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Min Infusion (min + infusion)
Selected AbstractsShort-term cortisol infusion in the brachial artery, with and without inhibiting 11,-hydroxysteroid dehydrogenase, does not alter forearm vascular resistance in normotensive and hypertensive subjectsEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 12 2002S. H. M. Van Uum Abstract Background Vascular tone is increased in primary hypertension, and glucocorticoids affect vascular tone. Local cortisol availability is modulated by activity of 11,-hydroxysteroid dehydrogenase (11,-HSD). As this activity may be decreased in patients with primary hypertension, vascular sensitivity to cortisol may be increased in these patients. We studied the acute effect of cortisol on forearm vascular resistance (FVR) by infusing cortisol directly into the brachial artery, both with and without inhibition of 11,-HSD, in normotensive and hypertensive subjects. Design Twenty normotensive volunteers and 20 patients with primary hypertension participated in the study. After a 10-min infusion of vehicle (glucose 5%), cortisol was infused into the brachial artery in three stepwise increasing doses (3·5, 10·5 and 35 µg per 100 mL of forearm volume), each for 10 min. Next, the participants received placebo or 500 mg glycyrrhetinic acid (GA) orally, and 150 min later the same infusion schedule was repeated. Forearm vascular resistance was measured during the last 5 min of the infused vehicle and of each dose. Arterial and forearm venous plasma samples for measurement of cortisol and cortisone were taken at the end of the infusions of glucose 5% and the highest cortisol dose. Results In both normotensive and hypertensive subjects, neither the infusion of cortisol nor the administration of GA changed FVR. Also 2 h after the cortisol infusion there remained no change in FVR in both the normotensive and hypertensive groups who received placebo. Following the infusion of the highest cortisol dose, total plasma cortisone levels in the venous plasma were decreased compared with levels in the arterial plasma (36 ± 3 and 49 ± 4 nmol L,1, respectively, P < 0·05). The protein-bound venous cortisone was 37·1 ± 4·8 nmol L,1 during the vehicle compared with 23·9 ± 3·7 nmol L,1 during the cortisol infusion (P < 0·01), whereas the free cortisone level was not altered by the cortisol infusion. Conclusions In both normotensive and hypertensive subjects, high-dose cortisol infusion both with and without 11,-HSD inhibition did not change FVR either immediately or after 2 h. We could not demonstrate in vivo 11,-HSD activity in the forearm vascular tissues. When binding of cortisone to CBG is changed, e.g. during cortisol infusion, arterio-venous changes in cortisone cannot reliably be used to assess (alterations in) local 11,-HSD activity. [source] Phase I,II trial of weekly gemcitabine plus high-dose 5-fluorouracil and leucovorin in advanced pancreatic cancerJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 3 2006HER-SHYONG SHIAH Abstract Background:, Pancreatic cancer is a dismal disease. Few drugs, including gemcitabine and 5-fluorouracil (5-FU), have notable antitumor effects against advanced pancreatic cancer. The purpose of the present study was to determine the maximum tolerated dose (MTD) of 5-FU and the efficacy and toxicity profile of weekly gemcitabine plus infusional 5-FU/leucovorin in advanced pancreatic cancer. Methods:, Patients with histo-/cytologically confirmed, advanced pancreatic cancer were eligible. Treatment consisted of a 30-min infusion of gemcitabine (800 mg/m2), followed by a 24-h infusion of 5-FU and leucovorin (300 mg/m2) at day 1, day 8 and day 15 every 28 days, and was termed the GemFL24 regimen. The dose of 5-FU was escalated from 1600, 2000, to 2600 mg/m2 in the phase I study, and fixed MTD for subsequent enrolled patients. Results:, Eighteen patients were enrolled in the phase I study, and 24 in phase II. The MTD of 5-FU was 2000 mg/m2, with major dose-limiting toxicities being febrile neutropenia and delayed recovery from neutropenia. The dose intensity of gemcitabine of the 35 patients with 5-FU dosage set at MTD was 593 mg/m2 per week. In the entire series of 42 patients, myelosuppression was the main toxicity, with grade 3 neutropenia in eight patients, and grade 3/4 thrombocytopenia in six. On an intention-to-treat analysis, the overall and clinical benefit response rates were 22% and 46%, respectively; with median progression-free and overall survival of 4.1 and 6.9 months, respectively. Conclusions:, The GemFL24 regimen is a feasible and moderately active treatment with manageable toxicities for advanced pancreatic cancer, and could be a basis for further combination with other anticancer drugs. [source] Comparison of the effects of intravenously and orally administered esomeprazole on acid output in patients with symptoms of gastro-oesophageal reflux diseaseALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 9 2005D. C. METZ Summary Background :,Intravenous esomeprazole may be beneficial for patients who cannot take oral medications. Aim :,To compare intravenous esomeprazole with oral esomeprazole for effects on maximal acid output during pentagastrin stimulation in patients with gastro-oesophageal reflux disease symptoms. Methods :,In four separate open-label, randomized, two-way crossover studies, adult patients were administered esomeprazole 20 or 40 mg once daily either orally or intravenously (by 15-min infusion or 3-min injection) for 10 days and switched to the other formulation with no washout period. Basal acid output and maximal acid output were measured on days 11, 13 and 21. Results :,In the four studies (total of 183 patients), least-squares mean maximal acid output ranged from 3.0 to 4.1 mmol/h after intravenous esomeprazole 40 or 20 mg and from 2.2 to 3.3 mmol/h after oral esomeprazole 20 or 40 mg. Differences between formulations were small and not statistically significant but did not meet the prospectively defined criterion for non-inferiority of the intravenous formulation. Median basal acid output values ranged from 0.04 to 0.27 mmol/h after intravenous administration and from 0.05 to 0.25 mmol/h after oral esomeprazole. Conclusions :,Intravenous esomeprazole is an acceptable alternative to the oral formulation for treatment of up to 10 days of duration. [source] Uterine blood flow responses to ICI 182 780 in ovariectomized oestradiol-17,-treated, intact follicular and pregnant sheepTHE JOURNAL OF PHYSIOLOGY, Issue 1 2005Ronald R. Magness Oestrogen dramatically increases uterine blood flow (UBF) in ovariectomized (Ovx) ewes. Both the follicular phase and pregnancy are normal physiological states with elevated levels of circulating oestrogen. ICI 182 780 is a pure steroidal oestrogen receptor (ER) antagonist that blocks oestrogenic actions in oestrogen-responsive tissue. We hypothesized that an ER-mediated mechanism is responsible for in vivo rises in UBF in physiological states of high oestrogen. The purpose of the study was to examine the effect of an ER antagonist on exogenous and endogenous oestradiol-17, (E2,)-mediated elevations in UBF. Sheep were surgically instrumented with bilateral uterine artery blood flow transducers, and uterine and femoral artery catheters. Ovx animals (n= 8) were infused with vehicle (35% ethanol) or ICI 182 780 (0.1,3.0 ,g min,1) into one uterine artery for 10 min before and 50 min after E2, was given (1 ,g kg,1i.v. bolus) and UBF was recorded for an additional hour. Intact, cycling sheep were synchronized to the follicular phase using progesterone, prostaglandin F2,(PGF2,) and pregnant mare serum gonadotrophin (PMSG). When peri-ovulatory rises in UBF reached near peak levels, ICI 182 780 (1 or 2 ,g (ml uterine blood flow),1) was infused unilaterally (n= 4 sheep). Ewes in the last stages of pregnancy (late pregnant ewes) were also given ICI 182 780 (0.23,2.0 ,g (ml uterine blood flow),1; 60 min infusion) into one uterine artery (n= 8 sheep). In Ovx sheep, local infusion of ICI 182 780 did not alter systemic cardiovascular parameters, such as mean arterial blood pressure or heart rate; however, it maximally decreased ipsilateral, but not contralateral, UBF vasodilatory responses to exogenous E2, by ,55,60% (P < 0.01). In two models of elevated endogenous E2,, local ICI 182 780 infusion inhibited the elevated UBF seen in follicular phase and late pregnant ewes in a time-dependent manner by ,60% and 37%, respectively; ipsilateral , contralateral effects (P < 0.01). In late pregnant sheep ICI 182 780 also mildly and acutely (for 5,30 min) elevated mean arterial pressure and heart rate (P < 0.05). We conclude that exogenous E2,-induced increases in UBF in the Ovx animal and endogenous E2,-mediated elevations of UBF during the follicular phase and late pregnancy are partially mediated by ER-dependent mechanisms. [source] Effect of dose and input rate on the brain penetration of BMS-204352 following intravenous administration to ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 6 2002Rajesh Krishna Abstract BMS-204352 is a novel maxi-K channel opener that is being developed for the treatment for stroke. The current study was designed to evaluate the plasma and brain pharmacokinetics of BMS-204352 in rats, in particular, assessing the effect of dose and input rate on brain penetration of BMS-204352. Rats (3 animals/group/time point) received a single intravenous dose of BMS-204352 as 5 mg/kg bolus, 5 mg/kg 30 min infusion, 5 mg/kg 60 min infusion, and 10 mg/kg bolus dose, into the jugular vein. Terminal blood (for plasma) and brain samples were collected for up to 9 h post-dose and samples were analyzed for the concentrations of intact BMS-204352 using a validated liquid chromatographic tandem mass spectrometric method (LC/MS/MS). As dose increased from 5 to 10 mg/kg, both BMS-204352 Cmax and AUC values increased in plasma and brain, somewhat greater in proportion to the increment in dose. Whereas the peak concentrations of BMS-204352 were affected by infusion time, overall AUCs were comparable across the bolus and infusion groups. Terminal disposition (T -half ranged from 1.6 to 2.7 h) of BMS-204352 was unaltered as a function of input rate. BMS-204352 crossed the blood,brain barrier with brain-to-plasma (B/P) ratios of approximately 7,11. Brain-to-plasma ratios appeared to be independent of dose and infusions produced somewhat higher brain penetration (B/P of ca. 11) as compared to bolus (B/P of ca. 7,8) dose. The decline of BMS-204352 in the brain paralleled that of plasma independent of the input rate and dose. Copyright © 2002 John Wiley & Sons, Ltd. [source] Quantification of heparin-induced TFPI release: a maximum release at low heparin doseBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2002Michiel J. B. Kemme Aims Heparin releases tissue factor pathway inhibitor (TFPI) from the endothelium and this release may decrease after repeated high dose heparin administration. The primary aim was to investigate and quantify this phenomenon during a short low dose heparin infusion. Also, the effects of heparin on tissue plasminogen activator (t-PA) were studied. Methods Nine healthy, nonsmoking, male volunteers (range 19,23 years) received a continuous heparin infusion (2000 IU) over 40 min. The endothelial TFPI release rate was estimated from the total TFPI concentration profile using a pharmacokinetic model. Results , Mean ,±,s.d. ,total ,and ,free ,TFPI ,increased ,from ,62.9 ± 9.4/8.3 ± 2.1 ng ml,1 at baseline to 237.2 ± 40.9/111.0 ± 19.9 ng ml,1 after 40 min infusion. The relationship between heparin concentration (anti-IIa activity) and TFPI concentration followed a maximum effect model and a clockwise loop (proteresis) was observed. The TFPI release rate rapidly increased to maximum of 200 ± 45 µg min,1 after 17.5 min heparin infusion but did not increase further although heparin concentrations further doubled. In contrast to TFPI, t-PA antigen decreased from 5.6 ± 1.0 at baseline to 4.5 ± 1.0 ng ml,1 at the end of infusion (t = 40 min) (difference of 1.1 ng ml,1 (95% confidence interval; 0.9, 1.3). Conclusions Our application of concentration-effect models and pharmacokinetic principles to these haemostatic variables showed that endothelial TFPI release has a maximum that is already reached at low heparin dose, corresponding with an anti-IIa activity of 0.08 IU ml,1. The relationship between anti-IIa activity and TFPI release rate showed signs of acute tolerance (clockwise loop) indicating exhaustion of endothelial TFPI pools. These findings may be of importance for the heparin dose used in conditions such as unstable angina, in which the favourable effects of heparin have been ascribed to its ability to release TFPI. [source] Disposition of WR-1065 in the liver of tumor-bearing rats following regional vs systemic administration of amifostineBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 1 2004Micha Levi Abstract Purpose,Amifostine is a prodrug in which selectivity is largely determined by the preferential formation and uptake of its cytoprotective metabolite, WR-1065, in normal tissues as a result of differences in membrane-bound alkaline phosphatase activity. It was hypothesized that amifostine may be a good candidate for regional drug delivery to the liver because of its large hepatic extraction and total body clearance. Methods,Rat livers were implanted with Walker-256 tumors. The tumor-bearing rats received 15 min infusions of amifostine (200 mg/kg) via the portal vein or the femoral vein. WR-1065 concentrations in the blood, liver and tumor were measured at various times. Results,The WR-1065 tumor portal dosing AUC15,60 was 40% of systemic dosing, and tumor concentrations following portal dosing were one-fifth of that following systemic dosing. The portal dosing WR-1065 liver AUC15,60 was 60% higher than the values for systemic dosing. The liver/tumor concentration ratios of WR-1065 following portal dosing were up to 8-fold higher than the ratio following systemic administration. Unfortunately, systemic exposure to WR-1065 was greater following portal vs systemic amifostine. Conclusions,Amifostine may provide increased liver protection and decreased tumor protection from radio- or chemotherapy when administered by the portal vein. However, portal dosing also increases systemic exposure to WR-1065, which is associated with hypotension. Copyright © 2004 John Wiley & Sons, Ltd. [source] | ||||||||||