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Previous investigations have suggested that beta-adrenoceptor-mediated responses were decreased in uremia. To evaluate this phenomenon further, beta 2-receptor density in mononuclear cells, plasma catecholamines and plasma parathyroid hormone were studied in two groups of normotensive patients: group U, twenty-five chronic uremic patients with end-stage renal failure; group C, twenty-eight control subjects. Each group was divided into three age and sex-matched subgroups. Beta 2-receptor density was determined using (-)125 iodocyanopindolol. Despite a significant increase in plasma epinephrine in the group of uremic patients, there was a significant increase in beta 2-adrenoceptor density. On the other hand the uremic state did not influence (-)125 iodocyanopindolol binding affinity and plasma norepinephrine. Parathyroid hormone, as expected, was significantly elevated in all the uremic subgroups. It can be concluded that the uremic state is associated with an unexpected upregulation of beta 2-receptor density in mononuclear cells. The role of an endogenous beta-blocking substance is suggested.

A highly sensitive and selective high-performance liquid chromatographic method, involving sample pre-treatment, column switching and fluorimetric detection, is described for the determination of dihydroergotamine in plasma and urine samples. The pre-chromatographic sample treatment consists of extraction by means of an Extrelut column for plasma samples, and pre-separation with enrichment steps on a Sep-Pak column for urine samples. The samples are then injected onto a pre-separation column (Aquapore), and the fraction containing dihydroergotamine are automatically diverted onto an analytical column (ODS reversed phase). An acetonitrile-ammonium carbamate gradient is used as the mobile phase. High recovery of dihydroergotamine from both plasma (87%) and urine (100%) and a detection limit as low as 100 pg/ml were achieved, with a linear response up to 5 ng/ml. The assay demonstrated a high degree of selectivity with regard to the extensive metabolism of dihydroergotamine especially to the main metabolite 8'-hydroxydihydroergotamine. The assay was successfully applied for more than one year to the determination of plasma and urine concentrations of dihydroergotamine after parenteral administration.

The pharmacokinetic properties of cyclosporine and mainly its absorption and hepatic elimination can vary in each patient in relation to the subject's individual characteristics (inter-subject variability), as well as in an individual patient during his treatment because of clinical episodes or drug interactions (intra-subject variabilities). Therefore, it appears compulsory to follow regularly cyclosporine blood levels or even to characterise each subject following a dose-test during the initiation of treatment, in order to adapt an individual posology aiming to minimise as far as possible the risk of nephrotoxicity.

Using isotope techniques, equilibrium dialysis, and incubation experiments, we characterized the binding of nicardipine to isolated plasma proteins, human serum, blood cells, and platelets. Nicardipine was mainly bound to lipoproteins, orosomucoïd, albumin, and erythrocytes in human blood. Nicardipine, pindolol, and imipramine were found to share the same site on orosomucoïd. The determinants of nicardipine binding to lipoproteins were triglycerides, phospholipids, and cholesterol ester. Nicardipine partitioned into erythrocytes, showing a constant ratio of distribution between the intra- and extracellular compartments. Nicardipine partitioned less to erythrocytes when increasing amounts of binding plasma proteins were present in the extracellular compartment. In human blood, 12 to 18% of total nicardipine was present in erythrocytes. The overall binding of nicardipine in serum varied from 98 to 99.5% and correlated with serum orosomucoïd and serum lipid concentrations.

An electron-capture gas-liquid chromatographic method was developed for measuring 3-hydroxy-guanfacine, the main metabolite of guanfacine in human plasma and urine. After extraction, the metabolite was derivatized by condensing the amidino group with hexafluoroacetylacetone and by methylating the NH and OH groups with methyl iodide. The obtained derivative possessed good bioanalytical gas chromatographic properties, using a capillary column. The O-glucuronide was measured after enzymatic hydrolysis. Unchanged guanfacine could be determined in urine together with its 3-hydroxy metabolite by this method.

Clinical pharmacology in elderly patients and its therapeutic implications come up against the difficulty to consider independently the factor age from the other factors, influencing the kinetics in this population. The knowledge of pharmacokinetics give essential informations for the development of new pharmaceutical forms, adjustment of dosage regimen and recommendations for drug intake in order to minimize the variations in bioavailability and to improve compliance. In regard of results, obtained in such studies, individualized treatment in function of age could possibly be considered. These different aspects are illustrated by recent studies on dihydroergotoxine, a geriatric drug for which improvements in therapy, based on new kinetic informations and the development of new galenical forms, can be expected. Though pharmacokinetics is a useful tool in clinical pharmacology in elderly patients, more informations of the influence of age on the physiology and biochemistry are needed to better explain the difference of response of this population to drug treatment.

The pharmacokinetics of guanfacine (GF, antihypertensive agent with central action) were studied in five patients with renal insufficiency (CCr less than 30 ml/min) after oral administration of a single 4 mg dose. GF was rapidly absorbed, the peak plasma levels (13.28 +/- 1.58 ng/ml) being reached within two hours. The plasma level decreased with a bi-exponential pattern, with a t 1/2 of the beta phase of 24.4 +/- 3.2 h. The plasma clearance was 212 +/- 40 ml/min and the renal clearance 13.9 +/- 5.2 ml/min. The comparison of these results with those observed in hypertensive patients with a normal renal function demonstrates a slower elimination (t 1/2 beta in the reference group of 16.7 h) and a decrease of the total and renal clearances (445 +/- 29 ml/min and 144 +/- 6 ml/min respectively of the reference group) which directly correlated with the decrease of the CCr. The volume of distribution, however, does not seem to be modified. In 5 other patients under chronic dialysis treated with GF for several months, the cumulation was not more improvement than in the chronic renal insufficient group. The dialysis did not appear to interfere with the elimination kinetics of the drug.

The effects of renal impairment and age on the pharmacokinetics of guanfacine were evaluated. In normal subjects, guanfacine was found to be rapidly and completely absorbed, with an absolute bioavailability close to 100% and therefore no evidence of a noticeable first-pass effect. Its kinetics were best described by a 2-compartment model, with an elimination half-life of the beta phase of 17 hours. The major route of excretion was in the urine, with urinary excretion of 80% of a given dose within 4 days. Linearity of dose and thus predictability of blood levels were observed for single doses and at steady state. Although cumulative urinary excretion and renal clearance of unchanged guanfacine were reduced in patients with renal insufficiency, total clearances, serum levels, elimination rates constants and elimination half-lives differed very slightly, or at most by a factor of 1.5 to 2 between patients with normal and severely impaired renal function. Age-related decreases in urinary excretion and renal clearance of guanfacine were observed in 6 elderly patients and were accompanied by an increased proportion of metabolites to parent drug, confirming the significant nonrenal clearance of the drug. Based on pharmacokinetic studies in these target groups and on the dual renal and nonrenal clearance of guanfacine, the drug may, most probably, be administered to elderly patients and patients with renal insufficiency without dosage adjustment.

An electron-capture GLC method was developed for measuring pindolol in human plasma and urine. The unchanged drug was extracted with benzene from alkalinized plasma or urine using propranolol as the internal standard. Both compounds subsequently were back-extracted into 0.1 M HCl and then into benzene. After evaporation of the organic phase, the compounds were derivatized with trifluoroacetylimidazole to form the trifluoroacetyl ester of pindolol and propranolol. These derivatives then were analyzed by electron-capture GLC. The method allowed the measurement of concentrations as low as 1 ng of pindolol/ml of plasma and was applied successfully to determinations of plasma levels in humans after oral administraton of a single 10-mg dose of pindolol.

The effects of nicardipine, 20 mg, three times daily, nicardipine slow release, 30 mg, twice daily and a placebo on brachial and carotid arteries diameters and flows have been investigated by the pulsed Doppler technique during a single blind and cross-over study performed in six healthy volunteers. Simultaneously, nicardipine plasma levels and relative bioavailability were determined. Nicardipine significantly increased brachial and carotid arteries diameters (by 16 and 10% respectively) and flows (by 60 and 35% respectively). These effects peaked after 4 h and lasted no longer than 6 h. Forearm vascular resistance was significantly decreased. Hence nicardipine dilated both large and small arteries. Nicardipine slow release elicited the same effects on brachial and carotid arteries diameters and flows as nicardipine. These effects peaked at 6 h and lasted up to 10 h. Although the profiles of the pharmacodynamic effects and of the kinetics of nicardipine were almost parallel in each individual after administration of both nicardipine formulations, there was no correlation between the nicardipine plasma relative bioavailability and its effects on brachial and carotid arteries blood flows when considering all subjects together.

Nine male minipigs Pitman Moore have been studied from weaning (To) and during 6 months and the following constituents have been measured: albumin, amylase, bilirubin, calcium, CK, cholesterol, creatinine, copper, iron, GGT, glucose, LDH, magnesium, PAL, phospholipids, potassium, proteins, sodium, ALT, ASP, triglycerides, urea, zinc. These animals were fed a standardized diet. At 6 months of age their weight increased progressively to 12 kg. Several factors of variation have been studied; time of blood sampling age of animals. We obtained the following results: values of bilirubin, CK and TGO were always lower at 8 a.m. than 12 a.m. and 6 p.m. The effects of age were variable. They are no variation in the values of only 4 parameters (calcium, sodium, potassium and triglycerides), while the others constituents were increased or decreased. Reference values for 21 blood parameters in Pitman Moore minipigs are described.

Endocrine cells possess voltage-sensitive Ca2+ channels involved in the modulation of hormonal secretion. Using the dihydropyridine, (+)-PN 200-110, we have investigated the binding characteristics of this ligand to pituitary membrane Ca2+ channels from normal rat, normal and adenomatous human pituitaries. [3H]PN 200-110 binds specifically to rat pituitary membranes to one class of sites (Kd = 0.41 +/- 0.10 mM; Bmax = 39 +/- 1.3 fmol/mg protein). At 37 degrees C, equilibrium is reached in 45 min and half-life of the binding is 13 min. No significant changes were observed for either the Kd or Bmax values between normal rat and human pituitaries or between the different types of adenomas (GH- and PRL-secreting and non-secreting). As the secretory activity of the pituitary adenomas, involving Ca2+ mobilization, varies from one adenoma to another, our results could indicate that, if there is a modified regulation of Ca2+ entry in the adenomas, it may not be related to a varying number of calcium channels, at least the channels labeled by the dihydropyridine (+)-PN 200-110.