Dose-dependent reduction of bile secretion in cyclosporine-treated rats.
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Animals↗
Biomedical subjects
A Fujimura
Publications and source records attributed to A Fujimura.
Recovery from lymphocytopenia and prognosis after adult extracorporeal membrane oxygenation.
Extracorporeal circulation severely impairs the host immune system. Also decreases in circulatory lymphocytes correlate with greater degrees of surgical damage. In this study, the pattern of recovery from lymphocytopenia after extracorporeal membrane oxygenation was retrospectively evaluated from a prognostic viewpoint. The results showed that the circulatory lymphocyte count of survivors returned to normal levels within 5 days after their being weaned from extracorporeal membrane oxygenation, while the circulatory lymphocyte count of nonsurvivors remained at low levels. Because it is easy to measure the number of peripheral lymphocytes, the changing pattern of the circulatory lymphocytes might be a simple and reliable prognostic factor after extracorporeal membrane oxygenation.
Aged↗
Effect of fibrin glue on small and large bowel anastomoses in the rat.
Fibrin glue has been used as a hemostatic and adhesive agent for many years, but its efficacy in digestive surgery is still controversial. In this study, we evaluated the effect of fibrin glue on the healing of the small and large bowel anastomotic portions by measurement of the anastomotic bursting pressure. Further, the efficacy of fibrin glue in preventing intra-abdominal adhesion formation was assessed. Our results indicated that fibrin glue enhanced the resistance towards an elevation of intraluminal pressure in small bowel, but not in large bowel. Concomitantly, the glue did not significantly attenuate postoperative adhesion formation. A sealing action of fibrin glue might protect against bleeding and microleakage, resulting in beneficial effects on small bowel anastomosis.
Anastomosis, Surgical↗
Introduction of DNA into rat liver with a hand-held gene gun: distribution of the expressed enzyme, [32P]DNA, and Ca2+ flux.
DNA-coated Au particles were accelerated by pressurized He gas to supersonic velocities for introduction of a gene into cells. Experimental and theoretical analyses both revealed a heterogeneous distribution of the particles per shot (1 mg Au = 2.4 x 10(7) particles with 2 microg [32P] DNA = 2.5 x 10(11) moles). For introduction of genes into the liver of living rats, the best results were obtained with a newly developed hand-held gene delivery system. The beta-galactosidase gene introduced into rat liver with Au particles by He at 250 psi was expressed (1.2 microunits/microg protein) in a limited area of the liver surface (8 x 8 mm, depth 0.5 mm). When the same gene gun was used on a monolayer of cultured COS7 cells (about 5 microm thick), cells were lost in the central area of heavy bombardment. Cell death caused by influx of Ca2+ was prevented by the use of the cytosol-type culture medium.
Animals↗
Hormone-cytokine response. Pneumoperitoneum vs abdominal wall-lifting in laparoscopic cholecystectomy.
BACKGROUND: Changes in blood hormone and cytokine were investigated in patients who underwent laparoscopic cholecystectomy via insufflation (CO2 group) vs those who had abdominal wall-lifting (Air group). METHODS: Seventeen female patients with cholecystolithiasis were randomly divided into two groups. Peripheral blood samples were obtained during perioperative period, and plasma hormone levels (ACTH, cortisol) and serum cytokine levels (TNFalpha, IL-1beta, IL-6, IL-10) were measured. RESULTS: The number of circulating lymphocytes significantly decreased at 1 h after surgery in both groups, but the decrease in the CO2 group was significantly smaller than that in the Air group. There was no significant difference in hormone elevation between groups. Serum concentrations of IL-6 and IL-10 in the Air group were significantly higher than in the CO2 group. CONCLUSIONS: CO2 insufflation may reduce cytokine production in laparoscopic cholecystectomy.
Abdominal Muscles↗
Decrease in oral bioavailability of cyclosporin A by coadministration of probucol in rats.
To assess the pharmacokinetic interaction of cyclosporin A with probucol, we administered cyclosporin A (10 mg/kg body weight) to rats orally or intravenously with or without pretreatment of probucol (10 mg/animal, daily for 8 days). The whole blood cyclosporin A concentration-time curves after oral administration showed a 34% reduction in peak concentration and a 30% decrease in area under the blood concentration-time curve (AUC) by administration of probucol. No apparent change in elimination half-life or volume of the central compartment was observed with the treatment of probucol. After intravenous administration of cyclosporin A, the blood levels could be described by a two-compartment open model. No differences were observed in the AUC, elimination half-life or total clearance of cyclosporin A by the pretreatment of probucol. Calculated bioavailability following oral administration of cyclosporin A decreased by 33% with the treatment of probucol. These results suggest that probucol may not profoundly influence the disposition of cyclosporin A. Coadministration of probucol could decrease the fraction of absorbed cyclosporin A after oral administration.
Administration, Oral↗
Daily variation in an intensity of kaolin-induced writhing reaction in mice.
The daily variation in an intensity of kaolin-induced writhing reaction was examined in mice kept under conditions of light; 07:00 - 19:00 and dark; 19:00 - 07:00. The number of writhes was counted for 30 minutes after a single intraperitoneal injection of kaolin at 00:00, 02:00, 04:00, 06:00, 08:00, 10:00, 12:00, 14:00, 16:00, 18:00, 20:00 and 22:00. The number of writhes showed a daily variation with a peak at 18:00 and a trough at 06:00. The intensity of writhing reaction was significantly reduced by pretreatment with the bradykinin B1 (Des-Arg9-[Leu8]-BK) and B2 (icatibant) receptor antagonists. Significant daily variation in this parameter was still observed in the group with the B1 antagonist, but disappeared in the B2 antagonist-treated group. These results suggest that the kaolin-induced writhing reaction shows the daily variation with a peak at the end of the resting period and a trough at the end of the active period. The B2 receptor mediated stimuli appears to be involved in this phenomenon.
Analgesia↗
[Application of gene gun for local-regional cancer].
We studied the in vivo gene transfusion using a gene gun, formerly used in plants and culture cells. The hand-held type gene gun (Helios Gene Gun System) is simple and convenient for effective gene transfection in living animals. This method has some advantages in that there is no need for use of viral vector, independence on the cell cycle and local inducement of plural genes. There is a great possibility for application to local-regional cancer.
Animals↗
Surgical treatment itself induces bacterial translocation.
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Animals↗
Lack of diurnal variation in glomerular filtration rates in the elderly.
The present study was undertaken to examine the effect of age on diurnal variation in glomerular filtration rate (GFR). The GFR, as estimated by creatinine clearance (Clcr), was determined during a 24-hour period in 10 younger (mean +/- SD age 42 +/- 9 years) and 10 older (mean age 75 +/- 4 years) patients with hypertension. Significant diurnal variations in Clcr were observed in the younger patients, with a peak during the day and trough during the night. Such were not observed in the older patients, however. These results suggest that diurnal variation in GFR is affected by age. Chronopharmacologic profiles of drugs, which are mainly excreted in urine by glomerular filtration, might be altered in these patients.
Adult↗
No evidence of a direct venodilatory effect of furosemide in healthy human subjects.
The present study was undertaken to examine whether furosemide, a loop diuretic, has a direct venodilatory effect in healthy male subjects. Furosemide, or amrinone, an inotropic agent with a vasodilatory action, was infused into a dorsal hand vein that had been preconstricted by phenylephrine. The diameter of the vein was measured by a linear variable differential transformer. Venodilation was observed during the infusion of amrinone, but such a response was not detected with furosemide. These findings do not support the hypothesis that furosemide has a direct venodilatory effect in healthy human subjects.
Adult↗
Influences of bathing and hot weather on the pharmacokinetics of a new transdermal clonidine, M-5041T.
The influences of bathing and hot weather on plasma concentrations of clonidine were examined during application of a new transdermal clonidine system, M-5041T, in eight healthy volunteers. An M-5041T patch containing 6 mg of clonidine was applied on the right chest for 96 hours during winter with or without bathing (40 degrees C for 5 minutes) and also during summer without bathing. Plasma concentrations and urinary excretion of clonidine were determined for a 160-hour period after application. Plasma concentrations of clonidine in the winter trials did not differ significantly with or without bathing. Plasma drug concentration as a whole was significantly higher in the summer trial than in the winter trial, however. The maximum plasma concentration (Cmax), area under the plasma concentration-time curve (AUC), and urinary excretion (Ae) of clonidine also tended to be higher in the summer trial. These results suggest that plasma levels of clonidine are higher after application of M-5041T during hot weather. Although the period of bathing used in this study was short, the influence of bathing seems to be negligible.
Administration, Cutaneous↗
Clinical pharmacology of multiple-dose losartan, an angiotensin II receptor antagonist, in patients with essential hypertension.
The pharmacokinetic and pharmacodynamic alterations of multiple doses of losartan, an angiotensin II receptor antagonist, were examined in nine patients with essential hypertension. Participants were given placebo once daily for the first 7 days (from day -7 to day -1), and then 50 mg of losartan for the next 9 days (from day 1 to day 9). The 24-hour blood pressure was measured on days -1, 1, and 7 and blood samples for measurement of losartan and its active metabolite, E-3174, were obtained on days 1 and 7. Plasma concentrations of uric acid and plasma clearance were determined before and during treatment with losartan, and at the end of the study. Pharmacokinetic parameters after the seventh dose, including maximum plasma concentration (Cmax) and time to Cmax (tmax) of losartan and E-3174, did not differ significantly from those after the first dose. The blood pressure lowering effect of losartan, however, was significantly greater after the seventh dose than after the first dose. Plasma uric acid decreased and its plasma clearance (ClUA) increased significantly during repeated administration with losartan. These values returned to pretreatment levels after the end of treatment. These results suggest that although the pharmacokinetic profiles of losartan and E-3174 do not change during repeated administration, the blood pressure lowering effect in hypertensive patients is greater after multiple doses than after a single dose.
Adult↗
Pharmacokinetics of a new thromboxane A2 receptor antagonist, S-1452, and its effect on platelet aggregation in healthy volunteers.
To study the pharmacokinetics of a new thromboxane A2 (TXA2) receptor antagonist, S-1452, eight healthy volunteers were given placebo or S-1452 orally on four occasions in step-wise increasing doses of 10 mg, 25 mg, and 50 mg separated by 2-week intervals. Blood samples for measurement of plasma concentrations of the drug and of its inhibitory effect on platelet aggregation were obtained for 24 hours after administration. Bleeding time after administration was measured. S-1452 was rapidly absorbed, with a peak plasma concentration at 30 minutes after administration. Thereafter, the drug was rapidly eliminated (elimination half-life, 0.4-0.5 hours), and no drug was detected at 6 hours. The inhibitory effect of S-1452 on platelet aggregation, which was stimulated by the TXA2 receptor agonist U-46619, persisted more than 6 hours after drug administration. Bleeding time was slightly prolonged after a single dose of S-1452. These results suggest that although S-1452 is rapidly eliminated in plasma, its inhibitory effects on platelet aggregation persist for a longer period. Careful observations are needed to prevent potential bleeding episodes during repeated treatment with the drug.
Administration, Oral↗
Comparison of the antagonistic activity of tamsulosin and doxazosin at vascular alpha 1-adrenoceptors in humans.
alpha 1-Adrenoceptor blockers such as prazosin and doxazosin are used to treat hypertension as well as benign prostatic hyperplasia (BPH), whereas the new alpha 1-adrenoceptor blocker tamsulosin is used only for BPH and does not reduce blood pressure at the doses used to relax prostatic smooth muscle. In contrast to prazosin, tamsulosin has a higher affinity for prostatic than vascular alpha 1-adrenoceptors in vitro. The functional correlate of this observation in humans is the subject of this study. The alpha 1-adrenoceptor blockade by oral tamsulosin (0.2 mg), doxazosin (1 mg) or placebo on finger tip vascular and dorsal hand venous alpha 1-adrenoceptors stimulated by cold treatment (immersion in ice water) and the alpha 1-adrenoceptor agonist phenylephrine, was thus studied in a 3-way crossover study in eight, healthy, male adults. Finger tip vasoconstriction after cold stimulation was assessed by laser Doppler flowmetry. A linear variable differential transformer was used to assess the drug effect on phenylephrine-induced venoconstriction. All study parameters were assessed at around 2 and 3.5 h after oral intake of doxazosin and tamsulosin respectively. The drug plasma levels were not significantly different. No significant differences were found for blood pressure or heart rate in the three treatments in supine and erect position. The reduction in finger tip blood flow after cold stimulation was significantly smaller after doxazosin treatment (P < 0.01) than after tamsulosin or placebo, whereas there was no significant difference between tamsulosin and placebo treatments. The infusion rate of phenylephrine producing a half-maximum venoconstriction was significantly larger after doxazosin than after tamsulosin (P < 0.05) or placebo (P < 0.01), whereas there was again no significant difference between tamsulosin and placebo treatments. The data suggest that, at doses producing equal plasma levels after single oral doses in human subjects, the blocking activity at vascular alpha 1-adrenoceptors is lower for tamsulosin than for doxazosin.
Administration, Oral↗
Effect of alpha 1-adrenoceptor antagonists, prazosin and urapidil, on a finger skin vasoconstrictor response to cold stimulation.
OBJECTIVES: Cold stimulation causes a finger skin vasoconstrictor response, which is regulated by stimulation of alpha-adrenergic receptors and is reduced by administration of prazosin. The purpose of this study was to investigate, using a laser Doppler flowmeter, whether the decrease in the finger skin vasoconstrictor response to cold stimulation produced by administration of two different alpha 1-adrenoceptor antagonists, prazosin and urapidil, was correlated with the corresponding plasma drug concentration, and whether this method could be used to evaluate the relative potency of these alpha 1-adrenoceptor antagonists in human subjects. METHOD: In thirteen healthy male subjects (20-42 y), finger tip skin blood flow was measured during cold stimulation before and 1, 2, 3, 6, and 9 h after administration of placebo, prazosin (1 mg) or urapidil (60 mg). RESULTS: Both prazosin and urapidil significantly decreased the vasoconstrictor response to cold stimulation. The degree of the decrement in the response indicated by the reduction ratio was significantly correlated with the plasma concentration of prazosin and urapidil. The alpha 1-adrenoceptor blocking activity of prazosin estimated by the regression lines was about 130-times more potent than that of urapidil. CONCLUSION: These findings suggest that the cold stimulation response of finger skin vasoconstriction may be used to evaluate the relative alpha 1-adrenoceptor blocking potency of drugs.
Administration, Oral↗
Influence of age on venodilator effect of isoproterenol and amrinone.
OBJECTIVE: To investigate the influence of age on the venodilator effect of isoproterenol, a beta-adrenoceptor agonist, and amrinone, a selective phosphodiesterase (PDE) III inhibitor, in human subjects. METHODS: In eight young and eight elderly male subjects, the drugs were infused into a dorsal hand vein preconstricted with phenylephrine and its diameter was measured using a linear variable differential transformer. RESULTS: The maximum venodilation (Emax) induced by isoproterenol was significantly smaller and the infusion rate of isoproterenol required to induce 50% of maximum venodilation (ED50) was significantly larger in the elderly than in the young subjects [Emax: 29.8 vs 95.1%, ED50: 97.3 vs 51.6 ng.min-1]. A significant age-related change in Emax or ED50 was not observed for amrinone (Emax: 95.8 vs 100.8%, ED50: 40.1 vs 31.6 micrograms.min-1). CONCLUSION: The data show that the venodilator effect of amrinone is not influenced by age. As amrinone increases cyclic AMP by inhibition of PDE III, it is suggested that the action of cyclic AMP is not altered by age. The decreased effect of isoproterenol might be caused by reduced production of cyclic AMP in elderly subjects.
Adrenergic beta-Agonists↗
Effect of food intake on pharmacokinetics and effects of a new thromboxane A2 receptor antagonist, S-1452.
OBJECTIVE: To examine the effect of food ingestion on the pharmacokinetics of a new thromboxane A2 (TXA2) receptor antagonist, S-1452, and the inhibitory effect on platelet aggregation. METHODS: Fifty milligrams of S-1452 was given orally to eight healthy subjects with or without food. Blood samples for determinations of plasma drug concentrations and of its effects on platelet aggregation were taken for a 12-h post-drug period. RESULTS: The maximum plasma concentration of S-1452 was reduced by 47% and the time to maximum concentration was prolonged from 0.5 to 1.9 h after dosing with food. The inhibitory effect of S-1452 on platelet aggregations induced by U-46619, a TXA2 receptor agonist, and collagen persisted up to 9 h after dosing with and without food. The degrees of inhibition in the two trials did not differ significantly at any point. CONCLUSION: These results suggest that although the absorption of S-1452 is delayed and, consequently, its plasma concentration is decreased after dosing with food, the inhibitory effect on platelet aggregation is not significantly influenced after 50 mg of the drug.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗