of LVFX was correlated.

Administration, Oral↗
PubMed2001

Dosing time-dependent pharmacological effects of anti-metabolites for rat cardiac graft.

Antimetabolites such as methotrexete and 6-mercaptopurine have been shown to have circadian variations in their toxicities. However, chronopharmacological profiles of mizoribine (Miz) that is newly synthesized as an anti-metabolic agent for immunosuppression, have not been evaluated. In this study, we examined the dosing time-dependent alterations in the pharmacokinetics and pharmacodynamics of Miz. In addition, chronopharmacology of azathiopurine (Aza) was also evaluated to compare with that of Miz. Initially, Miz (10 and 20 mg/kg) or Aza (20 mg/kg) was orally administered at 8:00 hr or 20:00 hr for 3 weeks to rats. To reveal the dosing time-dependent difference of pharmacokinetics, Miz (20 mg/kg) was orally given at 8:00 hr or 20:00 hr and blood was obtained for 12 hours. Finally, Miz (20 mg/kg) or Aza (20 mg/kg) was administered at 8:00 hr or 20:00 hr to rats with heterotopic allogeneic heart grafts. The Miz group treated at 8:00 hr and Aza group treated at 20:00 hr showed severe myelosuppression compared with their each opposite dosing time. AUC of Miz in the morning trial was twice as high as that in the evening trial. The graft survival durations of the Miz- and Aza-treated groups were significantly longer than those of the respective control groups, but were not affected by dosing time of each agent. These results suggest that the toxicity, but not efficacy of Miz is varied with the dosing time. The chronotoxicological phenomenon of Miz might be, at least in part, explained by the dosing time-dependent difference in serum drug concentrations and apparent clearance.

Animals↗
PubMed2000

Contribution of diet to the dosing time-dependent change of vitamin D3-induced hypercalcemia in rats.

We have recently reported that the degree of hypercalcemia as an adverse effect induced by a single large-dose of active vitamin D3 varied with its dosing time without alteration in therapeutic effect for secondary hyperparathyroidism in patients with chronic renal failure. The present study was conducted to elucidate an effect of intestinal calcium (Ca) absorption on the chronopharmacological profiles of vitamin D3. 1, 25-dihydroxy-cholecalciferol (D3, 2 microg/kg) or vehicle alone was orally administered at two different times (2 and 14 hours after lights on; HALO) to male Wistar rats (n= 10) kept in rooms with a 12 h light-dark cycle. Blood samples for serum Ca concentration were taken before and 3, 6, 9, and 12 hours after the administration. Urine was collected for 6 hours after dosing. An identical protocol was repeated using the same animals after 16 hours fasting by a cross-over fashion. Under free-fed condition, basal concentration of serum Ca was higher at a resting period (lights on) than during an active period (lights off). Serum Ca reached its peak at 6 hours after dosing in both timings, while the value was significantly higher in the 2 HALO trial than in the 14 HALO trial. Area under the serum Ca concentration-time curve from 0 to 12 hours (AUC0-12h) and urinary excretion of Ca for 6 hours were also significantly higher in the 2 HALO trial than in the 14 HALO trial. When fasted, basal Ca concentration was reduced compared with the free-fed condition, while the daily variation was maintained. Serum Ca concentration profiles from 3 to 12 hours after dosing were not significantly different between the 2 HALO and 14 HALO trials. The AUC0-12h of serum Ca or its urinary excretion was not different between both trials. Serum concentrations of parathyroid hormone and total protein, measured before and 6 hours after the dosing were not affected by the dosing schedule. We have concluded that intestinal Ca absorption is a major factor for the chronopharmacological phenomenon of D3-induced hypercalcemia in intact rats, while intestinal and renal involvement may be relatively small in the mechanism of the intrinsic diurnal variation of serum Ca.

Activity Cycles↗
PubMed2000

Different inhibition of enalaprilat and imidaprilat on bradykinin metabolizing enzymes.

Effects of angiotensin-converting enzyme (ACE) inhibitors, enalaprilat and imidaprilat, on bradykinin (BK) metabolizing enzymes, aminopeptidase P (APP), neutral endopeptidase (NEP) and carboxypeptidase N (CPN), were examined. APP activity in the mouse lung was inhibited by enalaprilat in a concentration-dependent manner while imidaprilat did not influence the enzyme activity. The inhibitory effects of these ACE inhibitors on the NEP activity in the mouse lung and the CPN activity in the mouse serum were negligible. These data suggested that the influence of enalaprilat on the APP activity and subsequent BK metabolism are different from those of imidaprilat.

Aminopeptidases↗
PubMed2000

The effect of a Rho kinase inhibitor Y-27632 on superoxide production, aggregation and adhesion in human polymorphonuclear leukocytes.

We investigated the involvement of p160ROCK (a Rho-associated coiled coil-forming protein kinase), one of Rho kinases on superoxide anion production (O(2)(-) production), aggregation and adhesion of human polymorphonuclear leukocytes under physiological condition, using a selective p160ROCK inhibitor, (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide (Y-27632). Y-27632 inhibited the O(2)(-) production stimulated by phorbol-12-myristate-13-acetate (PMA) in a dose-dependent manner. Stauroprorine blocked the PMA-induced O(2)(-) production while wortmannin did not. Y-27632 also inhibited the O(2)(-) production by guanosine 5'-O-(3-thiotriphosphate) (GTP(gamma)S) 100 microM. N-formyl-Met-Leu-Phe (fMLP)-induced O(2)(-) production was not influenced by Y-27632, but was inhibited by wortmannin. The enhanced O(2)(-) production by Ca-ionophore A23817 and thapsigargin was not inhibited by Y-27632. Y-27632 did not change the basal intracellular Ca(2+) concentration nor its elevation stimulated by fMLP. Polymorphonuclear leukocytes aggregation induced by PMA was dose-dependently decreased by Y-27632 while their aggregation stimulated by fMLP was enhanced by the agent. Polymorphonuclear leukocytes adhesion induced by PMA or fMLP was not influenced by Y-27632.These results suggest that p160ROCK is involved in the PMA-induced O(2)(-) production and aggregation in human polymorphonuclear leukocytes. This kinase might locate in downstream of protein kinase C in polymorphonuclear leukocytes.

Adult↗