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L Ståhle

Publications and source records attributed to L Ståhle.

At least 55 records · Page 3Linked to original sources
PubMed1993

Pharmacokinetics and extracellular distribution to blood, brain, and muscle of alovudine (3'-fluorothymidine) and zidovudine in the rat studied by microdialysis.

Microdialysis was applied to sample the free drug concentration in the extracellular fluid in brain, muscle, and blood of rats given alovudine (n = 6) (3'-fluorothymidine) or zidovudine (n = 5) (25 mg/kg s.c.). Alovudine and zidovudine were analyzed by means of high performance liquid chromatography (HPLC) with UV detection. The assay for zidovudine was validated by a radioimmunoassay. In addition, the plasma protein binding of the drugs was measured by microdialysis in vitro. The concentrations attained in blood and muscle were similar for each drug, with a Cmax of 57 microM (blood) and 54 microM (muscle) for alovudine and 38 and 46 microM, respectively, for zidovudine. In contrast the Cmax in brain was 8 microM for alovudine and 4 microM for zidovudine. The peak concentration was attained 20-40 min after injection in blood and muscle and 40-60 min after injection in the brain. The half-lives of zidovudine in both blood and muscle were 37 min and in brain 69 min. For alovudine the corresponding half-lives were significantly longer: 61, 58, and 105 min, respectively. The ratio of the AUC0-180 brain/blood was 0.257 for alovudine and 0.186 for zidovudine. The plasma protein binding of zidovudine was 10%, while alovudine was virtually unbound.

Animals↗
PubMed1992

Do autoreceptors mediate dopamine agonist--induced yawning and suppression of exploration? A critical review.

The hypothesis that stimulation of dopamine autoreceptors is the mechanism by which dopamine agonists induce yawning and suppression of exploration is critically examined. It is shown that the relation between reduced extracellular dopamine levels, assessed by microdialysis, and behavioural effects of dopamine agonists, a dopamine synthesis inhibitor and a granule storage blocker is highly inconsistent. The time-course and duration of the behavioural effects of dopamine agonists differ from the reduction of extracellular dopamine. Amphetamine cotreatment is shown to increase dopamine levels, while yawning and suppression of exploration can still be induced. The data strongly indicate that autoreceptors are not the mediators of these behavioural effects. It is proposed that postsynaptic receptors mediate dopamine agonist induced yawning and suppression of exploration. Evidence is also presented showing that yawning and suppression of exploration are not functionally equivalent.

Animals↗
PubMed1992

Pharmacokinetic estimations from microdialysis data.

Microdialysis has recently been adapted for sampling the extracellular fluid of various organs in order to measure drug concentrations, and the first clinical application has been published. My aim here is to provide simple rules about how to analyse pharmacokinetic data from such studies. The plotting of data on a time scale and the estimation of C (0) and slopes is not a trivial problem when multicompartmental models are assumed or sampling intervals are unequal. I have developed formulae and algorithms to solve the problem. A simple rule of thumb is given, suggesting when these formulae need to be applied. It is shown that the calculations of half-life and slopes is similar to standard methods for equal sample intervals and that calculation of AUC and clearance may be even more accurate for microdialysis data than for ordinary blood sampling, because of the time-integral character of the dialysis method. I have dealt with both zero-order and first-order kinetics.

Animals↗
PubMed1992

Penetration of zidovudine and 3'-fluoro-3'-deoxythymidine into the brain, muscle tissue, and veins in cynomolgus monkeys: relation to antiviral action.

Cynomolgus monkeys had microdialysis probes implanted under ketamine anesthesia into peripheral veins, thigh muscles, and the brain in order to sample the extracellular fluid for the concentrations of unbound nucleoside analogs. A dose of 25 mg of zidovudine or 3'-fluoro-3'-deoxythymidine (FLT) per kg was administered subcutaneously to each of three animals. Relatively high antiviral concentrations of FLT and zidovudine were present in peripheral tissues and in the brain. It was found that the concentration of zidovudine in the brain was approximately one-third of that in muscle and veins; the same relation was observed for FLT. The in vivo unbound concentrations of both drugs in the brain, muscle, and venous blood exceeded those reported to inhibit human immunodeficiency virus replication in vitro. In addition, in a correlative study we found that the appearance of p24 antigen in sera of monkeys infected with simian immunodeficiency virus was significantly delayed by both compounds (15 mg/kg three times daily for 9 days after infection). Thus, we have shown that the extracellular concentrations of unbound FLT and zidovudine in the brain and peripheral tissues attained with in vivo antiviral doses exceed in vitro antiviral concentrations.

Animals↗
PubMed1992

Pharmacokinetics and distribution over the blood brain barrier of two acyclic guanosine analogs in rats, studied by microdialysis.

The free extracellular concentrations of acyclovir and (R)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine (H2G) in the blood and in brain tissue of rats were measured in microdialysis samples by high-pressure liquid chromatography with UV detection. The half-life of acyclovir in blood was 2 h, while that of H2G was 28 min. The concentration attained in the brain compared with the concentration in blood was slightly lower for H2G than for acyclovir. The results show that the pharmacokinetic profiles of acyclic nucleosides may vary as a consequence of the structure of the acyclic chain corresponding to the sugar moiety.

Acyclovir↗
PubMed1992

Long-term tolerance and efficacy of 3'-azidothymidine and 3'-fluorothymidine treatment of asymptomatic monkeys infected with simian immunodeficiency virus.

Macaques chronically infected with simian immunodeficiency virus were treated with zidovudine (20 mg/kg of body weight per day for 9 weeks) or 3'-fluorothymidine (5 mg/kg of body weight per day for 9 weeks or three doses of 2 mg/kg per day for 24 days). Hematological changes in the treated animals included macrocytic anemia and leukopenia. Determination of antiviral effects in this model requires improved assay methods.

Anemia↗
PubMed1991

Drug distribution studies with microdialysis: I. Tissue dependent difference in recovery between caffeine and theophylline.

Microdialysis was applied to estimate concentrations of caffeine and theophylline in vitro or in vivo in blood, adipose tissue, muscle, liver and brain of rats. The in vivo and in vitro recovery of a compound was estimated by perfusing the dialysis probe with varying concentrations of caffeine and theophylline. The difference between the concentration in the dialysate and the concentration in the perfusion medium was plotted against the concentration in the perfusion medium and the slope of the resulting line was taken as an estimate of the recovery (difference method). In all experiments caffeine (20 mg/kg sc) and theophylline (20 mg/kg sc) were administered simultaneously. The recovery in vitro was virtually identical for caffeine and theophylline. The in vivo recovery of theophylline was significantly smaller than the recovery of caffeine in brain, liver, muscle and adipose tissue. The difference in recovery was significantly larger in the brain than in other tissues. The results show that the transport of a substance from the tissue to the dialysis probe may differ between tissues and between chemically very similar compounds. It is shown that the recovery of theophylline rapidly declines after death ensues which shows that energy-dependent processes are involved in the transport to the dialysis probe and not solely passive diffusion. It is suggested the differences in transport over brain capillaries explain the difference between caffeine and theophylline. It is concluded that the use of internal standards in microdialysis experiments requires validation in every specific application.

Adipose Tissue↗
PubMed1991

Drug distribution studies with microdialysis. II. Caffeine and theophylline in blood, brain and other tissues in rats.

Microdialysis was applied to estimate the pharmacologically active concentration of caffeine and theophylline in blood, adipose tissue, muscle, liver and brain of rats. The concentration of the drugs in the extracellular space was estimated by perfusion with varying concentrations of the drug through the microdialysis probe (difference method). Caffeine (20 mg/kg) was found to be evenly distributed with a free concentration of approximately 120 microM. Theophylline concentration in the brain was 91 microM and in other tissues approximately 120 microM. The rate of penetration into brain extracellular space was higher for caffeine than for theophylline. It is suggested that the lower levels of theophylline attained in the brain may to some extent explain the differences in clinical action profile between caffeine and theophylline.

Adipose Tissue↗
PubMed1991

Drug distribution studies with microdialysis. III: Extracellular concentration of caffeine in adipose tissue in man.

Microdialysis was applied to estimate the extracellular concentration of caffeine in subcutaneous abdominal adipose tissue of five healthy volunteers after oral administration of approximately 5 mg/kg (300 or 400 mg) of caffeine. The peak extracellular levels were in the range of 20 - 80 microM. The time-course in blood and in extracellular fluid was similar but the plateau concentrations were not closely correlated. The estimated mean concentration of five individuals was similar in blood and extracellular fluid. The intraindividual variation between probes was found to be small compared to the interindividual variation (8% versus 43%). It is concluded that microdialysis yield useful data on drug distribution in man and that distribution to adipose tissue may not strictly follow the concentrations in blood. A comparison with available information of the in vitro properties of caffeine shows that the levels attained in the extracellular fluid were too small to significantly affect phosphodiesterase but sufficiently high to block adenosine receptors.

Adipose Tissue↗
PubMed1991

A comparison between three methods for estimation of extracellular concentrations of exogenous and endogenous compounds by microdialysis.

In vitro models simulating tissues were used to test the validity of three methods for determining the free concentration of drugs and endogenous compounds in the extracellular space by means of microdialysis. Theophylline was used as a model substance. Recovery is defined as the proportion of compounds extracted from the medium surrounding the probe. The water recovery method is the use of recovery, determined in a water solution, to estimate concentrations in other media. This method was shown to underestimate the surrounding concentration when the effective rate of diffusion is smaller in the other medium than in water. The difference method measures the net transport over the dialysis membrane at varying concentrations in the perfusion medium. The point of equilibrium, where no net transport takes place, is used to estimate the surrounding concentration. The perfusion rate method involves two phases. In the first phase (calibration), surrounding media with different diffusion characteristics were used as tissue models. The amount recovered at different perfusion rates was measured and a multivariate regression method was used to calculate a mathematical model. In the second phase, the mathematical model was used to predict the concentration in the surrounding medium in new experiments. The two latter methods gave satisfactory predictions of the surrounding concentrations. Protein binding did not affect the methods. It is concluded that the difference method and the perfusion rate method may be used to estimate the in vivo concentration of drugs and endogenous compounds.

Animals↗
PubMed1991

Relating multivariate time-series by linear three-way decomposition (LTD) and partial least squares (PLS) analysis.

The problem of relating multivariate time-series which is common in drug development is considered. The mathematical and statistical problems involve relating two three-way tables. These tables have objects and time-points in common while the variables to be related are unique for each table. A modification is presented of the linear three-way decomposition (LTD) algorithm which directly incorporates the information that both objects and time-points are common to the two tables. A comparison is made with partial least squares (PLS) analysis both at the theoretical level and in their application to three sets of real data. Limitations of LTD are discussed, in particular the constraint imposed by the trilinearity requirement, and areas for future development are proposed.

Amphetamine↗
PubMed1991

Microdialysis of lipophilic compounds: a methodological study.

The influence of perfusion medium on in vitro recovery of 14C-oleate to microdialysis probes was investigated. Four perfusion media were investigated: water, 4% bovine serum albumin (BSA) in Ringer solution, 2.25% glycerol in water and a 20% soybean oil/egg phospholipid emulsion (Intralipid). The following order of recovery was found (highest recovery first): BSA = Intralipid greater than glycerol greater than water. The recoveries at 0.5 microliter/min. perfusion rate of the dialysis probe were 4.8%, 4.4%, 2.6% and 1.2% respectively. It was attempted to measure 14C-oleate after intravenous infusion. The samples were extracted with hexane/isopropyl alcohol in order to separate the free fatty acid from products of oxidation which are hydrophilic. Dialysis probes were implanted in interscapular adipose tissue, epididymal fat, muscle, liver and jugular vein of rats. We were not able to detect unbound fatty acids, neither basally nor after stimulation with 1 mg/kg norepinephrine intraperitoneally. However, products of oxidation from the infused oleate were released in response to norepinephrine stimulation. It is concluded that the recovery of lipophilic compounds in microdialysis devices can be improved by means of a lipophilic perfusion medium or by means of e.g. BSA to which the compound binds. The free fatty acid levels were too small to be measureable in vivo in the present study.

Animals↗
PubMed1991

Antiviral effects of 3'-fluorothymidine and 3'-azidothymidine in cynomolgus monkeys infected with simian immunodeficiency virus.

An acute infection with simian immunodeficiency virus (SIVSM) in cynomolgus monkeys was used to evaluate the antiviral effects of 3'-fluorothymidine (FLT) and 3'-azidothymidine [zidovudine (ZDV)]. Neither compound prevented the infection despite dosing prior to virus inoculation. FLT was about ten times more potent than ZDV in delaying the appearance of SIVSM antigen in the monkeys. The serum half-life of FLT was longer than that of ZDV and ZDV was bound to plasma proteins to about 60% while FLT was virtually unbound. It is proposed that the in vivo difference in potency between ZDV and FLT could, at least partly, be explained as the combined effects of a longer plasma half-life and a higher free concentration of FLT and possibly a higher intracellular concentration of the triphosphate of FLT.

Animals↗
PubMed1990

Theophylline concentration in the extracellular space of the rat brain: measurement by microdialysis and relation to behaviour.

The free extracellular concentration of theophylline in the brain was estimated from microdialysis samples. Two different methods were used to estimate extracellular concentrations by microdialysis, the perfusion rate method and the difference method. Theophylline 20 mg/kg (s.c.) gave a sufficiently stable level of theophylline in the brain 60 min after injection and lasting over the observation period to allow application of the two methods in vivo. The relation between dose and dialysate concentration was linear. It was found that doses of 20-24 mg/kg theophylline corresponded to a free extracellular concentration of 60-90 microM. The behaviour of theophylline-treated rats was assessed in parallel experiments by means of a holeboard apparatus. Behavioural activation was observed in the dose-range 3-30 mg/kg. It is concluded that behavioural effects of theophylline can be induced at a concentration well below that required to inhibit phosphodiesterase but within the range in which adenosine receptor blockade may be observed, suggesting that the latter mechanism is responsible for the behavioural effects of theophylline.

Animals↗
PubMed1990

Effects of halothane anaesthesia on extracellular levels of dopamine, dihydroxyphenylacetic acid, homovanillic acid and 5-hydroxyindolacetic acid in rat striatum: a microdialysis study.

The effects of halothane anaesthesia on striatal extracellular levels of dopamine, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5HIAA) were investigated in microdialysis experiments. Induction of anaesthesia was accompanied by a rapid increase in dopamine levels and a slower increase in DOPAC and HVA. 5HIAA was not affected. The reduction of dopamine levels induced by apomorphine 0.05 mg/kg appeared with a shorter latency in conscious rats than in anaesthetised rats but the maximum decrease was unaffected by anaesthesia. The decreases in dopamine and DOPAC induced by alpha-methyl-p-tyrosine 50 mg/kg were affected in opposite directions by halothane: the dopamine reduction was more pronounced while the DOPAC reduction was less pronounced in anaesthetized than in conscious animals. In no case was a qualitative shift in the response observed. It is concluded that halothane may influence the levels of dopamine as well as the response to dopaminergic drugs.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Yawning and suppression of exploration induced by dopamine agonists: no relation to extracellular striatal levels of dopamine.

The present study was aimed at testing the hypothesis that yawning and suppression of exploration induced by low doses of dopamine agonists in the rat are caused by a reduction of synaptic dopamine levels. The decrease in extracellular levels of dopamine in the corpus striatum induced by alpha-methyl-p-tyrosine (alpha MPT, 50-200 mg/kg IP), reserpine (2-5 mg/kg SC) and apomorphine (APO, 0.05 mg/kg SC) was measured in microdialysis experiments. Reserpine and alpha MPT reduced the dopamine levels to the same extent as APO. Exploratory behaviour was suppressed by APO, but not by alpha MPT (50 and 100 mg/kg) when tested in a separate experiment. Reserpine (2 mg/kg) suppressed exploration after 4 hr, but not after 3 hr. Changes in extracellular levels of dopamine were tested simultaneously with changes in yawning in another group of rats implanted with guide cannulae for microdialysis probes. There was a discrepancy in the time-course for the induction of yawning as compared to the changes in extracellular dopamine levels after APO (0.05 mg/kg) as well as after pergolide (0.02 mg/kg SC). Yawning appeared before and lasted shorter than the decrease in dopamine. The time-courses for APO-induced suppression of exploration and yawning were similar. The dose-response curve for APO-induced yawning was not changed by alpha MPT (200 mg/kg), while the suppression of exploration induced by APO, but not by pergolide, was enhanced by pretreatment with alpha MPT. The results show that yawning and suppression of exploration induced by dopamine agonists are not related to changes in extracellular levels of dopamine. It is proposed that these behaviours may be mediated by postsynaptic receptors.

Animals↗
PubMed1989

Yawning and suppression of exploration in amphetamine-treated rats, incompatibility with the autoreceptor hypothesis.

The hypothesis that yawning and suppression of exploration, induced by low doses of dopamine agonists, are mediated by stimulation of dopamine autoreceptors was tested by studying the influence of amphetamine on these behavioural models and on extracellular levels of dopamine sampled by microdialysis. Behaviour was measured in a holeboard apparatus. A low dose of amphetamine (0.2 mg/kg) caused slight activation of habituated rats. The same dose of amphetamine completely counteracted the decrease in extracellular dopamine levels caused by pergolide (0.02 mg/kg) and, instead, elevated the dopamine levels to 300% above baseline. The same or higher doses of amphetamine (0.5-1.0 mg/kg) did not completely antagonise suppression of exploration or yawning induced by apomorphine (0.05 mg/kg) or pergolide (0.02 mg/kg). The results suggest that both yawning and suppression of exploration induced by low doses of dopamine agonists are not mediated by dopamine autoreceptors, since these behaviours could be elicited when the extracellular levels of dopamine were elevated above baseline. The alternative hypothesis that these behaviours are mediated by sensitive post-synaptic receptors is suggested. It was also found that combined treatment with SCH 23390 (0.05 mg/kg) and amphetamine (2 mg/kg) induced yawning, which further supports the new hypothesis.

Amphetamine↗