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M Danhof

Publications and source records attributed to M Danhof.

At least 91 records · Page 5Linked to original sources
PubMed1997

The impact of arteriovenous concentration differences on pharmacodynamic parameter estimates.

In many pharmacodynamic investigations venous drug concentrations are measured and linked to effect-site concentrations by means of a traditional first-order effect-compartment model to estimate pharmacodynamic (PD) parameters. This analysis ignores the underlying physiology that arterial blood supplies both the venous sampling site and effect site. Recently, an extended effect-compartment model has been proposed that reflects physiology by postulating a first-order rate constant of equilibrium between arterial and effect-site concentrations (ke0) as well as first-order rate constant between arterial and venous concentrations (kv0). In the current paper, we evaluate the bias in PD parameter estimates if venous drug concentrations are measured and linked to effect-site concentrations by a traditional effect compartment as a function ke0, kv0, and the drug's elimination half-life (T1/2); we present an analytical solution to the differential equations characterizing the extended effect-compartment model; and we evaluate the performance of the extended effect-compartment model to estimate pharmacodynamic parameters on the basis of venous drug concentrations. Time profiles of venous drug concentrations and drug effect were simulated for a wide range of different values of the half-life of ke0 (T1/2,e0), the half-life of kv0 (T1/2,v0), and T1/2. The simulations showed that a significant bias (up to 90%) in PD parameter estimates occurred for certain values of T1/2,e0, T1/2,v0, and T1/2 if venous drug concentrations are linked to effect-site concentrations by a traditional effect-compartment model. This model misspecification is not apparent from the results of the fitting procedure. The extended effect-compartment model provided unbiased but imprecise PD parameter estimates. The extended effect-compartment model was also able to analyze instances in which the venous concentrations equilibrate slower with the arterial concentrations than the effect-site concentrations, and proteresis is observed in the concentration--effect relationship. It is concluded that if the apparent T1/2 of the drug in the time period in which the decline in pharmacological effect is most pronounced is greater than 5 times T1/2,e0 and T1/2,e0 is greater than T1/2,v0 there is no need to model the underlying arteriovenous equilibrium delay. Under these conditions a traditional first-order link between venous and effect-site concentrations will yield accurate and reliable (less than 10% bias) estimates of the PD parameters such as Emax, EC50 and N. If T1/2 is less than 5 times T1/2,e0 or if T1/2,v0 is greater than T1/2,e0, the underlying arteriovenous equilibration delay needs to be taken into account in the model to obtain unbiased estimates of the PD parameters. This applies for almost all values of T1/2.v0. Arteriovenous equilibration delay can be best taken into account by measuring arterial blood concentrations. If this is not possible, the extended effect-compartment link model can be used. However, a large number of effect measurements needs to be obtained to estimate the model parameters accurately.

Arteries↗
PubMed1997

Physiological indirect effect modeling of the antilipolytic effects of adenosine A1-receptor agonists.

The relationship between blood concentrations of the adenosine A1-receptor agonist N6-(p-sulfophenyl) adenosine (SPA) and its effect on both plasma nonesterified fatty acid (NEFA) and glycerol release was described on the basis of an integrated pharmacokinetic-pharmacodynamic model. An indirect response model rather than a hypothetical "link" model was used to account for the delayed response. For that purpose an empirical solution to the differential equation describing the physiological indirect response model is presented. The model-estimated rate constant for the output of the glycerol response was compared to the elimination rate constant after exogenous administration of glycerol. In a crossover designed study, chronically cannulated male Wistar rats were subjected to either SPA administration (120 microgram/kg for 15 min) for measurement of the effects on glycerol, or glycerol administration for determination of glycerol pharmacokinetics. Glycerol pharmacokinetics was determined in the presence of a stable level of SPA (171 +/- 6 ng/ml) to suppress endogenous glycerol levels completely. The indirect response model adequately described the relationship between SPA concentrations and plasma glycerol levels. The PD parameter estimates for EC50, EMAX, and Hill factor were 23 +/- 2 ng/ml, 74 +/- 3% (change from baseline), and 3.3 +/- 0.5, respectively. These values were not different from those obtained when analyzing the data on basis of the differential equation directly. Furthermore, the EC50 values for the reduction in glycerol or NEFA levels were identical (23 +/- 2 and 21 +/- 3 ng/ml, respectively) indicating that both PD endpoints reflect the same physiological process. The concentration-time profile after administration of glycerol could be described best on the basis of a biexponential function. The value for kout in the PK/PD model (0.19 +/- 0.03 min-1) corresponded very well to the terminal elimination rate constant determined after i.v. administration of glycerol (0.25 +/- 0.03 min-1). In conclusion, the antilipolytic effects of adenosine A1-receptor agonists can be described by the indirect suppression model. The rate constant describing the delay between concentration and glycerol effect was shown to be a true reflection of the removal of glycerol.

Adenosine↗
PubMed1997

Pharmacokinetic-pharmacodynamic modelling of the anti-lipolytic and anti-ketotic effects of the adenosine A1-receptor agonist N6-(p-sulphophenyl)adenosine in rats.

1. The purpose of this study was to develop and validate an integrated pharmacokinetic-pharmacodynamic model for the anti-lipolytic effects of the adenosine A1-receptor agonist N6-(p-sulphophenyl)adenosine (SPA). Tissue selectivity of SPA was investigated by quantification of haemodynamic and anti-lipolytic effects in individual animals. 2. After intravenous infusion of SPA to conscious normotensive Wistar rats, arterial blood samples were drawn for determination of blood SPA concentrations, plasma non-esterified fatty acid (NEFA) and beta-hydroxybutyrate levels. Blood pressure and heart rate were monitored continuously. 3. The relationship between the SPA concentrations and the NEFA lowering effect was described by the indirect suppression model. Administration of SPA at different rates and doses (60 microg kg[-1] in 5 min and 15 min, and 120 microg kg[-1] in 60 min) led to uniform pharmacodynamic parameter estimates. The averaged parameters (mean+/-s.e., n=19) were Emax: -80+/-2% (% change from baseline), EC50: 22+/-2 ng ml(-1), and Hill factor: 2.2+/-0.2. 4. In another group, given 400 microg kg(-1) SPA in 15 min, pharmacodynamic parameters for both heart rate and anti-lipolytic effect were derived within the same animal. The reduction in heart rate was directly related to blood concentration on the basis of the sigmoidal Emax model. SPA inhibited lipolysis at concentrations lower than those required for an effect on heart rate. The EC50 values (mean+/-s.e., n=6) were 131+/-31 ng ml(-1) and 20+/-3 ng ml(-1) for heart rate and NEFA lowering effect, respectively. 5. In conclusion, the relationship between blood SPA concentrations and anti-lipolytic effect was adequately described by the indirect suppression model. For SPA a 6 fold difference in potency was observed between the effects on heart rate and NEFAs, indicating some degree of tissue selectivity in vivo.

3-Hydroxybutyric Acid↗
PubMed1997

Population analysis of the non linear red blood cell partitioning and the concentration-effect relationship of draflazine following various infusion rates.

AIMS: To investigate the impact of the specific red blood cell binding on the pharmacokinetics and pharmacodynamics of the nucleoside transport inhibitor draflazine after i.v. administration at various infusion rates. It was also aimed to relate the red blood cell (RBC) occupancy of draflazine to the ex vivo measured adenosine breakdown inhibition (ABI). METHODS: Draflazine was administered to healthy volunteers as a 15-min i.v. infusion of 0.25, 0.5, 1, 1.5 and 2.5 mg immediately followed by an infusion of the same dose over 1 h. Plasma and whole blood concentrations were measured up to 120 h post dose, and were related to the ex vivo measured ABI, serving as a pharmacodynamic endpoint. The capacity-limited specific binding of draflazine to the nucleoside transporter located on the erythrocytes was evaluated by a population approach. RESULTS: The estimate of the population parameter typical value (%CV) of the binding constant Kd and the maximal specific binding capacity (Bmax) was 0.385 (3.5) ng ml-1 plasma and 158 (2.1) ng ml-1 RBC, respectively. The non-specific binding was low. The specific binding to the erythrocytes was a source of non-linearity in the pharmacokinetics of draflazine. The total plasma clearance of draflazine slightly decreased with increasing doses, whereas the total clearance in whole blood increased with increasing doses. The sigmoidal Emax equation was used to relate the plasma and whole blood concentration of draflazine to the ex vivo determined ABI. In plasma, typical values (%CV) of Emax, IC50 and Hill factor were 81.4 (1.9)%, 3.76 (9.3) ng ml-1 and 1.06 (3.4), respectively. The relationship in whole blood was much steeper with population parameter typical values (%CV) of Emax, IC50 and Hill factor of 88.2 (2.0)%, 65.7 (2.8) ng ml-1 and 4.47 (5.5), respectively. The RBC occupancy of draflazine did not coincide with the ex vivo measured ABI. The observed relationship between RBC occupancy and ABI was not directly proportional but similar for all studied infusion schemes. CONCLUSIONS: The findings of this study show that the occupancy of the nucleoside transporter by draflazine should be at least 90% in order to inhibit substantially adenosine breakdown in vivo. On the basis of these findings it is suggested that a 15 min infusion of 1 mg draflazine followed by an infusion of 1 mg h-1 could be appropriate in patients undergoing a coronary artery bypass grafting.

Adenosine↗
PubMed1997

A study of the effects of long-term use on individual sensitivity to temazepam and lorazepam in a clinical population.

AIMS: The central effects of benzodiazepines may be attenuated after chronic use by changes in pharmacokinetics, pharmacodynamics or both. This attenuation may be influenced by the dosing pattern and the characteristics of the user population. The objectives of this study were to evaluate drug sensitivity in long-term users of temazepam and lorazepam in a clinical population. METHODS: The sensitivity to benzodiazepine effects in chronic users (1-20 years) of lorazepam (n = 14) or temazepam (n = 13) was evaluated in comparison with age and sex matched controls. Drug sensitivity was evaluated by plasma concentration in relation to saccadic eye movement parameters, postural stability and visual analogue scales. RESULTS: Pharmacokinetics of lorazepam and temazepam did not differ between patients and control subjects. Chronic users of lorazepam showed clear evidence of reduced sensitivity, indicated by lack of any pharmacodynamic difference between patients and controls at baseline, when drug concentrations were similar to the peak values attained in the control subjects after administration of 1-2.5 mg of lorazepam. In addition, there was a two- to four fold reduction in the slopes of concentration-effect plots for measures of saccadic eye movements and body sway (all; P < or = 0.01). By contrast, sensitivity in chronic users of temazepam was not different from controls. The difference between the temazepam and the lorazepam group appears to be associated with a more continuous drug exposure in the latter, due to the longer half-life and a more frequent intake of lorazepam. This pattern of use may be partly related to the more anxious personality traits that were observed in the chronic users of lorazepam. CONCLUSIONS: Chronic users of lorazepam show evidence of tolerance to sedative effects in comparison with healthy controls. Tolerance does not occur in chronic users of temazepam. The difference may be related to pharmacological properties, in addition to different patterns of use, associated with psychological factors.

Adult↗
PubMed1997

Diclofenac plasma protein binding: PK-PD modelling in cardiac patients submitted to cardiopulmonary bypass.

Twenty-four surgical patients of both sexes without cardiac, hepatic, renal or endocrine dysfunctions were divided into two groups: 10 cardiac surgical patients submitted to myocardial revascularization and cardiopulmonary bypass (CPB), 3 females and 7 males aged 65 +/- 11 years, 74 +/- 16 kg body weight, 166 +/- 9 cm height and 1.80 +/- 0.21 m2 body surface area (BSA), and control, 14 surgical patients not submitted to CPB, 11 female and 3 males aged 41 +/- 14 years, 66 +/- 14 kg body weight, 159 +/- 9 cm height and 1.65 +/- 0.16 m2 BSA (mean +/- SD). Sodium diclofenac (1 mg/kg, im Voltaren 75 twice a day) was administered to patients in the Recovery Unit 48 h after surgery. Venous blood samples were collected during a period of 0-12 h and analgesia was measured by the visual analogue scale (VAS) during the same period. Plasma diclofenac levels were measured by high performance liquid chromatography. A two-compartment open model was applied to obtain the plasma decay curve and to estimate kinetic parameters. Plasma diclofenac protein binding decreased whereas free plasma diclofenac levels were increased five-fold in CPB patients. Data obtained for analgesia reported as the maximum effect (EMAX) were: 25% VAS (CPB) vs 10% VAS (control), P < 0.05, median measured by the visual analogue scale where 100% is equivalent to the highest level of pain. To correlate the effect versus plasma diclofenac levels, the EMAX sigmoid model was applied. A prolongation of the mean residence time for maximum effect (MRTEMAX) was observed without any change in lag-time in CPB in spite of the reduced analgesia reported for these patients, during the time-dose interval. In conclusion, the extent of plasma diclofenac protein binding was influenced by CPB with clinically relevant kinetic-dynamic consequences.

Adult↗
PubMed1997

Analysis of drug-receptor interactions in vivo: a new approach in pharmacokinetic-pharmacodynamic modelling.

Analysis of pharmacodynamic data using the empirical Hill equation only provides limited insights in the underlying factors that determine the shape and location of a concentration-effect curve, such as agonist affinity and efficacy. We have developed a method which allows for the estimation of agonist affinity and efficacy in vivo and yields more insight in the factors that determine pharmacodynamic variability. The method is based on the "operational model of agonism", which describes agonist concentration-effect curves in terms of the maximum system effect (Em), the slope of the transducer function (n), the agonist dissociation equilibrium constant (KA) and an efficacy parameter (tau). We applied the model to obtain estimates of apparent affinity and efficacy of a series of N6-cyclopentyladenosine (CPA) analogues for adenosine A, receptor-mediated in vivo effects on heart rate in rat [Van der Graaf et al. 1997]. In all cases, the model converged and estimates of apparent affinity (pKA) and efficacy (tau) were obtained which were highly consistent with results from in vitro radioligand-binding studies. In conclusion, we have shown that the operational model of agonism can provide meaningful measures of agonist affinity and efficacy in vivo. The model may serve as a practical guide for future development of partial adenosine A1 receptor agonists and help to elucidate the mechanisms underlying adenosine A1 receptor-mediated responses in vivo.

Adenosine↗
PubMed1997

8-Alkylamino-substituted analogs of N6-cyclopentyladenosine are partial agonists for the cardiovascular adenosine A1 receptors in vivo.

Partial adenosine A1 receptor agonists with reduced intrinsic activity at the cardiovascular system would be promising for therapeutic application (e.g., as antilipolytic agents). In the present study a series of 8-alkylamino [methyl (M)-, ethyl (E)-, propyl (P)-, butyl (B)- and cyclopentyl (CP)-] derivatives of N6-cyclopentyladenosine (CPA) were investigated in conscious normotensive rats. After intravenous administration of the compounds to rats, heart rate (HR) and mean arterial pressure were monitored continuously, and serial arterial blood samples were drawn for determination of the pharmacokinetics. The concentration-heart rate relationships of the compounds were described on the basis of an integrated pharmacokinetic-pharmacodynamic model. The blood concentration-time profiles of the compounds could be described best by a biexponential function. The derivatives of CPA had uniform pharmacokinetic properties. The larger volume of distribution at steady state of the 8-substituted analogs resulted in terminal half-lives (ranging from 17 to 24 min) which were significantly longer than for CPA (7 min). All derivatives of CPA produced less pronounced reductions in HR and MAP than CPA. The relationship between concentration and the reduction in HR was adequately described by the sigmoidal Emax model in individual rats given 8MCPA, 8ECPA and 8PCPA. 8BCPA and 8CPCPA were nearly inactive on heart rate. The in vivo EC50,u values for the reduction in HR (366 nM, 210 nM, 170 nM and 175 nM for 8MCPA, 8ECPA, 8PCPA and 8BCPA, respectively) were in the same order of magnitude as the affinities in receptor binding studies. The order of magnitude of the intrinsic activities (Emax) was CPA > 8MCPA > 8ECPA = 8PCPA > 8BCPA > 8CPCPA, which indicated partial agonism of the compounds in vivo. The in vivo parameter Emax correlated highly (r = 0.97) to the GTP shift observed in radioligand binding experiments.

Adenosine↗
PubMed1997

Mechanism-based pharmacokinetic-pharmacodynamic modeling of the effects of N6-cyclopentyladenosine analogs on heart rate in rat: estimation of in vivo operational affinity and efficacy at adenosine A1 receptors.

We have developed a pharmacokinetic-pharmacodynamic strategy based on the operational model of agonism to obtain estimates of apparent affinity and efficacy of N6-cyclopentyladenosine (CPA) analogs for the adenosine A1 receptor-mediated in vivo effect on heart rate in the rat. All analogs investigated produced a significant decrease of the heart rate after intravenous infusion. Individual concentration-effect curves were fitted to the operational model of agonism with the values of Emax and n constrained to the intrinsic activity (273 bpm) and Hill slope (1.18), respectively, obtained with the agonist that displayed the highest intrinsic activity, 5'-deoxy-CPA. In all cases, the model converged and estimates of apparent affinity and efficacy were obtained for each agonist. Affinity estimates correlated well with pKi values for the adenosine A1 receptor in rat brain homogenates. In addition, a highly significant correlation was found between the estimates of the in vivo efficacy parameter and the GTP shift (the ratio between Ki in the presence and absence of GTP). In conclusion, the operational model of agonism can provide meaningful measures of agonist affinity and efficacy at adenosine A1 receptors in vivo. The model should be of use in the development of partial adenosine A1 receptor agonists.

Adenosine↗
PubMed1997

Pharmacokinetic-pharmacodynamic characterization of the cardiovascular, hypnotic, EEG and ventilatory responses to dexmedetomidine in the rat.

This study characterizes the pharmacokinetic-pharmacodynamic (PK-PD) relationships of the cardiovascular, EEG, hypnotic and ventilatory effects of the alpha-2 adrenergic agonist dexmedetomidine in rats. Dexmedetomidine was administered by a single rapid infusion (n = 6) and by an infusion regimen of gradually increasing rate (n = 8). HR, mean arterial pressure (MAP) and EEG signals were recorded continuously, as was the time at which the rats woke up spontaneously from drug-induced sleep, a measure of hypnosis. Arterial concentrations of dexmedetomidine and blood gases were determined regularly. A sigmoidal Emax model was used to describe the HR, MAP and EEG concentration-effect relationships, with the EEG effect (activity in 0.5-3.5-Hz frequency band) linked to an effect-site model. The PK of dexmedetomidine could be described by a two-compartment model, with similar PK parameters for both infusion regimens. Plasma protein binding was 84.1[0.7]%. Because of complex cardiovascular homeostatic reflex mechanisms, HR and MAP could only be analyzed during gradually increasing infusions. The maximal decrease in HR was 35(2)%, and the maximal increase in MAP was 37(2)%. For both infusion regimens, similar PD parameters were found for the EEG and the hypnotic measure. These data suggest the absence of active metabolites or tolerance of the EEG and hypnotic effects. Judging on the basis of concentrations of dexmedetomidine (mean (S.E. M.)), HR decrease was the most sensitive response [EC50 of 0.65(0. 09) ng/ml], followed by increase in MAP [EC50 of 2.01(0.14) ng/ml], change in EEG activity [EC50 of 2.24(0.16) ng/ml] and the hypnotic measure [Cwake-up of 2.64(0.10) ng/ml]. Ventilatory effects were minor.

Adrenergic alpha-Agonists↗
PubMed1996

Hemodynamic effects and histamine release elicited by the selective adenosine A3 receptor agonist 2-Cl-IB-MECA in conscious rats.

The hemodynamic effects of the novel, selective adenosine A3 receptor agonist 2-chloro-N6-(3-iodobenzyl)adenosine-5'-N-methylcarboxamide (2-Cl-IB-MECA) were investigated in conscious rats. Intravenous administration of 200 micrograms/kg 2-Cl-IB-MECA resulted in a short-lasting hypotension, which was accompanied by a 50-100-fold increase in plasma histamine concentrations. Administration of a second dose of 2-Cl-IB-MECA did not elicit any hemodynamic effects. Also no histamine release was observed after the second dose. The observation of rapid tachyphylaxis in combination with histamine release suggests that mast cell mediator release plays a key role in the hemodynamic effects of adenosine A3 receptor agonists.

Adenosine↗
PubMed1996

A new sublingual formulation of apomorphine in the treatment of patients with Parkinson's disease.

A new formulation of a sublingual tablet with 10 mg apomorphine was examined in 13 patients with Parkinson's disease. Vitamin C (250 mg) was added sublingually to lower the salivary pH. Four patients received sublingual apomorphine and nine received sublingual apomorphine as well as vitamin C. Subcutaneous apomorphine was given to all patients. The study was designed as a randomized three-way cross-over study. Tmax, Cmax, and bioavailability (F) were determined. Clinical efficacy was assessed by hand-tapping during 30 s, walking time over 25 m, and a 4-point tremor score. The mean Tmax after subcutaneous apomorphine was 14.5 +/- 1.9 min with a mean Cmax of 19.2 +/- 3.8 ng/ml. The mean clearance of all patients was 3.8 +/- 0.6 L/min. The mean Tmax after sublingual apomorphine was 61.1 +/- 6.9 min vs. 61.7 +/- 8.2 min with vitamin C. The mean Cmax was 7.4 +/- 1.0 ng/ml (- vitamin C) vs. 4.3 +/- 1.3 ng/ml (+ vitamin C). These data resulted consequently in a not significantly different mean bioavailability, varying from 17.6% (- vitamin C) to 6.1% (+ vitamin C). The latency of onset of clinical efficacy varied between 25.0 +/- 8.5 min (- vitamin C) and 26.0 +/- 5.3 min (+ vitamin C). The duration of effect was lower (not significantly) when vitamin C was added: 88.0 +/- 12.5 min (- vitamin C) vs. 61.0 +/- 11.9 min (+ vitamin C). These data show that 10 mg apomorphine sublingually was effective in 56% of the patients. The combination with vitamin C did not significantly change the latency of onset or duration of clinical efficacy. Sublingual apomorphine should be considered as an alternative in the treatment of "off"-periods in Parkinson's disease, in particular when patients have the capacity to anticipate their off-periods.

Administration, Sublingual↗
PubMed1996

The implications of non-linear red blood cell partitioning for the pharmacokinetics and pharmacodynamics of the nucleoside transport inhibitor draflazine.

1. Draflazine, a nucleoside transport inhibitor, was administered as a 15 min i.v. infusion of 2.5 mg to eight healthy male subjects. Plasma and whole blood concentrations were measured up to 32 h post-dose, and were related to adenosine breakdown inhibition (ABI) measured ex vivo, which served as a pharmacodynamic endpoint. 2. The red blood cell/plasma distribution of draflazine was non-linear and characterized as a capacity-limited specific binding to the nucleoside transporter on the red blood cells. The binding (dissociation) constant Kd was 0.87 ng ml-1 plasma and the maximal specific binding capacity (Bmax) was 164 ng ml-1 RBC, which corresponds to about 14,000 specific binding sites per erythrocyte. Non-specific binding amounted to less than 15% of the total binding. 3. The pharmacokinetics of draflazine in blood were determined in each subject and characterized by a two-compartment pharmacokinetic model. The pharmacokinetic parameters (mean +/- s.d.) were: clearance 22.0 +/- 8.0 ml mm-1, volume of distribution at steady-state 39.8 +/- 4.7 l and terminal half-life 24.0 +/- 9.4 h. Concentrations in plasma were much lower, and could only be determined accurately in pooled plasma samples with a red blood cell binding assay. The pharmacokinetic parameters in pooled plasma were: clearance 551 ml min-1, volume of distribution at steady-state 349 l and terminal half-life 10.7 h. 4. A non-linear relationship was observed between the plasma or blood concentration of draflazine and the ABI determined ex vivo. This relationship was characterized by the sigmoidal Emax pharmacodynamic model. Based on concentrations in pooled plasma, values of the pharmacodynamic parameters were Emax 100%, IC50 10.5 ng ml-1 and Hill factor 0.9. When using whole blood concentrations, the relationship was much steeper with values (mean +/- s.d.) Emax 92.4 +/- 5.6%, IC50 76.0 +/- 15.3 ng ml-1 and Hill factor 3.5 +/- 0.9. 5. Binding to the nucleoside transporter on red blood cells is an important determinant of the pharmacokinetics of draflazine and a high degree of occupancy of the transporter by draflazine is required to inhibit adenosine breakdown ex vivo. It is suggested that red blood cell nucleoside transporter occupancy may serve as a useful pharmacodynamic endpoint in dose ranging studies with draflazine.

Adenosine↗
PubMed1996

Pharmacokinetic-haemodynamic relationships of 2-chloroadenosine at adenosine A1 and A2a receptors in vivo.

1. The purpose of the present study was to develop an experimental strategy for the quantification of the cardiovascular effects of non-selective adenosine receptor ligands at the adenosine A1 and A2a receptor in vivo. 2-Chloroadenosine (CADO) was used as a model compound. 2. Three groups of normotensive conscious rats received an short intravenous infusion of 1.4 mg kg-1 CADO during constant infusions of the A1-selective antagonist, 8-cyclopentyltheophylline (CPT; 20 micrograms min-1 kg-1), the A2a-selective antagonist, 8-(3-chlorostyryl) caffeine (CSC; 32 micrograms min-1 kg-1) or the vehicle. The heart rate (HR) and mean arterial blood pressure (MAP) were recorded continuously during the experiment and serial arterial blood samples were taken for analysis of drug concentrations. The ratio MAP/HR was also calculated, which may reflect changes in total peripheral resistance on the assumption that no changes in stroke volume occur. 3. During the infusion of CPT, CADO produced a reduction in both blood pressure and MAP/HR by activation of the A2a receptor. The concentration-effect relationships were described according to the sigmoidal Emax model, yielding potencies based on free drug concentrations (EC50,u) of 61 and 68 ng ml-1 (202 and 225 nM) for the reduction of blood pressure and MAP/HR, respectively. During the infusion of CSC, an EC50,u value of 41 ng ml-1 (136 nM) was observed for the A1 receptor-mediated reduction in heart rate. The in vivo potencies correlated with reported receptor affinities (Ki(A1) = 300 nM and Ki(A2a) = 80 nM). The maximal reductions in MAP/HR and heart rate were comparable to those of full agonists, with the Emax values of -12 +/- 1 x 10(-2) mmHg b.p.m.-1 and -205 b.p.m. respectively. 4. It is concluded that this integrated pharmacokinetic-pharmacodynamic approach can be used to obtain quantitative information on the potency and intrinsic activity of new non-selective adenosine receptor agonists at different receptor subtypes in vivo.

2-Chloroadenosine↗
PubMed1996

Population pharmacokinetics of ceftazidime in cystic fibrosis patients analyzed by using a nonparametric algorithm and optimal sampling strategy.

Postinfusion data obtained from 17 patients with cystic fibrosis participating in two clinical trials were used to develop population models for ceftazidime pharmacokinetics during continuous infusion. Determinant (D)-optimal sampling strategy (OSS) was used to evaluate the benefits of merging four maximally informative sampling times with population modeling. Full and sparse D-optimal sampling data sets were analyzed with the nonparametric expectation maximization (NPEM) algorithm and compared with the model obtained by the traditional standard two-stage approach. Individual pharmacokinetic parameter estimates were calculated by weighted nonlinear least-squares regression and by maximum a posteriori probability Bayesian estimator. Individual parameter estimates obtained with four D-optimally timed serum samples (OSS4) showed excellent correlation with parameter estimates obtained by using full data sets. The parameters of interest, clearance and volume of distribution, showed excellent agreement (R2 = 0.89 and R2 = 0.86). The ceftazidime population models were described as two-compartment kslope models, relating elimination constants to renal function. The NPEM-OSS4 model was described by the equations kel = 0.06516+ (0.00708.CLCR) and V1 = 0.1773 +/- 0.0406 liter/kg where CLCR is creatinine clearance in milliliters per minute per 1.73 m2, V1 is the volume of distribution of the central compartment, and kel is the elimination rate constant. Predictive performance evaluation for 31 patients with data which were not part of the model data sets showed that the NPEM-ALL model performed best, with significantly better precision than that of the standard two-stage model (P < 0.001). Predictions with the NPEM-OSS4 model were as precise as those with the NPEM-ALL model but slightly biased (-2.2 mg/liter; P < 0.01). D-optimal monitoring strategies coupled with population modeling results in useful and cost-effective population models and will be of advantage in clinical practice, as it allows pharmacokinetic-pharmacodynamic modeling with sparse data, thus describing the relationship between ceftazidime exposure and response in the treatment of acute exacerbations in patients with cystic fibrosis.

Adult↗
PubMed1996

Pharmacokinetic/pharmacodynamic relationship of benzodiazepines in the direct cortical stimulation model of anticonvulsant effect.

The in vivo concentration-anticonvulsant effect relationships of six benzodiazepines, midazolam, clonazepam, oxazepam, flunitrazepam, diazepam and clobazam were quantified in individual rats and correlated with the affinity to the GABAA-benzodiazepine receptor complex. Furthermore the interaction between midazolam and the benzodiazepine antagonist flumazenil was characterized. All benzodiazepines exhibited a nonlinear relationship between concentration and anticonvulsant effect without ceiling of the effect at higher concentration. The potency of most benzodiazepines was similar with values of the EC250, between 0.067 +/- 0.01 mg. l-1 for midazolam and 0.21 +/- 0.03 mg. l-1 for diazepam. The EC250,u of clobazam was 2.8 +/- 0.9 mg. l-1. These values were considerably larger than the Ki for binding at the GABAA-benzodiazepine receptor complex. No correlation was observed between EC250,u and Ki. Antagonism of the anticonvulsant effect of midazolam by flumazenil was associated with a remarkable change in the concentration-anticonvulsant effect relationship. Analysis of these data on basis of a composite model provided evidence for two separate effects of which only one is antagonized by flumazenil. The anticonvulsant effect at low midazolam concentration was characterized on basis of the sigmoid E maximal effect pharmacodynamic model. The value of the EC50,u was 0.0086 +/- 0.0013 mg. l-1 which is similar to the Ki for binding at the GABAA-benzodiazepine receptor complex. The second more pronounced anticonvulsant effect occurred at higher concentration and was described by an exponential function. The findings of this study indicate that the effect of benzodiazepines against seizures induced by cortical stimulation in vivo cannot be fully accounted for by an interaction at the GABAA-benzodiazepine receptor complex.

Animals↗
PubMed1996

Partial agonism of the nonselective adenosine receptor agonist 8-butylaminoadenosine at the A1 receptor in vivo.

The cardiovascular effects of the nonselective adenosine receptor agonist 8-butylaminoadenosine (BAA) were quantified in conscious normotensive rats. The potency and intrinsic activity for the A1 and A2a receptor were determined separately. The rats received a short intravenous infusion of 100 mg/kg BAA in combination with a continuous infusion of either the A1-selective antagonist 8-cyclopentyltheophylline (CPT) (8 micrograms/min/kg), the A2a-selective antagonist 8-(3-chlorostyryl)caffeine (CSC) (32 micrograms/min/kg) or the vehicle. Heart rate (HR) and mean arterial pressure (MAP) were recorded continuously as pharmacodynamic indices for adenosine receptor activation. The MAP/HR ratio was derived as an additional cardiovascular parameter. This ratio reflects changes in total peripheral resistance on the assumption that stroke volume remains constant. During the infusion of CSC, the potency and intrinsic activity for the A1 receptor were estimated by relating the negative chronotropic effect to BAA blood concentrations. The sigmoidal curve yielded a potency value based on unbound concentrations (EC50,u) of 1.9 +/- 0.4 micrograms/ml (mean +/- S.E.; n = 5). The maximal reduction (Emax) in HR (-85 +/- 9 beats/min) was significantly smaller than the values reported for full agonists. During A1 blockade, EC50,u values of 5.5 +/- 0.8 and 6.0 +/- 0.8 micrograms/ml were observed for the A2a receptor-mediated reductions in blood pressure and MAP/HR, respectively (mean +/- SE; n = 5). The Emax values for the hypotensive effect and the reduction in MAP/HR (-55 +/- 3 beats/min and -9.7 +/- 0.6 x 10(-2) mm Hg/ beats/min, respectively) were similar to those of a full A2a receptor agonist. This study shows that BAA is a partial agonist for the adenosine A1 receptor and a full agonist for the A2a receptor.

Adenosine↗