The changing epidemiology of hepatitis A in British Columbia: using health authority follow-up data to inform policy and practice.
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Adolescent↗
Biomedical subjects
B Edgar
Publications and source records attributed to B Edgar.
Informing river management policies and programs with science.
Conventional wisdom has it that we already have enough science to address the problems causing degradation of our environment, including rivers. This is not true. However it is the case that we could be using existing knowledge better, and that we could be doing more to learn the lessons from the huge sums being spent on river restoration and management. Informing good policy and practical on-ground management with R&D outputs has proven to be is difficult, but essential. This paper reviews some of the history of water and river management in Australia and how perceptions of rivers have evolved. It discusses the challenge of enhancing the linkages between science, policy and practice in river management. It outlines the knowledge exchange, R&D and capacity building strategies of the National Rivers Consortium--a new initiative whose founding partners are LWRRDC, the MDBC, CSIRO Land and Water and the Western Australian Waters and Rivers Commission. This strategic collaboration between policy makers, river managers and scientists brings together organisations with responsibility and expertise to improve the health and management of Australian rivers. The National Rivers Consortium is making a major investment in knowledge exchange and capacity building, based on direct personal contact and learning by doing. The Consortium is establishing a program of training activities targeting river managers and policy makers, based on the best available science and high quality information products. It will support river managers as they plan and implement river restoration and protection projects. The paper concludes with a discussion of the key knowledge gaps that remain impediments to the better management of Australia's unique and diverse river landscapes.
Australia↗
The interaction effect of grapefruit juice is maximal after the first glass.
OBJECTIVE: To compare the acute effect of grapefruit juice intake on the pharmacokinetics and haemodynamic effects of felodipine ER tablets with the interaction after 14 days intake of drug with juice. METHODS: Twelve healthy male volunteers were included in this cross-over trial and randomly allocated to a daily intake of a 10-mg felodipine extended release tablet with water or grapefruit juice for 14 days. The two study periods were separated by at least 14 days. The pharmacokinetics of felodipine and dehydrofelodipine, as well as the haemodynamic effects of the drug, were studied during day 1 and 14 in each period. RESULTS: Similarly to previous single-dose studies, the treatment during the first day with grapefruit juice increased the AUC (+73%) and Cmax (+138%) of felodipine when compared with the control treatment. On day 14 a similar effect of grapefruit juice was observed, with an increased AUC24 (+57%) and Cmax (+114%) of felodipine compared with the control experiment. A significant accumulation of felodipine occurred during both the control (+37%) and grapefruit juice (+25%) period. The extent of accumulation was not significantly different in the two treatment periods. The pharmacokinetics of the metabolite dehydrofelodipine were affected to a similar extent by the juice on day 1 and day 14. The first dose of felodipine together with grapefruit juice was associated with a significant additional increase in heart rate when compared with the control therapy, whereas there was no additional effect on blood pressure when therapy included grapefruit juice. On day 14 the intake of drug with juice resulted in an additional increase in heart rate and reduction in diastolic blood pressure in comparison with the control experiment. Furthermore, the vascularly related adverse events were more frequent in the period including grapefruit juice. CONCLUSION: The interaction between grapefruit juice and felodipine appears to be already fully developed after the first glass of grapefruit juice, as the change in pharmacokinetics in comparison with the control experiment is similar on day 1 and on day 14. Concomitant intake of 10 mg felodipine ER and the juice is associated with increased haemodynamic effects in healthy subjects both after a single dose and following 14 days of concomitant intake.
Adult↗
Effects of grapefruit juice ingestion--pharmacokinetics and haemodynamics of intravenously and orally administered felodipine in healthy men.
OBJECTIVE: To examine the effect of grapefruit juice on the metabolism of felodipine following intravenous and oral administration. METHODS: The study had a randomised, four-way, crossover design in 12 healthy males. Single doses of felodipine were given as an intravenous infusion for 1 h (1.5 mg) or as an oral extended release (ER) tablet (10 mg). Grapefruit juice (150 ml) or water was ingested 15 min prior to drug intake. RESULTS: Intake of grapefruit juice did not significantly alter the intravenous pharmacokinetics of felodipine compared to control treatment, whereas after oral drug administration it did lead to an increase in the mean AUC and Cmax by 72% and 173%, respectively, and the mean absolute bioavailability was increased by 112%. The fraction of the oral felodipine dose reaching the portal system was increased from 45% to 80% when intake of drug was preceded by grapefruit juice ingestion. The pharmacokinetics of the primary metabolite, dehydrofelodipine, was affected by the intake of juice, resulting in a 46% increase in Cmax. Juice intake immediately before oral felodipine resulted in more pronounced haemodynamic effects of the drug as measured by diastolic blood pressure and heart rate. However, the haemodynamic effects of the intravenous administration were not altered by juice intake. Vascular-related adverse events were reported more frequently when oral drug administration was preceded by juice intake compared with control treatment. Taking grapefruit juice immediately prior to intravenous felodipine administration did not cause any alteration in the adverse event pattern. CONCLUSION: The main acute effect of the grapefruit juice on the plasma concentrations of felodipine is mediated by inhibition of gut wall metabolism.
Administration, Oral↗
Relationship between time of intake of grapefruit juice and its effect on pharmacokinetics and pharmacodynamics of felodipine in healthy subjects.
In this randomised, cross-over study, in nine healthy males given felodipine ER 10 mg PO 200 ml grapefruit juice was found to increase the plasma levels of felodipine even when the juice was taken 24 hours before the drug. Grapefruit juice drunk simultaneously with and 1, 4, 10 or 24 hours before the drug administration resulted in a 32-99% increase in mean Cmax values of felodipine, relative to concomitant water and felodipine intake. The effect on AUC was also significant when juice was taken up to 10 h before the drug. The effect of the interaction decreased with increasing time between juice and drug intake. All treatments produced a significant decrease in diastolic blood pressure and an increase in heart rate in comparison with morning basal values. The change in haemodynamic variables was approximately the same after all treatment combinations. Headache was reported more frequently after treatments including grapefruit juice.
Adult↗
Diversification of cell cycle controls in developing embryos.
During embryogenesis, a genetic program coordinates cell proliferation with morphogenesis and cell differentiation. Recent studies using Drosophila have shown how, as development proceeds, this program directs different cell types to acquire unique modes of cell cycle regulation. As maternal cell cycle factors are exhausted and replaced by differentially expressed zygotic factors, an increasing repertoire of gene products become potential regulators of the cycle. Cyclin B, Cdc25, and Cyclin E each act as limiting regulators in Drosophila in specific cell types at particular developmental stages. The genes encoding these and many other candidate regulators have been cloned from mice, but their roles in vivo have yet to be understood.
Animals↗
Inhibition of 17 beta-estradiol metabolism by grapefruit juice in ovariectomized women.
In an open, randomized, cross-over study the concentrations of 17 beta-estradiol and estrone in serum were measured over 192 hours in 8 ovariectomized women after a single oral dose intake of 2 mg micronized 17 beta-estradiol. The subjects were studied with and without grapefruit juice intake containing the three natural flavonoids, naringenin, quercetin and kaempherol, which are found as glycosides in citrus fruit. These flavonoids interact with the metabolism of drugs such as 17 beta-estradiol and other steroids that are extensively metabolised through the P-450NF (P-450 IIIA4) enzyme or closely related P-450 systems. After administration of grapefruit juice, peak estrone (between 2-6 hours after tablet intake) concentrations increased significantly. The AUC0-48 and AUC0-192 for estrone but not 17 beta-estradiol, resulting from a single administration of micronized 17 beta-estradiol, were significantly altered. Combined measured estrogens (i.e. 17 beta-estradiol and estrone) also increased significantly. The relationship between the AUCs for 17 beta-estradiol and estrone was not altered by juice intake indicating that a metabolic step after estrone, i.e. further A and/or D ring conversion was inhibited. This study demonstrates that grapefruit juice may alter the metabolic degradation of estrogens, and increase the bioavailable amounts of 17 beta-estradiol and its metabolite estrone, presumably by affecting the oxidative degradation of estrogens. This food interaction may be one factor behind the interindividual variability in 17 beta-estradiol, estrone and estriol serum concentrations after exogenous administration of 17 beta-estradiol to patients.
Beverages↗
Using inhibitors to study embryogenesis.
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Animals↗
Renal effects of a nonhypotensive i.v. dose of felodipine.
To evaluate the natriuretic effect of a nonhypotensive dose of felodipine, 11 healthy volunteers (age: 21-28 years) on a high-sodium diet received the drug or its vehicle in a double-blind, randomized, crossover study. Administered intravenously at a dose level of 7.5 micrograms/min for 30 minutes followed by 5 micrograms/min for 120 minutes, felodipine increased natriuresis (546 +/- 69 vs. 454 +/- 39 mumol/min, P < 0.001) and diuresis (8.9 +/- 0.6 vs. 7.5 +/- 0.5 mL/min), compared to its vehicle. Renal plasma flow tended to be augmented, but there was a significant reduction of renal vascular resistance (0.085 +/- 0.004 vs. 0.101 +/- 0.012 mm Hg/mL/min, P < 0.03). The glomerular filtration rate was slightly decreased and proximal sodium reabsorption was diminished with no measurable effect on distal function. Felodipine stimulated plasma renin activity, but produced no changes in plasma atrial natriuretic factor, cGMP, aldosterone, and atrial vasopressin levels. In conclusion, felodipine induced natriuresis and diuresis while reducing proximal tubular sodium reabsorption.
Adult↗
The acute haemodynamic and renal effects of oral felodipine and ramipril in healthy subjects.
The aim of the present investigation was to compare the acute haemodynamic and renal effects of the calcium antagonist felodipine with the ACE inhibitor ramipril and with placebo. Single oral doses of felodipine 5 and 20 mg, ramipril 2.5 and 10 mg, and placebo were given to ten healthy subjects in a double-blind cross-over study. Blood pressure, heart rate, forearm blood flow (FBF), forearm vascular resistance (FVR), renal blood flow (RBF), renal vascular resistance (RVR), glomerular filtration rate (GFR), filtration fraction (FF), diuresis, and sodium excretion were recorded for 4.75 h after administration. Felodipine 20 mg caused a significant fall in diastolic blood pressure, maximal 12% compared with placebo, while there were no significant effects of felodipine 5 mg or the two doses of ramipril. Heart rate increased significantly after both doses of felodipine, maximal 28% after the 20 mg dose. There was also a small but significant increase in heart rate of 12% after ramipril 2.5 mg. FVR fell significantly after both doses of felodipine, maximal 38% after the 20 mg dose. There were no significant changes in FVR after any of the ramipril doses. Both doses of felodipine and both doses of ramipril caused significant reductions in RVR. Maximal reduction, 33%, was found after felodipine 20 mg. There were no significant changes in GFR or FF with either drug. Felodipine caused a significant increase in natriuresis, maximal 129% while ramipril did not.
Administration, Oral↗
Quinidine interaction with nifedipine and felodipine: pharmacokinetic and pharmacodynamic evaluation.
Conflicting findings suggest that serum quinidine concentrations may be decreased or increased by nifedipine. We performed a double-blind, placebo-controlled trial of Latin-square design. Twelve healthy men received 3 days of pretreatment with nifedipine prolonged action (20 mg twice a day) or felodipine extended release (10 mg every day), another dihydropyridine calcium antagonist, followed by coadministration of quinidine (400 mg). Quinidine pharmacokinetics were not changed by either dihydropyridine. However, 3-hydroxyquinidine area under the concentration-time curve (AUC) and 3-hydroxyquinidine/quinidine AUC ratio were decreased by felodipine, consistent with reduced metabolite formation. Heart rates and adverse events were higher with felodipine, demonstrating lack of bioequivalence with nifedipine. The QTc interval did not deviate from that expected for the observed quinidine concentration, suggesting the pharmacokinetics of active quinidine metabolites were not markedly altered among treatments. Quinidine disposition did not appear to be changed sufficiently to be clinically important by sustained-release nifedipine and felodipine.
Adolescent↗
Design and pharmacokinetics of Logimax, a new extended-release combination tablet of felodipine and metoprolol.
A new, once-daily combination tablet containing felodipine and metoprolol has been developed, using extended-release techniques to obtain even plasma concentrations throughout the dosing interval. The tablet consists of a hydrophilic matrix containing felodipine in which many small membrane-coated metoprolol pellets are embedded. On contact with gastrointestinal fluids, felodipine is released at an almost constant rate by erosion of the hydrophilic matrix. The release of metoprolol also follows near zero-order kinetics, and is mainly controlled by diffusion through the membrane covering each individual metoprolol bead. Smooth plasma concentration profiles are obtained for both drugs of the combination, similar to those found with the corresponding single-drug formulations: felodipine extended-release tablets and metoprolol controlled-release tablets. The new fixed combination tablet also consistently provides even plasma concentrations of felodipine and metoprolol after administration together with food and in elderly hypertensive patients. The convenience of one tablet per day for effective antihypertensive treatment with a combination of felodipine and metoprolol should improve patient compliance with the prescribed regimen.
Adult↗
Grapefruit juice: a possible source of variability in blood concentration of cyclosporin A.
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Adult↗
Acute effects of drinking grapefruit juice on the pharmacokinetics and dynamics of felodipine--and its potential clinical relevance.
The effect of drinking grapefruit juice on the acute pharmacokinetic and haemodynamic actions of the dihydropyridine calcium antagonist felodipine given as a 5 mg plain tablet has been studied in nine, healthy, middle-aged males. Compared to water, grapefruit juice caused an increase in Cmax from mean 6 to 16 nmol.l-1, and in the AUC from 23 to 65 nmol.h.l-1. The change in AUC corresponded to an increase in the systemic availability of felodipine from 15 to 45%, assuming no change in its clearance. This change was probably caused by inhibition of the oxidation of felodipine to the inactive dehydrofelodipine by flavonoids in grapefruit juice. The interaction with grapefruit juice is believed to be a class effect for the dihydropyridines, as oxidation of the dihydropyridine ring to the corresponding pyridine derivative is a major metabolic route for all these drugs. The higher plasma concentrations of felodipine taken with grapefruit juice resulted in a greater change in blood pressure measured in the morning 3 h after dosing (-9%) than did water (0%).
Adult↗
Yohimbine pharmacokinetics and interaction with the sympathetic nervous system in normal volunteers.
The pharmacokinetics of yohimbine and its effects on sympathoadrenal function were studied in 13 young, healthy, male volunteers after an IV bolus dose of 0.25 or 0.5 mg.kg-1. Pharmacokinetic analysis showed that distribution was rapid, with a half life between 0.4 and 18 min, and the elimination half life ranged between 0.25 and 2.5 h. The volume of distribution (Vss) was 74 l, (range 26 to 127 l). Only 0.5 to 1% of unchanged yohimbine was found in the urine, indicating that the major part of the drug was eliminated by hepatic clearance. Total plasma clearance was 117 l.h-1, which exceeds the hepatic plasma flow. This means that yohimbine is a high extraction drug with considerable extra-hepatic metabolism. Fractional urine sampling revealed that 0.5-1% of unchanged yohimbine was excreted in urine in a biphasic manner. The data also suggested the existence of a slower elimination phase, with a half life of 13 h. The venous plasma concentration of noradrenaline (NA) increased 3-fold within 15 min after the yohimbine injection while plasma adrenaline (A) and neuropeptide Y-like immunoreactivity (NPY-LI) remained unchanged. The plasma concentration-effect relationship of the changes in circulating NA followed counter-clockwise hysteresis. The results show that the hyperadrenergic state elicited by therapeutic doses of the alpha 2-adrenergic autoreceptor antagonist, yohimbine, is due to an interaction with NA but not to release of A or NPY in man.
Adult↗
Plasma concentration--effect relationships for felodipine: a meta analysis.
The plasma concentration versus antihypertensive effect relationship for the calcium antagonist felodipine was investigated in 67 patients with hypertension and 21 healthy subjects by use of the Emax model. No consistent effect of felodipine on blood pressure was observed in the healthy subjects. In patients with hypertension the plasma drug concentration and blood pressure versus time curves mirrored each other, indicating a close relationship between concentration and effect. The maximum effect (Emax) model fitted the diastolic blood pressure data of most patients, but the model was less often applicable in patients with low initial diastolic blood pressure levels. The average Emax values and the plasma felodipine concentration needed to obtain 50% of Emax for the patients with hypertension were 29 mm Hg and 8 nmol/L, respectively. The Emax values increased with increasing initial diastolic blood pressure levels but were similar in patients with high and low plasma felodipine concentrations. Age had negligible influence on the antihypertensive response to felodipine when compensation was made for the plasma concentrations.
Adult↗
Inhibition of dihydropyridine metabolism in rat and human liver microsomes by flavonoids found in grapefruit juice.
The effects of naringenin, quercetin and kaempferol, flavonoids found in grapefruit as glycosides, on the metabolism of nifedipine and the enantiomers of felodipine were studied in microsomes from rat and human liver. Flavonoid concentrations of 10, 50 and 100 mumol/l were added to rat liver microsomes. The metabolism of nifedipine, (R)- and (S)-felodipine was inhibited to a similar extent, and the inhibition was dependent on the chemical structure and the concentration of flavonoid. Naringenin had lower inhibitory potency than quercetin and kaempferol. These flavonoids exhibited the same order of inhibitory potency in human liver microsomes. No inhibition of naringenin was found, however, until higher concentrations, 300 and 500 mumol/l, were added. A likely mechanism is inhibition of cytochrome P-450 IIIA4, the isoenzyme that catalyzes the oxidation of the dihydropyridine ring to form the corresponding pharmacologically inactive pyridine metabolite. This is a predominant metabolic step that determines the extent of first-pass extraction of dihydropyridines. Grapefruit juice has been shown recently to increase the p.o. bioavailability of the dihydropyridine calcium antagonists nifedipine and felodipine. The interaction may be explained by an inhibition of the first-pass metabolism by flavonoids in grapefruit juice. Furthermore, the results indicate that the rat may be used for in vivo studies of interactions between flavonoids and dihydropyridines or other drugs that are metabolized by cytochrome P-450 IIIA4.
Adult↗
Renal effects of felodipine--a review.
Felodipine is a dihydropyridine calcium antagonist which lowers total peripheral resistance and blood pressure in doses which have no effect on cardiac conduction and contractility. It increases the urinary excretion of sodium and water due to decreased renal tubular reabsorption from the glomerular ultrafiltrate. This is observed at low doses which do not affect blood pressure, renal blood flow (RBF) or glomerular filtration rate (GFR). Felodipine decreases total renal vascular resistance and causes a transient increase in RBF in patients with normal RBF. In patients with low pretreatment values, RBF is increased during chronic treatment. Felodipine does not affect normal GFR. Thus filtration fraction may decrease. In patients with severe hypertension and reduced GFR, felodipine treatment results in good blood pressure control and increased GFR. In animal models of progressive renal disease due to hyperfiltration, felodipine has no negative effect on GFR, glomerulosclerosis or survival although proteinuria may increase. In salt-sensitive rats given high salt diet, resulting in hypertension, hypoperfused kidneys and progressive renal damage, felodipine treatment results in reduced blood pressure, increased RBF and GFR, and reduced proteinuria and glomerulosclerosis. In patients with previously refractory hypertension and progressive impairment of renal function, felodipine treatment results in good blood pressure control and a reduced rate of progression. In animals, felodipine limits the extent of renal damage after ischemia and reperfusion.
Animals↗