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M Danhof

Publications and source records attributed to M Danhof.

At least 55 records · Page 3Linked to original sources
PubMed1999

A combined specific target site binding and pharmacokinetic model to explore the non-linear disposition of draflazine.

The capacity-limited high-affinity target site binding of draflazine to the nucleoside transporters located on the erythrocytes is a source of nonlinearity in the pharmacokinetics of the drug. An attractive feature of draflazine is that the specific target site binding characteristics can be determined easily by simultaneously measuring plasma and whole blood concentrations of the drug. Measured drug concentrations following various infusion rates and infusion durations were used to develop a model in which the interrelated blood-plasma distribution, elimination, and specific target site binding of draflazine were incorporated simultaneously. The estimated binding (dissociation) constant Kd was 0.57 ng/ml plasma and the maximal specific erythrocyte binding capacity (BmaxRBC) was 163 ng/ml RBC. The maximal specific binding capacity to the tissues (Bmaxtissue) was estimated to be about 1 mg. The estimated volume of the central compartment (Vplasma + tissue fluids) was 12.9 L and the total intrinsic CL was 645 ml/min. After validation, the model was used to further investigate the impact of the specific high-affinity target site binding of draflazine on its disposition in plasma. The time required to reach steady-state plasma concentrations of draflazine decreased with an increasing infusion rate. Time profiles of the plasma concentrations were not always representative for the time profiles of the specific target site (RBC) occupancy of draflazine, but the t1/2,z in plasma paralleled that of the drug at target sites. The apparent Vd and the t1/2,z decreased with increasing single doses whereas the total CL remained constant. The recovery of draflazine was also dose dependent and increased with increasing doses. Finally, the total CL and apparent Vd of the first dose were greater than those of the second dose of draflazine.

Binding, Competitive↗
PubMed1999

Application of a combined "effect compartment/indirect response model" to the central nervous system effects of tiagabine in the rat.

Pharmacological inhibition of GABA uptake transporters provides a mechanism for increasing GABAergic transmission, which may be useful in the treatment of various neurological disorders. The purpose of our investigations was to develop an integrated pharmacokinetic-pharmacodynamic (PK/PD) model for the characterization of the pharmacological effect of tiagabine, R-N-(4,4-di-(3-methylthien-2-yl)but-3-enyl)nipecotic acid, in individual rats in vivo. The tiagabine-induced increase in the amplitude of the EEG 11.5-30 Hz frequency band (beta), was used as pharmacodynamic endpoint. Chronically instrumented male Wistar rats were randomly allocated to four groups which received an infusion of 3, 10, or 30 mg kg-1 of tiagabine or vehicle over 10 min. The EEG was continuously recorded in conjunction with frequent arterial blood sampling. The pharmacokinetics of tiagabine could be described by a biexponential equation. The pharmacokinetics of tiagabine were not dose dependent, and the pooled values for clearance, volume of distribution at steady state and terminal half-life were (mean +/- SE, n 23) 96 +/- 9 ml min-1 kg-1, 1.5 +/- 0.1 L kg-1 and 20 +/- 0.2 min. A time delay was observed between the occurrence of maximum plasma drug concentrations and maximal response. A physiological PK/PD model has been used to account for this time delay, in which a biophase was postulated to account for tiagabine available to the GABA uptake carriers in the synaptic cleft and the increase in EEG effect was considered an indirect response due to inhibition of GABA uptake carriers. The population values for the pharmacodynamic parameters characterizing the delay in pharmacological response relative to plasma concentrations were keo = 0.030 min-1 and kout = 81 min-1, respectively. Because of the large difference in these values the PK/PD model was simplified to the effect compartment model. Population estimates (mean +/- SE) were E0 = 155 +/- 6 microV, Emax = 100 +/- 5 microV, EC50 = 287 +/- 7 ng ml-1, Hill factor = 1.8 +/- 0.2 and keo = 0.030 +/- 0.002 min-1. The results of this analysis show that for tiagabine the combined "effect compartment-indirect response" model can be simplified to the classical "effect compartment" model.

Animals↗
PubMed1999

Rate of change of blood concentrations is a major determinant of the pharmacodynamics of midazolam in rats.

The objective of this investigation was to characterize quantitatively the influence of the rate of increase in blood concentrations on the pharmacodynamics of midazolam in rats. The pharmacodynamics of midazolam were quantified by an integrated pharmacokinetic-pharmacodynamic modelling approach. Using a computer controlled infusion technique, a linear increase in blood concentrations up to 80 ng ml(-1) was obtained over different time intervals of 16 h, resulting in rates of rise of the blood concentrations of respectively, 1.25, 1.00, 0.87, 0.46, 0.34 and 0.20 ng ml(-1) min(-1). In one group of rats the midazolam concentration was immediately brought to 80 ng ml(-1) and maintained at that level for 4 h. Immediately after the pretreatment an intravenous bolus dose was given to determine the time course of the EEG effect in conjunction with the decline of midazolam concentrations. The increase in beta activity (11.5-30 Hz) of the EEG was used as pharmacodynamic endpoint. For each individual animal the relationship between blood concentration and the EEG effect could be described by the sigmoidal Emax model. After placebo, the values of the pharmacodynamic parameter estimates were Emax = 82+/-5 microV, EC50,u = 6.4+/-0.8 ng ml(-1) and Hill factor = 1.4+/-0.1. A bell-shaped relationship between the rate of change of midazolam concentration and the value of EC50,u was observed with a maximum of 21+/-5.0 ng ml(-1) at a rate of change of 0.46 ng ml(-1) min(-1); lower values of EC50,u were observed at both higher and lower rates. The findings of this study show that the rate of change in plasma concentrations is an important determinant of the pharmacodynamics of midazolam in rats.

Algorithms↗
PubMed1999

Stereoselective central nervous system effects of the R- and S-isomers of the GABA uptake blocker N-(4, 4-di-(3-methylthien-2-yl)but-3-enyl) nipecotic acid in the rat.

1. The 'effect compartment' model was applied to characterize the pharmacodynamics of the R- and S-isomers of tiagabine in conscious rats in vivo using increase in the beta activity of the EEG as a pharmacodynamic endpoint. 2. No pharmacokinetic differences in plasma were observed between R- and S-tiagabine. The values for clearance and volume of distribution at steady-state were 103+/-10 versus 90+/-6 ml min(-1) kg(-1) and 1.8+/-0.2 versus 1.6+/-0.2 l kg(-1) for the R- and S-isomer, respectively. In contrast, plasma protein binding showed a statistically significant difference with values of the free fraction of 5.7+/-0.5 and 11.4+/-0.6%. In addition the rate constant for transport to the effect compartment was also different with values of 0.027 versus 0.067 min(-1). 3. For both isomers the relationship between concentration and EEG effect was non-linear and successfully characterized on basis of the Hill equation. A statistically significant difference in the value of EC(50) of 328+/-11 versus 604+/-18 ng ml(-1) was observed for R- and S-tiagabine respectively. The values of the other pharmacodynamic parameters were identical. 4. It is concluded that the differences in in vivo pharmacodynamics of R- and S-tiagabine can be explained by stereoselective differences in both the affinity to the GABA-uptake transporter and the degree of non-specific protein binding in plasma and at the effect site.

Animals↗
PubMed1999

Pharmacokinetics, induction of anaesthesia and safety characteristics of propofol 6% SAZN vs propofol 1% SAZN and Diprivan-10 after bolus injection.

AIMS: In order to avoid the potential for elevated serum lipid levels as a consequence of long term sedation with propofol, a formulation of propofol 6% in Lipofundin(R) MCT/LCT 10% (Propofol 6% SAZN) has been developed. The pharmacokinetics, induction of anaesthesia and safety characteristics of this new formulation were investigated after bolus injection and were compared with the commercially available product (propofol 1% in Intralipid(R) 10%, Diprivan-10) and propofol 1% in Lipofundin(R) MCT/LCT 10% (Propofol 1% SAZN). METHODS: In a randomised double-blind study, 24 unpremedicated female patients received an induction dose of propofol of 2.5 mg kg-1 over 60 s which was followed by standardized balanced anaesthesia. The patients were randomized to receive propofol as Propofol 6% SAZN, Propofol 1% SAZN or Diprivan-10. RESULTS: For all formulations the pharmacokinetics were adequately described by a tri-exponential equation, as the propofol concentrations collected early after the injection suggested an additional initial more rapid phase. The average values for clearance (CL), volume of distribution at steady-state (Vd,ss ), elimination half-life (t1/2,z ) and distribution half-life (t1/2, lambda2) observed in the three groups were 32+/-1.5 ml kg-1 min-1, 2. 0+/-0.18 l kg-1, 95+/-5.6 min and 3.4+/-0.20 min, respectively (mean+/-s.e.mean, n=24) and no significant differences were noted between the three formulations (P >0.05). The half-life of the additional initial distribution phase (t1/2,lambda1 ) in all subjects ranged from 0.1 to 0.6 min. Anaesthesia was induced successfully and uneventfully in all cases, and the quality of induction was adequate in all 24 patients. The induction time did not vary between the three formulations and the average induction time observed in the three groups was 51+/-1.3 s which corresponded to an induction dose of propofol of 2.1+/-0.06 mg kg-1 (mean+/-s.e. mean, n=24). The percentage of patients reporting any pain on injection did not vary between the formulations and was 17% for the three groups. No postoperative phlebitis or other venous sequelae of the vein used for injection occurred in any of the patients at recovery of anaesthesia nor after 24 h. CONCLUSIONS: From the above results, we conclude that the alteration of the type of emulsion and the higher concentration of propofol in the new parenteral formulation of propofol does not affect the pharmacokinetics and induction characteristics of propofol, compared with the currently available product. Propofol 6% SAZN can be administered safely and has the advantage of a reduction of the load of fat and emulsifier which may be preferable when long term administration of propofol is required.

Adult↗
PubMed1999

The comparative pharmacodynamics of remifentanil and its metabolite, GR90291, in a rat electroencephalographic model.

BACKGROUND: The purpose of this study was to investigate the in vivo pharmacodynamics and the pharmacodynamic interactions of remifentanil and its major metabolite, GR90291, in a rat electroencephalographic model. METHODS: Remifentanil and GR90291 were administered according to a stepwise infusion scheme. The time course of the electroencephalographic effect (0.5-4.5 Hz) was determined in conjunction with concentrations of the parent drug and the metabolite in blood. RESULTS: Administration of remifentanil resulted in concentrations of remifentanil and GR90291 in the ranges 0-120 ng/ml and 0-850 ng/ml, respectively. When the metabolite was administered, concentrations of the metabolite in the range 0-220 microg/ml and no measurable concentrations of remifentanil were observed. The mean +/- SE values of the pharmacokinetic parameters clearance and volume of distribution at steady state were 920+/-110 ml x min(-1) x kg(-1) and 1.00+/-0.93 l/kg for remifentanil and 15+/-2 ml x min(-1) x kg(-1) and 0.56+/-0.08 l/kg for GR90291. The relative free concentrations in the brain, as determined on the basis of the cerebrospinal fluid/total blood concentration ratio at steady state, were 25+/-5% and 0.30+/-0.11% for remifentanil and GR90291, respectively. Concentration-electroencephalographic effect relations were characterized on the basis of the sigmoidal Emax pharmacodynamic model. The mean +/- SE values for the maximal effect (Emax), the concentration at which 50% of the maximal effect is obtained (EC50), and Hill factor for remifentanil were 109+/-12 microV, 9.4+/-0.9 ng/ml, and 2.2+/-0.3, respectively (n = 8). For GR90291, the mean +/- SE values for EC50 and the Hill factor were 103,000+/-9,000 microg/ml and 2.5+/-0.4, respectively (n = 6). CONCLUSIONS: Analysis of the data on the basis of a previously postulated, mechanism-based pharmacokinetic-pharmacodynamic model for synthetic opioids revealed that the low in vivo potency of GR90291 can be explained by a low affinity to the mu-opioid receptor in combination with a poor brain penetration.

Analgesics, Opioid↗
PubMed1999

Characterization of the pharmacodynamic interaction between parent drug and active metabolite in vivo: midazolam and alpha-OH-midazolam.

The pharmacodynamic interaction between midazolam and its active metabolite alpha-OH-midazolam was investigated to evaluate whether estimates of relevant pharmacodynamic parameters are possible after administration of a mixture of the two. Rats were administered 10 mg/kg of midazolam, 15 mg/kg of alpha-OH-midazolam, or a combination of 3.6 mg/kg of midazolam and 35 mg/kg of alpha-OH-midazolam. Increase in the 11.5- to 30-Hz frequency band of the electroencephalogram was used as the pharmacodynamic endpoint. The pharmacodynamics of midazolam and alpha-OH-midazolam after combined administration were first analyzed according to an empirical and a competitive interaction model to evaluate each model's capability in retrieving the pharmacodynamic estimates of both compounds. Both models failed to accurately estimate the true pharmacodynamic estimates of midazolam and alpha-OH-midazolam. The pharmacodynamic interaction was subsequently analyzed according to a new mechanism-based model. This approach is based on classical receptor theory and allows estimation of the in vivo estimated receptor affinity and intrinsic in vivo drug efficacy. The relationship between stimulus and effect is characterized by a monotonically increasing function f, which is assumed to be identical for midazolam and alpha-OH-midazolam. The pharmacodynamic interaction is characterized by the classical equation for the competition between two substrates for a common receptor site. This mechanism-based interaction model was able to estimate the pharmacodynamic parameters of both midazolam and alpha-OH-midazolam with high accuracy. It is concluded that pharmacodynamic parameters of single drugs can be estimated after a combined administration when a mechanistically valid interaction model is applied.

Algorithms↗
PubMed1999

Mechanism-based pharmacokinetic-pharmacodynamic modeling of antilipolytic effects of adenosine A(1) receptor agonists in rats: prediction of tissue-dependent efficacy in vivo.

In this study, we analyzed the antilipolytic effects of six N(6)-cyclopentyladenosine analogs in rats and developed a mechanistic pharmacokinetic-pharmacodynamic model to quantify and predict the tissue-selective action of adenosine A(1) receptor agonists in vivo. Freely moving rats received an i.v. infusion of vehicle or compound over 15 min. Arterial blood samples were taken at regular time intervals for the determination of concentrations of drugs using HPLC analysis and of nonesterified fatty acids (NEFAs). All N(6)-cyclopentyladenosine analogs that were investigated produced a significant decrease in the NEFA plasma concentration after i.v. infusion. The pharmacokinetic behavior of each ligand was described by a standard two-compartment model. The pharmacokinetic parameter estimates then were used to simultaneously fit the individual (n = 6-8) time-NEFA concentration profiles for each agonist to a physiological indirect response model in combination with the Hill equation to obtain estimates of the NEFA elimination rate constant (k(e)) and upper asymptote (fractional inhibition), midpoint location, and midpoint slope parameter (alpha, pEC(50), and n(H), respectively) of the concentration-effect relationship. Subsequently, the data were analyzed with the operational model of agonism to obtain estimates of in vivo affinity and efficacy. It was estimated that the in vivo density and/or coupling of adenosine A(1) receptors mediating antilipolytic effects is approximately 38 times higher compared with the receptors mediating bradycardia. The model predicts that it is possible to design ligands that produce significant inhibition of lipolysis and are completely devoid of cardiovascular effects in vivo.

Adenosine↗
PubMed1998

Effects of repeated seizure induction on seizure activity, post-ictal and interictal behavior.

Individual variability and numerous interactions between pharmacokinetics, pharmacodynamics, and homeostatic factors complicate the study of the anticonvulsant effect in animal models of seizure activity. In theory, both individual variability and the contribution of these factors to the anticonvulsant effect can be determined by following the time course of the pharmacological response and the corresponding plasma concentrations in individual animals. Currently, there are several formal pharmacokinetic-pharmacodynamic models available for the analysis of such data, which yield accurate estimates of drug intrinsic activity and potency. However, most models of seizure activity are not suited for such an approach, either because they can be applied only once, or because the expression of seizures is not constant over time. In addition, the induction of seizures constitutes repeated jeopardy to the animals, which may profoundly change behavior and interfere in the anticonvulsant response as well as in different physiological processes. In this paper, we compare ictal, post-ictal, and interictal behavior in three different models of seizure activity in rats, namely, the electroconvulsive shock, amygdala kindling and the cortical stimulation model (CSM). The methods were compared in the same way as they are currently in use for the assessment of antiepileptic drug effect. Our results show that repeated seizure activity induced by cortical stimulation does not exacerbate ictal activity (eye closure, jerk, gasp, forelimb clonus, and hind-limb tonus) nor post-ictal behavior (chewing and freezing), while producing less serious changes in interictal behavior (walk, lean, upright rearing, exploratory, grooming, and rest) than kindling or electroconvulsive shock. We conclude that seizures induced by cortical stimulation are reproducible and qualitatively similar to kindling seizures. Our results also suggest that the electroconvulsive shock model is not suited for pharmacokinetic-pharmacodynamic studies and that the assessment of interictal behavior may contribute to the evaluation of overall antiepileptic drug effect in seizure disorders.

Analysis of Variance↗
PubMed1998

An integrated pharmacokinetic-pharmacodynamic approach to optimization of R-apomorphine delivery in Parkinson's disease.

R-apomorphine is a mixed dopamine D(1)/D(2) receptor agonist which is potentially useful in the management of Parkinson's disease. The delivery of R-apomorphine is complicated however by a number of pharmacokinetic and pharmacodynamic factors. This review describes the development of a transdermal iontophoretic delivery system for R-apomorphine on the basis of integrated pharmacokinetic-pharmacodynamic (PK/PD) investigations in patients with idiopathic Parkinson's disease. The pharmacokinetics and metabolic pathways of R-apomorphine were determined following intravenous infusion of 30 µg kg(-1) in 15 min in 10 patients. A stepwise infusion protocol was used to determine the therapeutic window. A wide interindividual variability in both pharmacokinetics and pharmacodynamics and a narrow therapeutic concentration range were observed. This shows the need for individualized and carefully controlled delivery of R-apomorphine in Parkinson's disease. Transdermal iontophoretic transport was studied both in vitro in human stratum corneum and dermatomed full skin and in vivo in patients with Parkinson's disease. These studies showed that the delivery of R-apomorphine by transdermal iontophoresis is feasible and furthermore that the rate of delivery can be carefully controlled by variation of the current density. It is concluded that the delivery of R-apomorphine by transdermal iontophoresis may be an attractive tool in future clinical pharmacological investigations in patients with Parkinson's disease aiming at characterization of the influence of chronic treatment and disease progression on the pharmacokinetics and pharmacodynamics. Ultimately these studies may result in a system which is suitable for clinical application.

Journal Article↗
PubMed1998

Validation and testing of a new iontophoretic continuous flow through transport cell.

A new continuous flow through transport cell is presented. The design is based on a minimisation of contributions of the cell conformation and experimental protocol to the overall transport kinetics. The system is validated by measuring the washout period of methylene blue and apomorphine. Preliminary results on the iontophoretic transport of apomorphine across human stratum corneum are presented. These data are used to calculate the deviation of the measured apparent flux from the calculated intrinsic flux across the membrane. The steady state iontophoretic flux was 90 +/- 6 nmol cm-2 h-1 when a 15 mM apomorphine solution was applied in the anodal chamber at a current density of 500 microA cm2. At any point in time the contribution of the cell to the transport rate was < or = 3%. The supporting membrane does not contribute significantly to the overall transport rates. Sink conditions are guaranteed at a flow rate > or = 6.5 ml h-1. For this new transport cell it can be concluded that the apparent flux that was measured, at validated experimental conditions, is a reliable estimate for the intrinsic flux.

Apomorphine↗
PubMed1998

Phamacokinetic-pharmacodynamic modelling of behavioural responses.

Drug concentrations at the site of action in studies on behavioural pharmacology, are seldom constant. Therefore, observed changes in behaviour can be due to the natural time course of behavioural processes, but equally to changes in drug concentration, and it is therefore crucial to separate the former from the latter. One solution is keeping drug concentrations constant. However, one can also exploit the variation in drug concentration caused by absorption, distribution and elimination of a drug. This is done by simultaneous measurement of drug effect and concentration, while the drug enters and leaves a biologically relevant compartment, such as blood or cerebrospinal fluid. The concept of determining concentration-effect curves in individual animals, by monitoring in parallel drug effect and changes in concentration in one single experiment, has not yet found wide application in behavioural studies. The fact that behavioural processes, like any other physiological process, change over time, may have contributed to the scarcity of pharmacokinetic-pharmacodynamic (PK/PD) studies in behavioural pharmacology. However, there are now mathematical techniques that allow PK/PD modelling even if the effect parameter changes over time or cannot be properly assessed in every instance. Here we use PK/PD modelling to characterize fear-induced ultrasonic vocalizations and the anxiolytic effect of buspirone. This approach reduces the number of animals required to assess concentration-effect relationships. More importantly, it allows the identification of differences in individual drug response over a wide range of concentrations. Consequently, we suggest that PK/PD modelling can be used as a tool to study drug-induced changes in behavioural response. An introduction in PK/PD modelling is presented.

Animals↗
PubMed1998

Pharmacokinetic-pharmacodynamic modelling of the analgesic effect of alfentanil in the rat using tooth pulp evoked potentials.

The purpose of the present study was to develop an animal model for the investigation of the concentration-effect relationship of alfentanil using tooth pulp evoked potentials (TPEP). Six chronically instrumented, freely moving rats received a computer-controlled intravenous infusion of alfentanil resulting in seven pseudo-steady-state blood concentration levels, each maintained for 30 min. At each concentration level, the tooth pulp of the rat upper incisor was electrically stimulated in a time-randomized order with different current intensities (400-800 microA, 1 msec duration) and the electroencephalogram (EEG) was recorded concomitantly. Arterial blood samples were collected serially and assayed for alfentanil using RIA. Repetitive evoked EEG responses were averaged per stimulus intensity and per session. The decrease of the area under the negative peak 15 msec after stimulation (% of preadministration value) was used as pharmacological endpoint. The concentration-TPEP effect of alfentanil was investigated by nonlinear mixed effect modeling (NONMEM). When the observed TPEP effect was plotted versus the alfentanil blood concentration no hysteresis or proteresis was observed, and the two could directly be related to each other on the basis of the sigmoidal Emax pharmacodynamic model. The (population) pharmacodynamic estimates were (+/-S.E.): Emax = 108 +/- 10%, EC50 = 24 +/- 17 ng/ml, Hill factor = 0.81 +/- 0.37. A large interindividual variability for EC50 (omegaEC50) of 164 +/- 107% was observed. The residual variability was 14 +/- 10%. It is concluded that the TPEP is a useful tool for the systematic investigation of the concentration-analgesic effect relationship of centrally acting analgesics in the freely moving rat.

Alfentanil↗
PubMed1998

Influence of different fat emulsion-based intravenous formulations on the pharmacokinetics and pharmacodynamics of propofol.

PURPOSE: The influence of different intravenous formulations on the pharmacokinetics and pharmacodynamics of propofol was investigated using the effect on the EEG (11.5-30 Hz) as pharmacodynamic endpoint. METHODS: Propofol was administered as an intravenous bolus infusion (30 mg/kg in 5 min) or as a continuous infusion (150 mg/kg in 5 hours) in chronically instrumented male rats. Propofol was formulated as a 1% emulsion in an Intralipid 10%-like fat emulsion (Diprivan-10, D) or as a 1%- or 6% emulsion in Lipofundin MCT/LCT-10% (P1% and P6%, respectively). EEG was recorded continuously and arterial blood samples were collected serially for the determination of propofol concentrations using HPLC. RESULTS: Following bolus infusion, the pharmacokinetics of the various propofol emulsions could adequately be described by a two-compartmental pharmacokinetic model. The average values for clearance (Cl), volume of distribution at steady-state (Vd,ss) and terminal half-life (t1/2, lambda 2) were 107 +/- 4 ml/min/kg, 1.38 +/- 0.06 l/kg and 16 +/- 1 min, respectively (mean +/- S.E. n = 22). No significant differences were observed between the three propofol formulations. After continuous infusion these values were 112 +/- 11 ml/min/kg, 5.19 +/- 0.41 l/kg and 45 +/- 3 min, respectively (mean +/- S.E., n = 20) with again no statistically significant differences between the three propofol formulations. Comparison between the bolus- and the continuous infusion revealed a statistically significant difference for both Vd,ss and t1/2, lambda 2 (p < 0.05), whereas Cl remained unchanged. In all treatment groups infusion of propofol resulted in a burst-suppression type of EEG. A profound hysteresis loop was observed between blood concentrations and EEG effect for all formulations. The hysteresis was minimized by a semi-parametric method and resulted in a biphasic concentration-effect relationship of propofol that was described non-parametrically. For P6% a larger rate constant onset of drug effect (t1/2,keo) was observed compared to the other propofol formulations (p < 0.05). CONCLUSIONS: The pharmacokinetics and pharmacodynamics of propofol are not affected by to a large extent the type of emulsion nor by the concentration of propofol in the intravenous formulation.

Anesthetics, Intravenous↗
PubMed1998

Selectivity of action of 8-alkylamino analogues of N6-cyclopentyladenosine in vivo: haemodynamic versus anti-lipolytic responses in rats.

1. A1 adenosine receptor agonists with reduced intrinsic activity may be therapeutically useful as result of an increased selectivity of action. In this study the tissue selectivity of three 8-alkylamino substituted analogues of N6-cyclopentyladenosine (CPA) was investigated for haemodynamic and anti-lipolytic effects using an integrated pharmacokinetic-pharmacodynamic approach. 2. Chronically instrumented male Wistar rats received intravenous infusions of 4.0 mg kg(-1) 8-methylaminoCPA (8MCPA), 12.0 mg kg(-1) 8-ethylaminoCPA (8ECPA), 20.0 mg kg(-1) 8-butylaminoCPA (8BCPA) or vehicle during 15 min. During experimentation, serial arterial blood samples were drawn for the determination of agonist concentrations and plasma non-esterified fatty acid (NEFA) levels. Blood pressure and heart rate were monitored continuously. In addition to the CPA analogues, each rat received a rapid bolus infusion of CPA to determine the maximal effects of the full agonist. 3. The concentration-time profiles of the CPA analogues could be described by a bi-exponential function. Values for clearance, volume of distribution at steady state and elimination half-life were 44+/-5, 48+/-6 and 39+/-2 ml min(-1) kg(-1), 0.97+/-0.09, 0.84+/-0.10 and 1.05+/-0.07 1 kg(-1) and 25+/-2, 28+/-2 and 40+/-2 min for 8MCPA, 8ECPA and 8BCPA, respectively (mean+/-s.e.mean, n=6-8). 4. Different models were used to derive the concentration-effect relationships for heart rate and NEFA, yielding estimates of potency (EC50) and intrinsic activity (Emax) for both effects of the compounds in vivo. On heart rate the compounds acted as partial agonists, with Emax values of -173+/-14, -131+/-11 and -71+/-6 beats min(-1) for 8MCPA, 8ECPA and 8BCPA, respectively. These Emax values were significantly lower than the maximal effect of CPA (-208+/-8 beats min(-1)). With regard to the anti-lipolytic effect all three compounds were full agonists and lowered NEFA levels to the same extent as CPA (69%). The estimated Emax values were 63+/-5, 63+/-4 and 68+/-2%, respectively. 5. Furthermore, the compounds were more potent in causing anti-lipolytic than cardiovascular effects. The EC50 values for the NEFA and heart rate lowering effects were 37+/-15, 68+/-22 and 659+/-108 ng ml(-1) and 164+/-22, 341+/-76 and 975+/-190 ng ml(-1) for 8MCPA, 8ECPA and 8BCPA, respectively (mean+/-s.e.mean, n=6-8). 6. This study demonstrates that partial agonists for the A1 adenosine receptor have increased selectivity of action in vivo. The 8-alkylamino analogues of CPA may be useful anti-lipolytics with less pronounced haemodynamic side effects.

Adenosine↗
PubMed1998

Pharmacokinetic-pharmacodynamic modelling of the EEG effect of alfentanil in rats: assessment of rapid functional adaptation.

1. The purpose of the present investigation was to quantify rapid functional adaptation in the concentration-pharmacological effect relationship of alfentanil in rats using quantitative EEG parameters as a pharmacodynamic endpoint. Three groups of 6-7 rats received in a randomized fashion two consecutive infusions of 2.00, 3.14, or 4.24 mg/kg(-1) of alfentanil in 20, 40 or 60 min, respectively. The EEG was continuously recorded and frequent arterial blood samples were collected for determination of the alfentanil concentration by gas chromatography. 2. The pharmacokinetics of alfentanil were most adequately described by a bi-exponential function. The values (mean+/-s.e., n=20) of clearance, volume of distribution at steady-state and terminal half-life were 45+/-3 ml x min(-1) x kg(-1), 0.91+/-0.09 l/kg(-1) and 23+/-1 min, respectively, and independent of the administered dose. 3. Increase in power in the 0.5-4.5 Hz (delta) frequency band of the EEG was used as the measure of the pharmacological response. By pharmacokinetic-pharmacodynamic modeling the individual concentration-EEG effect relationships of alfentanil were derived which were successfully quantified by the sigmoidal Emax pharmacodynamic model. When the results of the first of the two consecutive infusions were compared, no systematic differences in the pharmacodynamic parameters were observed for the different infusion rates. The averaged values of the pharmacodynamic parameters of alfentanil were (mean+/-s.e., n=20): E0=56+/-3 microV, Emax=93+/-8 microV, EC50=235+/-27 ng x ml(-1) and Hill factor=1.6+/-0.1, respectively. For the second of the two consecutive infusions a significantly higher value of the EC50 of 404+/-56 ng x ml(-1) was observed (P < 0.05), while the values of the other pharmacodynamic parameters were unchanged. Simulations according to a mechanism-based model indicated that the observed change in concentration effect relationship can be explained by a 40% loss of functional mu-opioid receptors. 4. The results of the present study show that upon the administration of a single intravenous dose, acute functional adaptation does not interfere with the assessment of the concentration-EEG effect relationship of alfentanil. Upon repeated administration however functional adaptation may be a complicating factor.

Adaptation, Physiological↗
PubMed1998

Adaptive changes in the pharmacodynamics of midazolam in different experimental models of epilepsy: kindling, cortical stimulation and genetic absence epilepsy.

1. The objective of this investigation was to determine quantitatively whether experimental epilepsy is associated with a change in the pharmacodynamics of benzodiazepines in vivo. For that purpose the pharmacodynamics of midazolam were quantified by an integrated pharmacokinetic-pharmacodynamic approach in three different models of experimental epilepsy: amygdala kindling, cortical stimulation and genetic absence epilepsy. 2. The time course of the EEG effect was determined in conjunction with the decline of drug concentrations after intravenous administration of 10 mg kg(-1) midazolam. The pharmacokinetics of midazolam were most adequately described by a bi-exponential equation. No influence of epilepsy on the pharmacokinetics of midazolam was observed. 3. The increase in beta activity (11.5-30 Hz) of the EEG as derived by Fast Fourier Transformation analysis was used as pharmacodynamic endpoint. For each individual rat the increase in beta activity was directly related to the concentration in blood on the basis of the sigmoidal Emax pharmacodynamic model. In all three models a significant reduction in the maximal effect was observed, in amygdala kindling 28%, in the cortical stimulation model 49% and in genetic absence epilepsy 37%. No differences in the other pharmacodynamic parameters, E0 EC50,u and Hill factor, were observed. 4. It is inferred that in three different models of epilepsy there is a similar change in GABAergic functioning which is associated with a significant reduction in the intrinsic activity of midazolam in vivo. These models provide therefore a useful basis for further studies on the mechanism of epilepsy-induced changes in pharmacodynamics of anti-epileptic drugs.

Amygdala↗