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Biomedical subjects

B Edgar

Publications and source records attributed to B Edgar.

At least 37 records · Page 2Linked to original sources
PubMed1990

Pharmacokinetics and hemodynamic and diuretic/natriuretic effects of felodipine administered as an extended-release tablet.

In this study the pharmacokinetics, and the hemodynamic and diuretic/natriuretic effects of three different doses of felodipine ER-10, 20, and 40 mg--were evaluated in healthy subjects. There was a linear correlation between the dose of felodipine, Cmax, and AUC24, showing that the absorption was linearly related to the dose. The diastolic blood pressure was reduced by 15-20% after the two highest doses. The maximal blood-pressure lowering effect was seen 4 hours after drug intake, and a small reduction in diastolic blood pressure was still present after 24 hours. This was, however, not statistically significant but was related to a sustained effective plasma concentration of the drug (6 nmol/l). Systolic blood pressure was not affected. The two highest doses of felodipine ER produced a significant increase in heart rate 2 and 6 hours after the dose, compared with placebo. There was also a significant decrease in forearm vascular resistance after the 20- and 40-mg doses. Both diuresis and natriuresis were significantly increased by about 100% each during the first 4 hours after the 20-mg dose. Following the 40-mg dose, diuresis and natriuresis were lower than after 20 mg and were not significantly different from placebo.

Administration, Oral↗
PubMed1990

The influence of infusion rate on the hemodynamic effects of felodipine.

The hemodynamic effects of the calcium entry blocker felodipine were studied during and after different infusion rates. Eight healthy normotensive volunteers had their individual pharmacokinetics of felodipine determined, and they subsequently entered a double-blind, randomized, crossover study. Individualized infusions of felodipine were given by a computerized infusion pump to reach plasma concentrations of 6 ng/ml (15.6 nmol/L) after 20 minutes, to be sustained for 8 hours (fast infusion) or the same plasma concentration after 8 hours (slow infusion). Control infusions with saline and vehicle were given. Blood pressure, heart rate, ECG conduction times, and baroreceptor sensitivity by the Valsalva test were measured, as well as the plasma concentrations of felodipine. The infusion system used produced the expected plasma concentration-time profiles with higher plasma concentrations after the fast infusion until 8 hours. Both slow and fast infusion increased heart rate (p less than 0.05) and produced a similar decrease in diastolic blood pressure (p less than 0.05). Slow infusion therefore reduced blood pressure more effectively. The tachycardia after the fast infusion was more pronounced during the first hour of the infusion but was indistinguishable from the slow infusion later, when plasma concentrations were still significantly different. Baroreceptor responsiveness was diminished by both felodipine treatments. There was no obvious difference in side effects caused by the two infusion regimes. The initial tachycardia after felodipine can be diminished by a slow rate of administration of the drug with a similar effect on blood pressure.

Adult↗
PubMed1990

Plasma concentration profiles and antihypertensive effect of conventional and extended-release felodipine tablets.

1. The rate and extent of felodipine absorption from an oral solution, conventional and extended-release tablets were investigated in two groups of healthy volunteers (n = 18 + 15). 2. The antihypertensive effect of felodipine conventional tablets twice daily (n = 71) and extended-release tablets once daily (n = 76) were compared in a parallel-group study in hypertensive patients. 3. As from a solution, felodipine was completely absorbed from the two solid dosage forms. The rate of absorption increased in the order extended-release tablets, conventional tablets, solution. 4. The extended-release tablet gave more sustained plasma concentrations than the conventional tablet. 5. The extended-release tablet given once daily gave similar blood pressure control to the conventional tablet given twice daily.

Adult↗
PubMed1989

Pharmacokinetics of felodipine in patients with liver disease.

Nine patients (6 males, 3 females) with biopsy-proven liver cirrhosis participated in an open, cross-over, three centre study of the effect of impaired liver function on the pharmacokinetics of felodipine. Two of the nine patients had undergone porto-caval anastomosis. Each patient was given 0.75 mg i.v. and 10 mg p.o. on separate occasions. The results of this study have been compared with published data from younger subjects and elderly hypertensive patients. The mean peak plasma concentration normalized to a dose of 10 mg (Cmax 46 nmol/l) was twice as high in the cirrhotic patients as in the healthy subjects, but the bioavailability, f, (17.0%) was comparable. Subjects with a porto-caval shunt did not have higher f than the mean for the group. The volume of distribution at steady-state, Vss, was significantly lower than in the healthy subjects. Protein binding was significantly lower in the patients with cirrhosis: 99.46% compared to 99.64% in the healthy subjects. The weight-corrected clearance was 1/3 of the value in healthy subjects. No correlation between systemic availability and oral clearance was found, so it is proposed that felodipine is metabolized both in the liver and also in the gut wall. The results suggest that at least the starting dose should be reduced in patients with severe liver disease.

Adult↗
PubMed1989

Plasma concentration-effect relationship of felodipine intravenously in patients with congestive heart failure.

The pharmacodynamics of felodipine were analyzed in patients with congestive heart failure in a randomized, double-blind, placebo-controlled study. Felodipine at a dose of 1 mg (n = 11) or placebo (n = 12) was given intravenously during a 60-min period. Hemodynamic measurements and plasma samples were obtained every 15 min during a 2-hour period. An increase in heart rate (HR, +8%, p less than 0.01) and cardiac output (CO, +36%, p less than 0.001), and a decrease in mean arterial pressure (MAP, -24%, p less than 0.001) and systemic vascular resistance (SVR, -46%, p less than 0.001), were found. Pulmonary artery, right atrial, wedge pressure, and stroke-work index did not change. Linear regression analysis showed a significant correlation between felodipine plasma levels and changes in HR (r = 0.71, p less than 0.05), MAP (r = 0.94, p less than 0.01), CO (r = 0.73, p less than 0.05), and SVR (r = 0.88, p less than 0.01). A strong hyperbolic correlation was demonstrated between individual plasma levels and changes in MAP (r = 0.97, p less than 0.001). Hysteresis analysis showed that plasma levels are directly related to the concentration at the receptor site. A clockwise hysteresis was found in HR, CO, and SVR, but not in MAP. It is concluded that changes in flow and resistance are based on a physiological adjustment, a baroreflex-mediated response to vasodilation induced by felodipine, resulting in MAPs that remain closely related to felodipine plasma levels over a wide range.

Aged↗
PubMed1989

Pharmacokinetics of felodipine after intravenous and chronic oral administration in patients with congestive heart failure.

1. In a randomized, parallel, double-blind study felodipine was administered to 11 and placebo to 12 patients with congestive heart failure. The kinetics of felodipine were studied after acute intravenous administration and after chronic oral treatment for 8 weeks. The relationship between cardiac output and pharmacokinetics was analyzed. The pharmacokinetic data were compared with data from young healthy individuals and hypertensive patients. 2. After oral therapy, significant correlations were found between cardiac output and AUC and systemic bioavailability (F). Furthermore, cardiac output before therapy was also significantly correlated with absorption characteristics. No relationship could be demonstrated between cardiac output and i.v. pharmacokinetics. A comparison of patients with heart failure and young healthy individuals revealed that the AUC was three times higher in heart failure patient, while Vss and the ratio of the AUC of the pyridine metabolite to that of felodipine were similar. Oral clearance was reduced by 50% and the terminal half-life was concomitantly increased. Pharmacokinetic data for felodipine are similar in patients with heart failure to published data from elderly hypertensive patients. 3. An increase in liver blood flow during chronic oral therapy, induced by felodipine itself, appears to explain an increase in bioavailability and thus to higher plasma drug concentrations. Thus, it is advisable to start felodipine treatment at a low dosage in patients with congestive heart failure.

Administration, Oral↗
PubMed1989

Pharmacokinetics of felodipine in patients with impaired renal function.

1. The pharmacokinetics of felodipine and its effects on blood pressure and heart rate were studied in eight male patients aged between 28 and 57 years with a glomerular filtration rate, GFR, between 8 and 68 ml min-1, following single i.v. and oral administration. 2. Clearance, Cmax, AUC, Vss and V, of felodipine were unaffected by the renal disease. The metabolite excretion (14C-labelled) was slower than in healthy subjects. Initial renal clearance of these metabolites correlated with individual GFR values. The total amount of the dose excreted in the urine was also decreased.

Administration, Oral↗
PubMed1989

Ethanol enhances the hemodynamic effects of felodipine.

The acute hemodynamic and pharmacokinetic interactions between the vasodilating/diuretic drugs ethanol and felodipine, a 1,4-dihydropyridine calcium entry blocker, were assessed in 10 patients with untreated borderline hypertension. A non-intoxicating dose of ethanol or placebo was administered in a randomized, crossover, double-blind manner followed by felodipine 5 mg. Maximum hemodynamic effects occurred at four hours. Felodipine plus ethanol decreased mean (+/- SE) supine total peripheral resistance (13 +/- 2 vs 17 +/- 2 mmHg/L/min, p = 0.05) and diastolic blood pressure (68 +/- 3 vs 75 +/- 2 mmHg, p less than 0.05) associated with increased heart rate (72 +/- 3 vs 67 +/- 2 bpm, p less than 0.05) and cardiac index (3.7 +/- 0.4 vs 3.0 +/- 0.3 L/min/m2, p less than 0.05) more than felodipine alone. Greater differences were apparent in standing blood pressure. Co-administration of ethanol decreased standing systolic (113 +/- 8 vs 126 +/- 5 mmHg, p less than 0.01) and diastolic (69 +/- 5 vs 82 +/- 3 mmHg, p less than 0.01) blood pressure to a greater degree, but heart rate was not altered (87 +/- 6 vs 84 +/- 3 bpm). Substantial four hour diuresis occurred with both treatments (807 +/- 126 vs 806 +/- 169 ml). Adverse effects were frequent but most often occurred with felodipine plus ethanol (17 vs 11) as a result of postural lightheadedness (5 vs 1) related to hypotension. Felodipine bioavailability was not influenced by ethanol. However felodipine plasma concentrations greatly exceeded the expected concentrations, possibly due to a pharmacokinetic interaction with the grapefruit juice vehicle. Ethanol can enhance felodipine hemodynamics to produce clinically relevant adverse effects.

Adult↗
PubMed1988

Dose-dependent effects of felodipine on diuresis and natriuresis in healthy subjects.

We compared the effects of various acute doses of felodipine and placebo on diuresis and natriuresis in healthy men. The subjects were given felodipine, 1 and 3 mg as an intravenous infusion, and 5, 15, and 40 mg as an oral solution on 5 separate days. On each day blood pressure and heart rate were recorded and urine was collected for analysis of volume and sodium for 24 h. Felodipine induced a dose-dependent increase in heart rate and a dose-dependent decrease in diastolic blood pressure. These effects were maximal within 30 min of drug administration. Felodipine induced a maximal increase in diuresis of about 150% compared with placebo and a maximal increase in natriuresis of about 240%. The renal effects were most pronounced during the first 4 h after dose intake. During the 8-24 h interval, diuresis and natriuresis were lower than after placebo, but when the whole 24-h period was considered, no significant differences were found between felodipine and placebo in regard to sodium and water excretion. The most pronounced effects on diuresis and natriuresis were seen after moderate doses (3 mg i.v. and 15 mg orally). The response to the highest dose (40 mg orally) was somewhat less probably due to the excessive drop in diastolic blood pressure.

Adult↗
PubMed1988

Effect of indomethacin on the pharmacokinetics and pharmacodynamics of felodipine.

1. We studied the effects of pre-treatment with oral indomethacin (25 mg four times daily for 3 days) on the pharmacokinetics, haemodynamics and diuretic properties of oral felodipine (10 mg single dose) in 12 healthy male volunteers using a placebo controlled double-blind four-way crossover protocol. 2. Felodipine with or without indomethacin pretreatment reduced standing diastolic blood pressure (P less than 0.001) at 0.5 to 3.0 h after dosing compared with placebo or indomethacin alone. Systolic blood pressures during indomethacin treatment alone were consistently higher than the other three treatment groups (P less than 0.01), presumably due to sodium and fluid retention. 3. Felodipine and felodipine plus indomethacin produced significantly greater excretion of urine and urinary sodium, but not of urinary potassium or creatinine when compared with placebo (P less than 0.01) over an 8 h period. 4. The pharmacokinetic parameters of felodipine (Cmax, tmax, t1/2 and AUC), the concentration-response curves for blood pressure lowering effects, the reflex tachycardia, diuretic properties and side-effects profile of felodipine were not significantly altered by indomethacin pretreatment in normal volunteers.

Adult↗
PubMed1988

Pharmacokinetics and blood pressure effects of felodipine in elderly hypertensive patients. A comparison with young healthy subjects.

The pharmacokinetics and antihypertensive effects of felodipine, a new dihydropyridine calcium channel blocker, were studied in elderly hypertensive patients, 67 to 79 years of age and in young healthy subjects, 20 to 34 years of age following oral administration of 5 mg twice daily to steady-state. A single intravenous dose of 3H-felodipine (0.04mg) was given together with the oral dose on the study day. Cmax (17 nmol/L), Cmin (5 nmol/L) and AUC (82 nmol/L.h) were 3 times higher in the elderly than in the young subjects. Systemic availability was about 15% in both groups. Plasma clearance (CL) was reduced from 56.1 L/h in the young to 25.4 L/h in the elderly. There was no effect of age on the volume of distribution at steady-state (Vss). Reduced hepatic blood flow and enzyme activity or increased gut wall metabolism are possible reasons for the altered pharmacokinetics in the elderly. Blood pressure was reduced in the elderly from 190/99 to 177/91 mm Hg 12 hours after 5mg felodipine during twice daily dosage. The effect on blood pressure correlated with plasma concentrations of felodipine.

Adult↗
PubMed1987

Sequences and studies of bacteriophage T4 rII mutants.

We have sequenced more than 80 mutants of the bacteriophage T4 rIIA and rIIB genes. These include deletions about whose origin we have speculated, mutations affecting the rIIB promoters, various pseudo-revertants of the rII- phenotype, including mutations that bring about the reinitiation of translation following termination, mutations that affect regulation of rIIB translation by regA, the toxic minute plaquing mutants FC237 and FC238 and their detoxifiers, and many more of the classic frameshifts from the Cambridge collection. These mutants have been sequenced using dideoxy-mediated chain termination by either Escherichia coli DNA polymerase using single-stranded DNA as a template or by avian retroviral reverse transcriptase using mRNA or DNA as the template molecule. We list the sequence changes of the mutants with pertinent historic and phenotypic data. The mutants that facilitate translation reinitiation are discussed, and we discuss a model that could account for the generation of many of the mutations.

Base Sequence↗
PubMed1987

Clinical pharmacokinetics of felodipine. A summary.

Felodipine is completely absorbed from the gastrointestinal tract. However, the amount reaching the systemic circulation is reduced to about 15% because of first-pass degradation. The bioavailability is constant within the dose interval of 5 to 40mg orally. The frequency histogram of the area under the plasma concentration-time curve (AUC) seems to be normally distributed. The disposition of felodipine is independent of the administered dose over the intravenous dose interval (1-3 mg). The plasma concentration-time curve declines in 3 distinct phases. The mean elimination half-life of felodipine is approximately 25h. Felodipine is extensively distributed to extravascular tissues. The volume of distribution of felodipine is about 10 L/kg, implying that less than 1% of the amount of drug in the body is localised in the blood. Felodipine is more than 99% bound to plasma proteins. Mean total clearance from the blood is 1 to 1.5 L/min and, therefore, felodipine is considered a high clearance drug. Felodipine is metabolised completely and no unchanged drug is eliminated in the urine. The first step in the metabolism involves oxidation to the corresponding pyridine derivative by the cytochrome P-450 system. Identified metabolites in plasma and urine are devoid of vasodilating activity. Long term treatment, and the presence of hypertension and impaired renal function do not affect the disposition of felodipine. Elderly people may have higher plasma levels than the young and middle-aged. Impaired liver function significantly decreases systemic clearance. Cimetidine and food affect felodipine kinetics, but with negligible clinical implications. Therapeutic concentrations of felodipine do not interact with highly protein-bound drugs and these drugs have no effect on the binding of felodipine to human plasma proteins in vitro. Plasma levels of digoxin and metoprolol tended to increase during felodipine treatment. There is a significant correlation between plasma concentrations of felodipine and haemodynamic effects in both healthy subjects and hypertensive patients during short term as well as during long term treatment.

Adult↗
PubMed1987

Pharmacokinetics and haemodynamic effects of felodipine as monotherapy in hypertensive patients.

The acute and steady-state pharmacokinetics and dynamics of felodipine as monotherapy have been studied in 12 hypertensive patients. Felodipine was acutely administered by a constant infusion, 1.5 mg over a 30-min period, or as a 10-mg tablet. Chronic administration was performed on a fixed dose of 10 mg b.i.d. for 28 days. The systemic availability of felodipine after the acute dose was 15%, and at steady state 12% (N.S.), with a 3-fold variation between patients. The mean plasma clearance was 0.6 L/h. The half-life measured in the 4- to 10-h interval after dose was about the same: 3.4, 3.2, and 3.3 h after the i.v. dose, the acute oral dose, and at steady state, respectively. The mean terminal half-life was 24.5 h after the oral dose at steady state. Both the intravenous and the oral doses of felodipine decreased the diastolic blood pressure for about 8 hours after dosing. The reduction in diastolic blood pressure was about 20 mmHg 1 to 2 hours after dose. Supine diastolic blood pressure was significantly reduced up to 48 h after dose at steady state. Maximum reduction of diastolic blood pressure (-22 mmHg) already occurred on the first day of treatment, while systolic blood pressure was further decreased during chronic treatment. There was a correlation between the individual maximum decrease in diastolic blood pressure after the acute oral dose with that after repeated administration (r2 = 0.70, p less than 0.01). Changes in heart rate were non-significant at steady state.

Administration, Oral↗