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D D Breimer

Publications and source records attributed to D D Breimer.

At least 37 records · Page 2Linked to original sources
PubMed1999

The sensitivity of pharmacodynamic tests for the central nervous system effects of drugs on the effects of sleep deprivation.

Various methods are used to quantify sedative drug effects, but it is unknown how these surrogate measures relate to clinically relevant sleepiness. This study assessed the sensitivity of different surrogates of sedation to clinically relevant sleepiness induced by sleep deprivation. Nine healthy volunteers completed a balanced three-way cross-over study with 1-week wash-out periods. Adaptive tracking, smooth-pursuit and saccadic eye movements, body sway, digit symbol substitution (DSST), visual analogue scales (VAS) and electroencephalograms (EEG) were evaluated on three occasions: (1) during the day after normal sleep, (2) during wakefulness at night; and (3) during the day after a night of sleep deprivation. VAS of alertness showed a gradual decline at night and a constant average reduction of 38 percent [95% Confidence intervals (CI), 28-47%] during the day after sleep deprivation. Average mood scores diminished by 14 percent (95%, CI 2-24%) during the day after sleep deprivation. Adaptive tracking, saccadic eye movements and body sway tended to deteriorate at night, but overall this was not statistically significant. After a night of sleep deprivation, adaptive tracking decreased by 21 percent (95% CI, 11-30%), saccadic eye movements decreased by 9-10 percent (95% CI, 5-13%/6-15%) and body sway increased by 37 percent (95% CI, 5-79%). In contrast, EEG beta2-amplitudes declined significantly at night by 18 percent (95% CI, 6-29%), without changes during the day after sleep deprivation. Smooth pursuit, DSST and other EEG-amplitudes remained unchanged. These results emphasize that reductions in adaptive tracking, saccadic peak velocity and body sway caused by sedative drugs really reflect sedation. They also provide a level of clinical significance for these surrogates of sedation. EEG parameters and smooth pursuit were unaffected by sleep deprivation, so drug-induced changes in these measures may not reflect sedation in a stricter sense. The motivation and alertness necessary for DSST may overcome mild sedation.

Adult↗
PubMed1999

The role of probenecid-sensitive organic acid transport in the pharmacokinetics of N-methyl-D-aspartate receptor antagonists acting at the glycine(B)-site: microdialysis and maximum electroshock seizures studies.

The purpose of the present study was to determine whether the probenecid-sensitive organic acid transporter is responsible for the short duration of action of a new group of N-methyl-D-aspartate receptor glycine(B)-site antagonists, MRZ 2/570, 2/571, and 2/576. A prolongation of their anticonvulsant activity from 60 to 180 to 240 min, was found in mice after pretreatment with probenecid (200 mg/kg i.p.). Microdialysis studies in rats showed that this is likely due to a change in central nervous system concentrations of these drugs because cotreatment with probenecid caused an increase in the brain extracellular fluid half-life (0.5- to 4-fold) and the brain area under the curve (1.8- to 3.6-fold). In serum the half-life of MRZ 2/576 (30 mg/kg) was also increased by coadministration of probenecid from 15.6 +/- 1.3 to 40.6 +/- 6.0 min. At steady state (MRZ 2/576, 20 mg/kg/h i.v.), brain extracellular fluid concentration was elevated 2.5-fold by concomitant administration of probenecid. These results clearly show that these glycine(B)-site antagonists are rapidly cleared from the systemic circulation and the central nervous system by the probenecid-sensitive organic acid transport system. Moreover, the present data show that MRZ 2/570, 2/571, and 2/576 reach the brain in concentrations (1.34-2.32 microM) above the range of their in vitro potencies at the glycine site of the N-methyl-D-aspartate receptor (0.1-1.0 microM).

Animals↗
PubMed1998

[Transport of drugs across the blood-brain barrier].

The blood-brain barrier prevents an indifferent medicine existing in the blood to enter also in the brain. This barrier has got an anatomical base: it is first consisting in a cerebrovascular layer of endothelial capillary vessels of the peripheral tissue. It is moreover covered by outgrowths of the flial cells, which are called astrocytes. There are, for that reason, important limits to a size of molecules which can reach the cerebral tissue through a paracellular way (through what is called in English "tight-junctions"). Most medicines must use the transcellular way. Lipophily is necessary to follow that way. Year after year, it appeared, thanks to a comparative study of the substances, that there exists--grosso modo--a positive correlation between the lipophilic level and the permeation-level of a substance in the cerebral tissue. There are, however, several exceptions: it is so that hydrophilic substances, possessing an important nourishing function (such as glucosis, amino-acids) seem to penetrate much more easily than we could expect when we consider their physicochemical characteristics. This is the result of the fact that there exist specifical transport-mechanisms for these substances at the level of the endothelial cell-membranes, allowing the penetration of such substances. There exist, on the contrary, lipophilic components that penetrate the cerebral tissue much less strongly than we should expect. This happens because there also exist pumping-mechanisms at the level of the hemato-encephalic barrier. The concerning substance, which was recently discovered is the "glycoprotein P", which is also responsible for the "multi-drug-resistance" and for the resistance of tumors to cytostatics. This phenomenon relies on a very efficient pumping of substances which have penetrated cells in which this protein expressed itself in the membranous structure. In order to obtain a better understanding of the function of the hemato-encephalic barrier, comprising the transport of medicines, it is most important to have reliable experimental models. It is to that aim that, during former years, the technique of cultivating endothelial cerebrovascular cells was developed. These cells are isolated from brains of calves or rats and, subsequently, cultivated on a laboratory medium; about a week later, they have grown a single and confluent layer. This layer represents a kint of "hemato-encephalic barrier" in vitro, which allows us to study the transfer of substances through the layer and thus also the details concerning the transport mechanisms, as well as the factors influencing the permeability of the cells-layer (for instance the inflammatory stimuli). Concerning the "in vivo" research, the technique of intracerebral microdialysis in lab-animals proved to be very promising. In order to effect this microdialysis, a semipermeable microcannula is introduced in the brain tissue, across which an iso-osmotic liquid is being injected continuously. The substances staying in the interstitial liquid of the cerebral tissue will diffuse under the influence of a concentration gradient, into the dialysing liquid and they will also be ready to be analysed. Thanks to this technique, it is possible to follow, in the same animal, the evolution of the concentration in the brain of a substance which has, for instance been injected in a peripheral region. In this way, we obtain, indirectly and in vivo, informations about the functioning-process of the "hemato-encephalic barrier". We can, moreover, effect measures on a specific spot, for instance in tumoral brain tissue: this allows us to study the influence of specific transport-mechanisms. These rather recent techniques, as well in vitro as in vivo, will allow us, in consequence, to increase, during the next years, our understanding of the way the hemato-encephalic barrier functions as to the transfer of medicines towards the central nervous system. This understanding may lead us to new strategies allowing

Animals↗
PubMed1998

BBB transport and P-glycoprotein functionality using MDR1A (-/-) and wild-type mice. Total brain versus microdialysis concentration profiles of rhodamine-123.

PURPOSE: The effect of P-glycoprotein (Pgp) on brain distribution using mdr1a (-/-) mice was investigated. METHODS: Fluorescein (Flu) and FD-4 were used to check whether blood-brain barrier (BBB) integrity was maintained in mdr1a (-/-) mice. The Pgp substrate rhodamine-123 (R123) was infused and total brain, blood and brain microdialysate concentrations in mdr1a (-/-) mice and wild-type mice were compared. RESULTS: Maintenance of BBB integrity was indicated by equal total brain/blood ratios of Flu and FD-4 in both mice types. R123 concentrations in brain after i.v. infusion were about 4-fold higher in mdr1a (-/-) than in wild-type mice (P < 0.05), without changes in blood levels. After microdialysis experiments the same results were found, excluding artifacts in the interpretation of Pgp functionality by the use of this technique. However the 4-fold ratio in brain was not reflected in corresponding microdialysates. No local differences of R123 in the brain were found. By the no-net-flux method in vivo recovery appeared to 4.6-fold lower in mdrla (-/-) mice compared with wild-type mice. CONCLUSIONS: Pgp plays an important role in R123 distribution into the brain. Using intracerebral microdialysis, changes in in vivo recovery by the absence or inhibition of Pgp (or active efflux in general) need to be considered carefully.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Penetration of dexamethasone into brain glucocorticoid targets is enhanced in mdr1A P-glycoprotein knockout mice.

Mice with a genetic disruption of the multiple drug resistance (mdr1a) gene were used to examine the effect of the absence of its drug-transporting P-glycoprotein product from the blood-brain barrier on the distribution and cell nuclear uptake of [3H]-dexamethasone in the brain. [3H]-dexamethasone (4 microg/kg mouse) was administered s.c. to adrenalectomized mdr1a (-/-) and mdr1a (+/+) mice. One hour later, the mice were decapitated, and the radioactivity was measured in homogenates of cerebellum, blood, and liver following extraction of the radioactive steroid. The frontal brain was cut in sections for autoradiography. In the cerebellum of the mdr1a mutants, the amount of [3H]-dexamethasone relative to blood was about 5-fold higher than observed in the controls, whereas the ratio in blood vs. liver was not different. Using autoradiography, it was found that brain areas expressing the glucocorticoid receptor (GR) in high abundance, such as the hippocampal cell fields and the paraventricular nucleus (PVN), showed a 10-fold increase in cell nuclear uptake of radiolabeled steroid. The amount of retained steroid increased toward levels observed in the pituitary, which contains a similar density of GRs. The [3H]-dexamethasone concentration in pituitary was not affected by mdr1a gene disruption. The GR messenger RNA expression pattern in hippocampus was not different between the wild types and mdr1a mutants, which rules out altered receptor expression as a cause of the enhanced dexamethasone uptake. In conclusion, the present study demonstrates that the brain is resistant to penetration by dexamethasone because of mdr1a activity at the level of the blood-brain barrier. The data support the concept of a pituitary site of action of dexamethasone in blockade of stress-induced ACTH release. Dexamethasone poorly substitutes for depletion of the endogenous glucocorticoid from the brain and therefore, in this tissue, may cause a condition resembling that of adrenalectomy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Effect of the Mdr1a P-glycoprotein gene disruption on the tissue distribution of SDZ PSC 833, a multidrug resistance-reversing agent, in mice.

The involvement of mdr1a P-glycoprotein (P-gP) on the tissue distribution of the multidrug resistance-reversing agent SDZ PSC 833 was assessed by use of mdr1a (-/-) mice. The mdr1a (-/-) and wild-type mdr1a (+/+) mice received a 4-h constantrate i.v. infusion (2 micrograms/min) of [14C]SDZ PSC 833. Mice were sacrificed at 0, 0.5, 1, 2 and 4 h during infusion and at 0.5, 1, 3, 8 and 24 h after stopping the infusion. Blood and tissues were analyzed on total (14C) and parental SDZ PSC 833 concentrations. Mdr1a (-/-) mice exhibited increased SDZ PSC 833 accumulation in cerebrum, cerebellum and somewhat in testes and small intestine compared with the wild-type mice. The difference between mdr1a (-/-) and (+/+) brain (cerebrum and cerebellum) penetration depended on SDZ PSC 833 blood concentrations, because this cyclosporin analog apparently governs its own brain penetration by inhibiting the P-glycoprotein pump in mdr1a (+/+) mice. Thus the mdr1a (-/-)/(+/+) ratio of brain concentrations tended to decrease and increase at high and low blood concentrations, respectively. These findings clearly demonstrate the interaction of SDZ PSC 833 with the P-glycoprotein present at the blood-brain barrier. The SDZ PSC 833 distribution in other mdr1a P-glycoprotein-expressed tissues, as well as its metabolism and elimination, was not affected by the mdr1a gene disruption. This suggests that factors other than mdr1a P-gP are involved in the disposition of this multidrug resistance-reversing agent.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Methodological considerations of intracerebral microdialysis in pharmacokinetic studies on drug transport across the blood-brain barrier.

For the study of the pharmacokinetics of drugs in the brain a number of in vivo techniques is available, including autoradiography, imaging techniques, cerebrospinal fluid sampling and in vivo voltammetry, which all have their specific advantages and limitations. Intracerebral microdialysis is a relatively new in vivo technique. It permits monitoring of local concentrations of drugs and metabolites at specific sites in the brain which makes it an attractive tool for pharmacokinetic research. In the use of this technique a number of factors should be considered. These include: type of probe, surgical trauma, post-surgery interval, perfusion flow rate, as well as composition and temperature of the perfusion medium. In particular in studies on drug transport across the blood-brain barrier (BBB), effects of insertion of the probe on BBB functionality is important. It appears that BBB functionality is not significantly affected if surgical and experimental conditions are well-controlled. The relationship between dialysate concentrations and those in the extracellular fluid of the periprobe tissue, the recovery of the drug, depends on periprobe processes governing the actual concentration of the drug at that site. These include extracellular-microvascular exchange, metabolism, and diffusion of the drug. Several methods have been proposed to determine recovery values. In particular the no net flux method and the extended no net flux method are useful in practice. Several microdialysis studies on BBB transport of drugs are presented showing that intracerebral microdialysis is capable to assess local BBB transport profiles. Compared with other in vivo techniques, intracerebral microdialysis is the only (affordable) technique that offers the possibility to monitor local BBB transport of drugs in unanaesthetized animals, under physiological and pathological conditions.

Animals↗
PubMed1997

Partition coefficients (n-octanol/water) of N-butyl-p-aminobenzoate and other local anesthetics measured by reversed-phase high-performance liquid chromatography.

For the determination of the logarithmic partition coefficients between n-octanol and water (log P(o/w)) of local anesthetics, the pH of the aqueous phase needs to be adjusted to high values to ensure that the local anesthetics are in the unionized form. Using the shake-flask or the stir-flask method, this high pH may catalyze hydrolysis, leading to increasing amounts of impurities in time. These impurities exclude non-selective quantification methods like UV spectrometry and require repetitive quantitative analysis of both liquid phases resulting in a tedious and time-consuming method. A rapid reversed-phase HPLC method was developed to measure log P(o/w) of the local anesthetics N-butyl-p-aminobenzoate, methyl-p-aminobenzoate, benzocaine, procaine, mepivacaine, prilocaine, lidocaine, bupivacaine, etidocaine, tetracaine and oxubuprocaine.

1-Octanol↗
PubMed1997

Pharmacodynamics of temazepam in primary insomnia: assessment of the value of quantitative electroencephalography and saccadic eye movements in predicting improvement of sleep.

BACKGROUND AND OBJECTIVE: Quantitative electroencephalographic parameters and saccadic eye movements are frequently used as pharmacodynamic measures of benzodiazepine effect. We investigated the relationship between these measures and the hypnotic effect. METHODS: The correlation between the pharmacodynamic measures and sleep quality was determined in 21 patients with primary insomnia. The pharmacokinetic-pharmacodynamic relationships were characterized after administration of 20 mg oral temazepam. The hypnotic effect was determined on the basis of polysomnographic sleep recordings and a subjective sleep evaluation questionnaire. Correlations between pharmacodynamic measures and the improvement of sleep were investigated. RESULTS: The pharmacokinetic-pharmacodynamic relationships for the parameters derived from electroencephalography and saccadic eye movements showed considerable interindividual variability. Administration of temazepam led to a significant improvement in the objective parameters sleep period efficiency, wake time after sleep onset, and sleep efficiency and in the subjective assessment of sleep quality. No significant correlations were observed between the pharmacokinetic-pharmacodynamic-derived parameters and the improvement in objective or subjective sleep parameters. CONCLUSION: In subjects with primary insomnia the administration of 20 mg oral temazepam results in changes in both the pharmacodynamic measures and in quality of sleep. No individual correlations between the pharmacodynamic measures and quality of sleep were observed. We concluded that the investigated pharmacodynamic measures are of value in the first assessment of clinical efficacy and for the selection of the dose(s) to be investigated in subsequent trials that aim at showing clinical efficacy. However, the conclusive quantification of clinical efficacy should be performed only on the basis of the clinical end point itself.

Adult↗
PubMed1997

Abnormal glutathione conjugation in patients with tyrosinaemia type I.

Previous studies have suggested that tyrosinaemia type I may be associated with reduced glutathione availability due to conjugation of tyrosinaemia-associated reactive intermediates with glutathione. In the present study, the glutathione/ glutathione S-transferase system of two tyrosinaemia patients and three healthy controls were characterized by administering the racemic sedative drug bromisoval, a probe drug for assessing glutathione conjugation activity in vivo. Furthermore, concentrations of glutathione and glutathione S-transferase class alpha (GSTA) isoenzymes as well as the glutathione S-transferase class mu phenotype were assessed in the blood of six tyrosinaemia patients. The excretion of bromisoval mercapturates in healthy children was comparable to that observed in healthy adults. Tyrosinaemia patients were found to have a very high urinary recovery of bromisoval mercapturates (> or = 60% of the dose compared to about 30% for healthy, age-matched children and adults), which could be attributed mainly to a higher urinary excretion of the mercapturate derived from S-bromisoval. Healthy children and adults predominantly excrete the (R)-bromisoval mercapturate. The differences in amount excreted as well as in stereoselectivity of the urinary excretion of bromisoval mercapturates in tyrosinaemia patients are possibly related to an increased activity of specific glutathione S-transferase isoenzymes. Plasma glutathione and blood cell glutathione disulphide concentrations in tyrosinaemia patients were normal. Low blood cell glutathione concentrations were in general found only in two patients with a poor clinical condition. These results indicate that, in contrast to previous suggestions, reduced glutathione availability is not a generalized problem in (stabilized) tyrosinaemia patients.

Adult↗
PubMed1997

In vivo function tests of hepatic drug-oxidizing capacity in patients with liver disease.

Aminopyrine, antipyrine and trimethadione have been widely used for some time as probe drugs to assess non-selective P450 liver function. They have proved useful in evaluating pre- and post-operative liver function when performing surgery, transplantations, etc., in addition to a general evaluation of liver function and drug interactions. Progress has recently been made both in these non-selective P450 function tests and in the analysis of drug-metabolizing enzymes at a molecular level, which has resulted in more selective P450 function tests. The caffeine (CYP1 A2), chlorzoxazone (CYP2E1), lidocaine (CYP3 A) and midazolam (CYP3 A) function tests and the erythromycin breath test (CYP3 A) are currently being used as specific probes. The future use of these tests needs to be discussed in terms of potential clinical implications.

Aminopyrine↗
PubMed1997

Epidural and intrathecal n-butyl-p-aminobenzoate solution in the rat. Comparison with bupivacaine.

BACKGROUND: Epidural administration of an aqueous suspension of n-butyl-p-aminobenzoate (BAB) to humans results in long-lasting sensory blockade without motor block. The dose-response of BAB administered epidurally and intrathecally as a solution was studied in rats to define the local anesthetic properties in an established animal model. METHODS: The time course of changes in tail withdrawal latency and motor function were determined in rats after epidural or intrathecal administration of solutions of BAB or bupivacaine. The dose-response relation was determined and median effective dose values were calculated. RESULTS: After epidural and intrathecal administration of BAB solutions, the onset and duration of the antinociceptive action were comparable to bupivacaine. Median effective dose values for tail-withdrawal latency of 6 s or more were significantly greater for BAB. After both routes of administration, BAB clearly affected motor function. CONCLUSIONS: When administered epidurally and intrathecally as a solution, BAB is a local anesthetic of relative low potency with onset and duration of action comparable to those of bupivacaine. These findings suggest that the long-lasting action obtained after applying BAB suspension results from the slow dissolution (continuous release) of the solid BAB deposited in the epidural space.

Anesthesia, Epidural↗
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↗