PubMed Health⌕ Search

Biomedical subjects

J Grevel

Publications and source records attributed to J Grevel.

52 records · Page 3Linked to original sources
PubMed1987

Kinetic-effect models and their applications.

This article focuses on mathematical models that analyze the time course of drug effects in humans. Any such model, whether parametric or nonparametric, is termed a kinetic-effect model (KEM). These models serve to describe (interpolation) and to predict (extrapolation) the effect-time profile. KEMs are applicable to many problems in pharmaceutics, pharmacology, and clinical pharmacology.

Humans↗
PubMed1986

Pharmacokinetics of oral cyclosporin A (Sandimmun) in healthy subjects.

Extensive pharmacokinetic (PK) profiles after oral dosing of 300 mg cyclosporin A (CsA) were determined in whole blood by radioimmunoassay (RIA) in 14 healthy male volunteers, using two-compartment models with either first order (M1) or zero order (M0) absorption. According to zero order absorption the mean of the following PK parameters was determined: terminal half-life = 12.1 +/- 5.0 h, apparent volume of distribution at steady-state = 5.6 +/- 2.11 X kg-1, apparent clearance = 0.51 +/- 0.11 l X h-1 X kg-1. The time lag between drug ingestion and first blood level was short, 0.38 +/- 0.11 h. Drug absorption lasted for 2.8 +/- 1.6 h. The end of absorption was indicated in each individual by a sharp drop in blood levels. The observations support the assumption that CsA is absorbed in the upper part of the small intestine with a clear-cut termination (absorption window). This assumption may explain the high degree of variability in the bioavailability of CsA.

Adult↗
PubMed1986

Relationship between plasma concentrations and cardiac beta-adrenoceptor blockade--a study with oral and intravenous bopindolol.

Bopindolol, an esterified beta-adrenoceptor blocking drug, was administered to nine healthy male volunteers in oral (1 mg and 4 mg) and intravenous (1 mg) doses. Plasma concentrations determined using a radio-receptor assay (RRA) and high pressure liquid chromatography (h.p.l.c.) yielded almost identical results, indicating that hydrolysed bopindolol, the major metabolite, is responsible for the pharmacological activity of the drug. After intravenous administration the half-life for the formation of the hydrolysis product was about 0.3 h. The elimination of hydrolysed bopindolol from the plasma, determined with a one-compartment model occurred with a half-life of about 4 h. There were indications for a longer beta phase of elimination with a half-life of about 8 h, which, owing to the relative insensitivity of the method for concentrations present after more than 24 h, could not be determined exactly. The absolute bioavailability of the active compound is about 70%. Cardiac beta-adrenoceptor blockade was determined as the reduction in exercise-induced tachycardia. With oral doses the maximum effect was reached after 3 h (-29 beats min-1 after 1 mg, -40 beats min-1 after 4 mg). After intravenous administration most of the effect was present after 0.5 h but the maximum effect (-33 beats min-1) was only reached at 3 h. Bopindolol possesses a long duration of action: after 48 h 33% of the maximum effect of the oral dose of 4 mg was still present.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1986

Description of the time course of the prolactin suppressant effect of the dopamine agonist CQP201-403 by an integrated pharmacokinetic-pharmacodynamic model.

Six male volunteers (mean age 24 years) received a single oral dose of 0.025 mg CQP201-403 and placebo in a randomised double-blind crossover design. Fifteen plasma samples were collected over 48 h and were assayed by radioimmunoassay for drug substance and prolactin (PRL). Three of the samples were drawn during sleep on the first study day. The pharmacological effect (E%) of CQP201-403 was expressed as reduction in plasma PRL levels. The pharmacokinetic (PK)-pharmacodynamic (PD) model consisted of two kinetic compartments and an effect compartment linked to the central compartment. A sigmoid Emax model (Hill equation) described the relationship between the drug concentration in the effect compartment and E%. Curve-fitting of PK and PD data provided individual parameter estimates which served to generate computer-simulated PK and PD profiles after single and multiple doses in order to: investigate the in vivo concentration-effect relationship; evaluate the consequence of dosage reduction on the steady-state PD profile; and study the robustness of the response to changes in drug potency and bioavailability.

Adult↗
PubMed1986

Pharmacodynamic models of various beta blockers: an explanation for the long duration of action of bopindolol.

Models describing the time course of effects (pharmacodynamic models) of various beta blockers in man are used to explain the long duration of action of bopindolol. No matter what effect is used [reduction in exercise heart rate (RER) or isoproterenol dose ratio (DR)] human data show clearly that bopindolol is very potent compared to other beta blockers such as atenolol, metoprolol, pindolol, practolol, and propranolol. In pharmacokinetic terms, however, these drugs show no pronounced difference in their elimination half-life (ranging between 4 and 8 h). Also the site of action of the therapeutic effects (beta 1 receptors) is obviously identical for all beta blockers. Furthermore, there is no evidence to suggest that bopindolol (the prodrug) or hydrolyzed bopindolol (the active substance) is further metabolized to a slowly eliminated active metabolite. Thus, drug disposition provides no argument to explain the long-lasting effects of bopindolol as compared other beta blockers. The long duration of action of bopindolol seems to reflect an usually flat plasma concentration-response curve.

Adrenergic beta-Antagonists↗
PubMed1986

Absorption of cyclosporine A after oral dosing.

Variability in the absorption of CsA seems to contribute to the observed lack of correlation between the size of the oral dose and the trough concentration at steady state. Absorption is probably improved by thorough dispersion of the oral solution of CsA in the drink the patient prefers. Evidence for GI metabolism of CsA has only been gathered in animal experiments. The importance of bile for absorption of CsA into the portal blood is established. The bioavailability of CsA does not seem to be determined by the metabolism during the first passage through the liver. Enterohepatic recycling is likely for CsA metabolites and unlikely for unchanged CsA. A pharmacokinetic model that assumes zero-order absorption of CsA describes human data better than a model with first-order absorption. According to the zero-order model, CsA is absorbed only in the upper part of the small intestine by a mechanism that operates under saturation. Two independent findings in transplantation patients support this model. First, it was shown that small doses of CsA produce disproportionally high blood concentrations, probably due to a better bioavailability. Second, accelerated transit times in the intestine (diarrhea) lead to unexpectedly low blood concentrations, probably due to poor bioavailability. Further factors have been identified that cause low absorption of CsA: liver dysfunction and external bile drainage after liver transplantation. The influence of food on the absorption of CsA is still not determined conclusively, but it seems that giving CsA together with a standard breakfast results in higher blood concentrations. The observed increase in the bioavailability of CsA with time after transplantation could be caused by the attempt to steadily lower the dose.

Administration, Oral↗
PubMed1985

Characterization of a labile naloxone binding site (lambda site) in rat brain.

A high-affinity binding site selective for naloxone and other 4,5-epoxymorphinans (lambda site) has been previously described in rat brain. Following homogenization of freshly dissected brain, the lambda sites convert from a high-affinity to a low-affinity state. When measured with [3H]naloxone, the decay is very rapid at 20 degrees C (t 1/2 less than 2 min), whereas it is progressively slowed at lower temperatures. Proteinase inhibitors, antoxidants, and sulfhydryl group-protecting agents failed to prevent this conversion. Kinetic measurements of mu and lambda binding at varying temperatures demonstrated that the decrease in lambda binding does not coincide with the concurrent increase in mu binding and that the loss of high-affinity lambda binding at 20 degrees C can be partially restored when the temperature is lowered to 0 degrees C. The low-affinity state of the lambda site is rather stable in the Tris buffer homogenates and is susceptible to digestion by a protease. The (-)-isomer of WIN 44,441, a benzomorphan drug, binds to lambda sites with moderate affinity (dissociation constant, KD = 63 nM), whereas the (+)-isomer does not (KD greater than 10,000 nM), thus establishing stereoselectivity of the binding process. Neither the high-affinity nor the low-affinity state of lambda binding is significantly affected by the presence of 100 mM sodium chloride or 50 microM Gpp(NH)p, (a GTP analog), which is in contrast to the dramatic effect of these agents on the established opioid receptor system. Naltrexone, naloxone, nalorphine, and morphine (in this order of decreasing potency) bind to the lambda site in vivo in intact rat brain over dosage ranges that are commonly employed in pharmacological studies.

Animals↗
PubMed1983

An opiate binding site in the rat brain is highly selective for 4,5-epoxymorphinans.

In vitro binding studies have demonstrated the existence of multiple opiate receptor types. An additional site in the rat brain (termed the lambda site) is distinct from the established types by its selectivity for 4,5-epoxymorphinans (such as naloxone and morphine). While the lambda site displays a high affinity for naloxone in vivo and in vitro in fresh brain membrane homogenates, these sites rapidly convert in vitro to a state of low affinity. The regional distribution of the lambda site in the brain is strikingly different from that of the classic opiate receptor types.

Animals↗
PubMed1983

In vivo characterization of four types of opioid binding sites in rat brain.

Opioid receptor multiplicity was studied in the brain of intact rats by two experimental approaches. The first involved in vivo labeling by administration of [3H] tracers s.c. to intact rats. The second method was based on ex vivo labeling by incubating fresh brain homogenates immediately after sacrifice with suitable receptor type-specific tracers. The ex vivo labeling approach thus can measure the in vivo receptor occupancy of unlabeled ligands, provided that these ligands do not equilibrate between bound and free form over the assay period. The results suggest the presence of four separate types of opioid binding sites that resemble the mu, delta, kappa, and the newly identified lambda sites.

Analgesics, Opioid↗
PubMedDate not supplied

Population pharmacokinetics. Theory and clinical application.

Good therapeutic practice should always be based on an understanding of pharmacokinetic variability. This ensures that dosage adjustments can be made to accommodate differences in pharmacokinetics due to genetic, environmental, physiological or pathological factors. The identification of the circumstances in which these factors play a significant role depends on the conduct of pharmacokinetic studies throughout all stages of drug development. Advances in pharmacokinetic data analysis in the last 10 years have opened up a more comprehensive approach to this subject: early traditional small group studies may now be complemented by later population-based studies. This change in emphasis has been largely brought about by the development of appropriate computer software (NONMEM: Nonlinear Mixed Effects Model) and its successful application to the retrospective analysis of clinical data of a number of commonly used drugs, e.g. digoxin, phenytoin, gentamicin, procainamide, mexiletine and lignocaine (lidocaine). Success has been measured in terms of the provision of information which leads to increased efficiency in dosage adjustment, usually based on a subsequent Bayesian feedback procedure. The application of NONMEM to new drugs, however, raises a number of interesting questions, e.g. 'what experimental design strategies should be employed?' and 'can kinetic parameter distributions other than those which are unimodal and normal be identified?' An answer to the later question may be provided by an alternative non-parametric maximum likelihood (NPML) approach. Population kinetic studies generate a considerable amount of demographic and concentration-time data; the effort involved may be wasted unless sufficient attention is paid to the organisation and storage of such information. This is greatly facilitated by the creation of specially designed clinical pharmacokinetic data bases, conveniently stored on microcomputers. A move towards the adoption of population pharmacokinetics as a routine procedure during drug development should now be encouraged. A number of studies have shown that it is possible to organise existing, routine data in such a way that valuable information on pharmacokinetic variability can be obtained. It should be relatively easy to organise similar studies prospectively during drug development and, where appropriate, proceed to the establishment of control systems based on Bayesian feedback.

Demography↗
PubMedDate not supplied

Pharmacokinetics of high-dose metoclopramide in cancer patients.

The introduction of new cytotoxic drug regimens has been associated with an increase in the incidence and severity of adverse effects. This in turn has highlighted the need for more effective adjuvant therapy. The use of metoclopramide for the prophylaxis of nausea and vomiting, in high intravenous doses (50 to 1000 mg), has become established since 1981. As a lipid-soluble drug, metoclopramide has a large volume of distribution. The reported mean values after high doses range between 2.8 and 4.6 L/kg. The mean values for total body clearance and terminal half-life range from 0.31 to 0.69 L/kg/h and from 4.5 to 8.8 hours, respectively. The values of these pharmacokinetic parameters are essentially similar to those obtained after conventional doses (less than 50mg). Pharmacokinetic parameters appear unaffected by age, although no high-dose study has been conducted in children. Bodyweight is apparently correlated with clearance. An influence of renal function indices on terminal half-life and clearance has been shown, which is rather surprising since renal clearance accounts for only 20% of the total clearance. No thorough investigations exist which examine the influence of hepatic disease, cancer type and cytotoxic drug regimen on the disposition of metoclopramide. A relationship between dose (or concentration) and therapeutic or adverse effects of metoclopramide is outlined. The therapeutic benefit of high doses (up to 14 mg/kg) may be dependent on age, and on the combination of cytotoxic drugs. The advantages of high doses of metoclopramide are most apparent when the drug is used as protection against the adverse effects of high doses of cisplatin (greater than 60 mg/m2). Despite considerable pharmacokinetic variability, intravenous administration of high doses of metoclopramide is relatively safe due to its large therapeutic index.

Adult↗