Arterial structural changes and pressor responsiveness to noradrenaline.
Explore the source record for details and available documents.
Adult↗
Biomedical subjects
E Strocchi
Publications and source records attributed to E Strocchi.
Pharmacokinetics of a controlled release preparation of naproxen.
The pharmacokinetics of a controlled release preparation of naproxen (750 mg) was compared with that of standard release naproxen, in 12 healthy volunteers. The plasma levels of naproxen and urinary recoveries of naproxen and metabolites were determined both after single doses and chronic administration. The experimental data show that the bioavailability of the controlled release preparation is equal to that of standard release naproxen; however, the controlled release preparation allows more constant plasma levels of naproxen and, when administered once a day for prolonged periods, is capable of maintaining effective concentrations for most of the dosing period.
Adult↗
[Significance of the degree of oxidative hepatic metabolism in conditioning the pharmacokinetics and the pharmacodynamics of propafenone].
The aim of this study was to evaluate plasma concentrations of propafenone (P) and 5-hydroxy-propafenone (5-OH-P) at steady state in 36 patients with ventricular premature beats, Lown class greater than or equal to 2, submitted to antiarrhythmic treatment with propafenone either in acute administration (AA) (300-450 mg) or in chronic administration (CA) (150-300 mg t.i.d. for 14-21 days followed by a wash out), and to define the relationship existing between metabolic oxidative capacity and P and 5-OH-P pharmacokinetics and pharmacodynamics. Antiarrhythmic treatment resulted efficacious in 31/36 cases (86%) during AA and in 28/36 cases (78%) during CA. At steady state a wide interindividual variability was observed in plasma concentrations of P (mean = 835 +/- 619 ng/ml, coefficient of variation = 74%), in plasma concentrations of 5-OH-P (mean = 142 +/- 93 ng/ml, coefficient of variation = 65%) and of their ratio (mean = 6.51 +/- 8.53, coefficient of variation = 131%), without significant differences between responders and nonresponders. In a subgroup of 14 subjects, characterized as extensive oxidizers of dbrisoquine, a significant correlation (r = 0.97, p less than 0.001) was observed between the ratio of P and 5-OH-P plasma concentrations at steady state and oxidative metabolic capacity (expressed as debrisoquine/4-hydroxy-debrisoquine ratio). Oxidative metabolic capacity was also correlated with P half life (r = 0.82, p less than 0.002 in AA and in CA) and with the ratio of P and 5-OH-P area under curve (r = 0.91, p less than 0.001 in AA and r = 0.90) changes at the electrocardiogram (mean values = + 20% for QRS, +26% for PR). In conclusion, oxidative metabolic pathway is a crucial point in propafenone metabolization; indeed the extent of metabolic oxidative capacity, evaluable by analysis of debrisoquine oxidation, is responsible for a wide interindividual variability of P and 5-OH-P plasma concentrations, present even in a population of debrisoquine extensive oxidizers and, moreover, influences the extent of electrocardiographic changes of PR and QRS intervals, which are related to 5-OH-P plasma levels, but not to P plasma levels.
Adult↗
ACE inhibition and pressor responsiveness to norepinephrine in hypertensive patients.
The pressor response to norepinephrine (NE) was assessed in normal renin essential hypertensive patients before and after they were randomly assigned to receive in parallel groups of treatment a single dose of an angiotensin converting enzyme (ACE) inhibitor (captopril or lisinopril) or a prolonged therapy with lisinopril (30-45 days) or with hydrochlorothiazide (9 days). Blood pressure was significantly reduced by all treatments. The pressor response to NE was unchanged after the single administration of the ACE inhibitors, while it was blunted after chronic administration of lisinopril and after the diuretic. On the basis of these results, it is suggested that the attenuation of the sympathetically mediated vasoconstriction may represent an additional mechanism contributing to the antihypertensive effect of ACE inhibitors administered chronically.
Adult↗
Minimal effective concentration values of propafenone and 5-hydroxy-propafenone in acute and chronic therapy.
We evaluated the antiarrhythmic efficacy and the minimal effective concentrations of propafenone and its metabolite 5-hydroxy-propafenone during a) acute intravenous infusion (1.5 mg/kg in bolus followed by 45 minutes infusion), b) an acute oral single-dose test (450 mg), and c) 14-day chronic therapy (300 mg tid) followed by a washout. Oxidative metabolism was assessed by a debrisoquine oral test in every patient. Eleven patients with stable ventricular premature beats (VPBs) greater than or equal to 300/hr and Lown class greater than or equal to 3 completed the study. The main results emphasized a certain discrepancy between the clinical effect of the acute intravenous infusion (efficacy in 5 out of 11 patients) and of the acute oral test and chronic therapy (efficacy in 11/11), with a time lag of the ECG changes during the acute intravenous infusion. The minimal effective concentrations were lower after acute oral administration compared with chronic treatment both for propafenone (200 +/- 189 ng/ml vs. 492 +/- 530 ng/ml; p less than 0.05) and for 5-hydroxy-propafenone (82 +/- 40 ng/ml vs. 149 +/- 80 ng/ml; p less than 0.02). A linear correlation was demonstrated between drug/metabolite ratios of propafenone and debrisoquine, either after acute oral (r = 0.91) or after chronic administration (r = 0.84). The pharmacokinetics of propafenone was nonlinear and showed wide interindividual variations.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗
Pharmacokinetics of heparin and low molecular weight heparins.
The main kinetic features of heparin and low molecular weight heparins (LMWHs) are reviewed. The complexities related to the study of a nonhomogeneous drug containing fractions with different molecular weight and pharmacological effects are discussed along with the possible bias due to the prevalent use of indirect measures of drug concentration. Available data show that LMWHs have longer half-lives with respect to that of heparin and higher bioavailabilities after subcutaneous administration; experimental and clinical evidences suggest that the kinetics of heparin and LMWHs can only be described taking into account the presence of an endogenous pool from which these drugs are released with different speeds and after various types of manipulations.
Animals↗
Angiotensin converting enzyme inhibitors, thiazide diuretics and magnesium balance. A preliminary study.
Serum and mononuclear cell magnesium content were determined in a cross-sectional study performed in four groups of hypertensive patients on chronic treatment with atenolol (n = 11), enalapril (n = 10), thiazide diuretics (n = 12), or enalapril + thiazides (n = 11). Our study shows that in patients treated with the thiazides alone, in spite of normal serum potassium and magnesium levels, mononuclear cell magnesium was decreased. To the extent that mononuclear Mg content mirrors the body ion stores, our results indicate that thiazides induce a Mg depletion not detectable by monitoring serum levels.
Adult↗
[Determination of oxidative phenotype in a sample population and correlation with the pharmacokinetics of propafenone].
UNLABELLED: Propafenone, like other cardioactive drugs (metoprolol, propranolol, encainide) is submitted to oxidative metabolism, evaluable by assessment of debrisoquine oxidative capacity. Two phenotypes have been described: extensive and poor oxidizers, with interethnic differences in the prevalence of poor oxidizers. Aims of this study were: 1) to assess the oxidative phenotype in a sample of the Italian population and 2) to evaluate the relationships between oxidative capacity and propafenone pharmacokinetics or pharmacodynamics. The ratio between debrisoquine (D) and 4-hydroxy-debrisoquine (4-OH-D) in the urines after D administration (10 mg) was employed to characterize oxidative phenotype in 90 subjects (42 arrhythmia patients and 48 healthy volunteers). In 10 patients, extensive oxidizers of debrisoquine, we studied propafenone (P) and 5-hydroxy-propafenone (5-OH-P) kinetics after acute oral administration (450 mg) and chronic oral treatment (300 mg tid for 2 weeks), followed by wash out. RESULTS: 1) the prevalence of poor oxidizers (D/4-OH-D ratio greater than 12.6) in our population resulted to be 6.6%, like in other studies in Caucasians; 2) propafenone kinetics was strictly related to oxidative capacity since D/4-OH-D ratio strictly correlated with the ratio of P and 5-OH-P areas under curve in acute (r = 0.91) and in chronic administration (r = 0.90) and with P half-life in acute (r = 0.82) and in chronic administration (r = 0.82); 3) QRS widening both during chronic treatment and after acute administration correlated with oxidative capacity (r = -0.78 and -0.68 with D/4-OH-D ratio respectively) and with 5-OH-P areas under curve (r = 0.84 and 0.70 respectively); it did not correlate with P areas under curve. In conclusion both kinetics and electrophysiological effects of propafenone strictly correlate with oxidative capacity, even in extensive oxidizers. Thus even a small reduction in oxidative capacity may have relevant consequences during propafenone oral treatment.
Adult↗
Interaction study of fenoldopam--digoxin in congestive heart failure.
The potential interaction between fenoldopam, a DA1 selective agonist, and digoxin has been studied in 10 patients with heart failure (NYHA Class II or III) on chronic digoxin treatment. Plasma levels and urinary recovery of the glycoside were monitored for 24 h before and after 9 days of treatment with fenoldopam 100 mg tid. Fenoldopam caused a small, non-significant decrease in the mean steady state plasma concentration and area under the plasma concentration curve of digoxin. As the clearance of digoxin was unchanged there does not appear to be an interaction between fenoldopam and digoxin at the level of the renal tubule.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
The incidence of cough during treatment with angiotensin converting enzyme inhibitors.
The incidence of cough during treatment with angiotensin converting enzyme (ACE) inhibitors was studied using retrospective analysis of outpatient records and a questionnaire; for a more precise evaluation, all reported cases of cough were reviewed according to criteria for the operational assessment of side effects, and those found unrelated were excluded. Cough during treatment with ACE inhibitors appears to be more frequent than previously recorded and substantial differences between patients treated with captopril or enalapril seem unlikely.
Angiotensin-Converting Enzyme Inhibitors↗
The role of pharmacokinetics in the clinical treatment of metastases.
Explore the source record for details and available documents.
Antineoplastic Agents↗
HPLC analysis of doxorubicin, epirubicin and fluorescent metabolites in biological fluids.
A specific, sensitive and reliable HPLC method for the determination of doxorubicin (DX), epirubicin (epiDX) and their known fluorescent metabolites [doxorubicinol (DXol), epirubicinol (epiDXol) 7-deoxy-adriamycinone (metabolite C), adriamycinone (metabolite D), 7-deoxy-13-dihydro-adriamycinone (metabolite E), 13-dihydro-adriamycinone (metabolite F), 4'-O-beta-D-glucuronyl-4'-epiDX (metabolite G) and 4'-O-beta-D-glucuronly 13-dihydro-4'-epiDX (metabolite H)] in biological fluids (human plasma, bile and urine) has been developed and tested. Plasma samples were solid-phase-extracted (C18-bonded silica cartridges). Urine and bile samples were injected directly after the addition of the internal standard and dilution with 0.3 M phosphoric acid. Complete separation of unchanged drugs and metabolites was achieved with a mobile phase consisting of 75.6% 10 mM KH2PO4 and 24.4% CH3CN (the pH of the solution was adjusted to 4.3 with 0.03 M H3PO4) at a flow rate of 1.5 ml/min. For the analyses we used a cyanopropyl chromatographic column (25 cm x 4.6 mm i.d.; particle size 5 micron) and fluorescence detection with excitation wavelength set at 470 nm and emission at 580 nm. Sensitivity was better than 0.3 ng/ml for all substances analysed. The mean absolute recovery of unchanged drugs and metabolites was between 88.3% (metabolite E) and 98.92% (metabolite G). Intra- and interassay precisions (plasma samples) were better than 10.6% and 13.0%.
Body Fluids↗
Epirubicin and doxorubicin comparative metabolism and pharmacokinetics. A cross-over study.
The pharmacokinetics and metabolism of doxorubicin (DX) and epirubicin (epiDX) were investigated in eight cancer patients who received 60 mg/m2 of both drugs independently by intravenous (i.v.) bolus at 3-week intervals according to a balanced cross-over design. Unchanged DX and epiDX plasma levels followed a triexponential decay. Half-lives (t/2) of the three decay phases were longer for DX (t/2 alpha: 4.8 vs. 3 min; t/2 beta 2.57 h vs. 1.09 h; t/2 gamma 48.4 vs. 31.2 h). According to a model-independent analysis, the different plasma disposition kinetics of the two compounds appears to be related to a higher plasma clearance (PlCl) and to a lower mean residence time (MRT) of epiDX (PlCl: 75.0 l/h, range: 35.6-133.4 l/h; MRT: 31.6 h, range: 7.0-41.5 h;) compared to DX (PlCl: 56.8 l/h, range: 24.4-119.5; MRT: 45.6 h, range: 26.0-83.1 h). No statistically significant differences could be detected for the volume of distribution at steady state (Vss) (epiDX, 31.8 l/kg; DX, 33.3 l/kg). Metabolites common to both compounds were detected in plasma: the 13-dihydro derivatives doxorubicinol (DXol) and epirubicinol (epiDXol), together with minor amounts of four aglycones (7-deoxy adriamycinone, adriamycinone, 7-deoxy 13-dihydro adriamycinone, and 13-dihydro adriamycinone). Following epiDX administration, two additional major metabolites were detected: the glucuronic acid conjugates of epiDX (4'-O-beta-D-glucuronyl-4'-epiDX) and epiDXol (4'-O-beta-D-glucuronyl 13-dihydro-4'-epiDX). This additional detoxication route appears to account for the more efficient and faster elimination of epiDX than of DX. In the urine collected in the 6 days after treatment, 12.2% of the DX and 11.9% of the epiDX dose was excreted as unchanged drug and fluorescent metabolites. A comparable renal clearance was calculated for DX (4.7 l/h, range 1.4-7.0 l/h) and epiDX (4.4 l/h, range 1.7-7.0 l/h). One patient with hepatic metastases and abnormal bilirubin serum level had percutaneous biliary drainage because of extrahepatic obstruction. The elimination of both drugs was significantly impaired in this patient; nevertheless, elimination of epiDX was still more efficient and faster than that of DX (PlCl: 35.6 vs. 24.4 l/h; MRT: 39.0 vs. 83.1 h; t/2 gamma: 47 vs. 74 h). This patient's biliary excretion accounted for 35.4% of the epiDX dose and 18.2% of the DX dose.
Chromatography, High Pressure Liquid↗
Characterization of a Na+/K+-ATPase inhibitor from human plasma: preliminary data.
The role of an endogenous sodium pump inhibitor in the pathogenesis of hypertension has been reported in several papers. Unfortunately, because of the unknown structure and lack of biochemical characterization, some discrepancies have arisen. In this study we report a method to obtain extracts from human plasma that are able to inhibit Na+/K+-ATPase in vitro. Preliminary characterization was carried out, which showed that the extracts are able to inhibit Na+/K+-ATPase, pNPPase, and [3H]ouabain binding to red blood cells. The enzyme inhibition is not due to vanadate, FFA, or bivalent cations, and it seems to be reversible, dose-dependent, and largely prevented in E1 conformation of the enzyme. These results seem to support the hypothesis that human plasma contains a sodium pump inhibitor with many characteristics of a "ouabainlike" compound.
Blood Chemical Analysis↗
Medroxyprogesterone acetate plasma pharmacokinetics after intravenous administration in rabbits.
Medroxyprogesterone acetate (MAP) plasma pharmacokinetics was followed up in a total of 30 New Zealand rabbits after i.v. administration (0.1, 0.5, and 1.0 mg/kg) of either an aqueous suspension or a homogeneous solution of the drug in dimethylsulphoxide (DMSO). A well-defined triphasic decay of MAP plasma levels was noticeable in the animals treated with DMSO solutions. A delayed concentration peak was often present when aqueous suspensions were used, so if is not feasible to fit the experiment with simple polyexponential equations. Model-independent pharmacokinetic analysis (statistical moment theory) revealed a significant dependence of plasma clearance and mean residence time on the dose administered in both conditions.
Animals↗
Ciclosporin A: correlation of blood levels with acute graft-versus-host disease after bone marrow transplantation.
Thirty patients undergoing allogeneic bone marrow transplantation (BMT) for hematologic malignancies received ciclosporin A (CS-A) as prophylaxis of graft-versus-host disease (GVHD). CS-A trough levels were determined in whole blood by radioimmunoassay (RIA); results were not used to adjust the CS-A dosage. Neither the dose of CS-A administered nor the CS-A concentration and fluctuation of blood levels during the first 15 days after BMT correlated with acute GVHD. Conversely in the 13 patients with acute GVHD, CS-A concentrations in the 10 days prior to the onset of the disease were increasingly lower with increasing severity of GVHD. Moreover, patients without GVHD had higher CS-A concentrations in a matched period of time. Upon withdrawal of CS-A treatment, 7 patients developed GVHD. There was no possibility to predict who would do so, but the analysis of CS-A disappearance profiles indicates that effective CS-A concentrations might be lower during long-term treatment than the concentrations required early after transplant. Despite these relationships, CS-A concentration is of little predictive value in the individual patient because of the considerable overlap among patients.
Acute Disease↗
The metabolic effects of enalapril.
The metabolic effects of Enalapril (EN) were compared in a cross over study with those of Propranolol (PPL). Long term treatment with the ACEI did not modify the lipid and glucose profile and increased urate excretion, while PPL increased triglycerides and decreased urate clearance.
Adult↗
Long term metabolic effects of enalapril alone or in combination with hydrochlorothiazide.
Explore the source record for details and available documents.
Adult↗