Biomedical subjects

L Ståhle

Publications and source records attributed to L Ståhle.

At least 37 records · Page 2Linked to original sources

PubMed1999

Distribution to the skin of penciclovir after oral famciclovir administration in healthy volunteers: comparison of the suction blister technique and cutaneous microdialysis.

Penciclovir is a drug active against herpes simplex viruses located in the epidermis basal layer. The aim of this study was to compare the suction blister technique and microdialysis as methods to measure the penciclovir concentration in the skin after a single dose (250 mg) of its prodrug, famciclovir. Suction blister fluid, microdialysates and plasma were sampled from 11 healthy volunteers for 5 h after famciclovir administration. Both the suction blister technique and microdialysis showed that penciclovir reaches the skin in concentrations sufficient to inhibit herpes virus replication. The maximum concentration in both suction blister fluid and in microdialysate was observed later than in plasma. The microdialysis concentration was decreased by cooling of the skin surface and by adrenaline-mediated vasoconstriction. The microdialysis recovery of penciclovir was studied with respect to the flow-rate of perfusion medium through the microdialysis probe. Microdialysis and the suction blister technique can be used to study the time-concentration profile of penciclovir in the skin and microdialysis allows a continuous sampling of the drug for a prolonged time after administration.

2-Aminopurine↗

PubMed1999

Distribution and elimination of the solute and water components of urological irrigating fluids.

OBJECTIVE: Irrigating fluids are used to dilate mucosal spaces and to remove blood and cut tissue from the operating field during endoscopic procedures. We have studied their disposition, since irrigating solutions are sometimes absorbed and may therefore be regarded as intravenous drugs. MATERIAL AND METHODS: The distribution and the rate of elimination of four irrigating fluids containing glycine, mannitol and sorbitol were studied after infusing 0.75 ml/kg/min of them over a period of 20 min in 10 male volunteers. Kinetic calculations were based on 12 blood samples collected over 120 min using traditional pharmacokinetics for the solutes and volume kinetics for the water component. RESULTS: The solutes had distribution half-lives of between 3 and 7 min; the elimination half-lives were 39 min (glycine), 97 min (mannitol) and 33 min (sorbitol). The volume of distribution during steady state was between 20 and 36 litres, while the volume of the body fluid space expanded by the water component of the irrigating fluids varied between 6 and 9 litres. Although the solutes became distributed over a much larger space than the infused fluid volume, the intersubject variation was smaller for the solute concentrations than for the dilution of the plasma fraction of the blood. CONCLUSIONS: The kinetics of the solute and water components of urological irrigating fluids can be analysed and compared using computer-based mathematical models.

Adult↗

PubMed1999

Microdialysis for pharmacokinetic studies of ceftazidime in rabbit vitreous.

The method of microdialysis was used for collecting series of samples from the rabbit vitreous after systemic and intravitreous administration of ceftazidime. The purpose of the study was to compare the method with traditional pharmacokinetic sampling. Ceftazidime was injected intramuscularly (1 mg/kg) or intravitreally (1 mg) in rabbits, with a previously implanted microdialysis probe in the vitreous. The membrane was perfused with a buffer, and the dialysate was collected in samples where the concentration of the drug was analyzed by HPLC. After intramuscular administration, blood samples were taken to calculate systemic pharmacokinetics. The same procedures were repeated with rabbits with mild intraocular inflammation induced by the injection of 400 EU of endotoxin into the vitreous, 12-15 hr before drug administration. Pharmacokinetic parameters, such as half-life and AUC, were calculated. The penetration into the vitreous after intramuscular injection was higher (42%) in inflamed than in non-inflamed eyes (20%), suggesting an interference with the blood retinal barrier. Other kinetic parameters did not differ significantly between the groups. The advantage of the method is that fewer experimental animals can be used to obtain the necessary data compared to traditional pharmacokinetic methods. In conclusion, intraocular dialysis with chronically implanted probes is a technique well suited for pharmacokinetic studies of systemically administered ceftazidime or other drugs that will pass a dialysis membrane.

Administration, Topical↗

PubMed1999

Lamotrigine drug interactions in a TDM material.

Using therapeutic drug monitoring (TDM) data from our laboratory, we have studied the concentration/dose relationship for lamotrigine and the influence of drug interactions in clinical practice. One hundred forty-nine lamotrigine samples from 104 adult patients were included in the study. The samples were collected as steady-state trough values, 9-16 hours after dose intake. Concomitant drug treatment was specified on the analysis request form. Lamotrigine serum concentrations were determined by high-performance liquid chromatography (HPLC). In 20 patients in monotherapy, the concentration/dose (C/D) ratio was 65 (range: 50-84) nmol/L/mg (mean and 95% confidence interval, antilog from lognormal distribution). In 37 patients with concomitant carbamazepine treatment, the C/D ratio was less than half that of the patients in monotherapy; 31 (2146) nmol/L/mg, and in 14 patients with phenytoin, it was even lower; 17 (13-23) nmol/L/mg. Valproic acid significantly increased the C/D to 251 (200-320) nmol/L/mg in 13 patients. Triple therapy with valproic acid and either carbamazepine or phenytoin (23 patients) yielded a C/D slightly above that of monotherapy, whereas a few patients on phenobarbital had a C/D slightly below that of monotherapy. The within-group C/D variation was comparatively small. The C/D ratio in a mixed lamotrigine TDM material shows a widespread intra- and interindividual variation, which can largely be explained by pharmacokinetic interactions with concomitantly used antiepileptic drugs. These results support the use of TDM in lamotrigine therapy.

Adolescent↗

PubMed1999

Estimation of topiramate in subdural cerebrospinal fluid, subcutaneous extracellular fluid, and plasma: a single case microdialysis study.

PURPOSE: To estimate topiramate (TPM) concentrations in subdural cerebrospinal fluid (CSF), subcutaneous extracellular fluid (ECF), and plasma and to study the correlation of TPM concentrations in these three different compartments. METHODS: In this single case study of a patient with drug-resistant partial epilepsy undergoing presurgical evaluation with subdural EEG monitoring, we used microdialysis to estimate concentrations of unbound TPM in CSF of the subdural space and ECF of abdominal subcutaneous tissue. Blood samples were drawn for estimation of TPM concentrations in plasma. RESULTS: The correlation between unbound TPM concentrations in subdural CSF and abdominal subcutaneous ECF was good. The mean ratio of ECF/CSF TPM concentration was 0.93 (SD+/-0.03) and the correlation coefficient was 0.98. The mean ratio of ECF/total plasma TPM was 0.75 (SD+/-0.06), and the correlation coefficient was 0.99. The mean ratio of CSF/total plasma TPM was 0.81 (SD+/-0.06), and the correlation coefficient was 0.97. CONCLUSIONS: Assuming a protein binding of TPM of approximately 13%. it is concluded that, based on nine microdialysis samples from a single subject, TPM levels in the CSF at the cortical surface are approximately the same as the unbound plasma levels. Additional patients should be studied to confirm the results.

Adult↗

PubMed1998

Monitoring in situ liver metabolism in rats using microdialysis. Comparison of microdialysis mass-transport model predictions to experimental metabolite generation data.

The generation of metabolites from two model compounds, phenacetin and acetaminophen, included in the perfusion fluid of a microdialysis probe implanted into rat liver was studied. When 60 microM phenacetin was included in the perfusion fluid using a flow rate of 1.0 microL/min, acetaminophen and acetaminophen sulfate were recovered at concentrations that ranged between 0.4 and 1.6 microM. Acetaminophen sulfate ([AS]gain) diffused back into the microdialysis probe on a micromolar percentage basis of 8.9+/-2.4% (n = 3) when acetaminophen was passed through the probe at a concentration between 11 and 12 microM. When 220-240 microM acetaminophen was passed through the probe, the percentage of acetaminophen sulfate recovered was 4.8+/-1.4% (n = 3) (P < 0.1 compared to the 11 microM group). No acetaminophen glucuronide was detected in the dialysate samples. A mathematical model that describes mass transport in microdialysis sampling was used to predict the concentration of metabolite that could be recovered into the dialysate after the loss of a substrate compound that undergoes metabolism. The model predicts a metabolite recovery of 23.6% using estimates for phenacetin metabolism and 21.5% using estimates for acetaminophen metabolism. The results presented here indicate that microdialysis has potential to be used to study local in situ metabolism and with further refinements of the microdialysis mass-transport model may be used to estimate in vivo metabolic formation rates.

Acetaminophen↗

PubMed1998

Two commonly expanded CAG/CTG repeat loci: involvement in affective disorders?

An association between bipolar affective disorder and CAG/CTG trinucleotide repeat expansions (TRE) has previously been detected using the repeat expansion detection (RED) method. Here we report that 89% of RED products (CAG/CTG repeats) > 120 nt (n = 202) detected in affective disorder patients as well as unaffected family members and controls correlate with expansions at two repeat loci, ERDA1 on chromosome 17q21.3 and CTG18.1 on 18q21.1. In a set of patients and controls in which we had previously found a significant difference in RED size distribution, the frequency of expansions at the CTG18.1 locus was 13% in bipolar patients (n = 60) and 5% in controls (n = 114) (P < 0.07) with a significantly different size distribution (P < 0.03). A second set of patients were ascertained from 14 affective disorder families showing anticipation. Twelve of the families had members with RED products > 120 nt. The RED product distribution was significantly different (P < 0.0007) between affected (n = 53) and unaffected (n = 123) offspring. Using PCR, a higher frequency (P < 0.04) of CTG18.1 expansions as well as a different (P < 0.02) repeat size distribution was seen between affected and unaffected offspring. In addition, a negative correlation between RED product size and the age-of-onset could be seen in affected offspring (rs = -0.3, P = 0.05, n = 43). This effect was due to an earlier onset in individuals with long CTG18.1 expansions. No difference in ERDA1 expansion frequency was seen either between bipolar patients (35%, n = 60) and matched controls (29%, n = 114), or between affected and unaffected offspring in the families. We conclude that expanded alleles at the CTG18.1 locus confers an odds ratio of 2.6-2.8 and may thus act as a vulnerability factor for affective disorder, while the ERDA1 locus seems unrelated to disease.

Bipolar Disorder↗

PubMed1998

Validation of microdialysis sampling for subcutaneous extracellular valproic acid in humans.

This article is the second in a series of studies aimed at monitoring valproic acid pharmacokinetics in patients with epilepsy by subcutaneous microdialysis. In the current study, a detailed investigation on healthy volunteers is made of the relationship between total concentrations in plasma, free concentrations in plasma, and dialysate concentrations. Particular emphasis is put on validating that the in vivo recovery under standard conditions (30 mm dialyzing membrane and 0.5 microl/minute perfusion rate) is sufficiently close to 100%. It was found that the recovery was very close to 100% at 0.5 microl/minute and by in vitro studies it could be excluded that valproic acid binds to the dialysis equipment. The correlation between unbound plasma concentrations and microdialysis concentrations of valproic acid was acceptable (r = 0.80), and they did not differ systematically from one another. It is concluded that microdialysis can be used to sample subcutaneous extracellular valproic acid in a clinical setting giving reliable estimates of the unbound concentration in plasma.

Anticonvulsants↗

PubMed1998

Pharmacokinetics and distribution over the blood-brain barrier of zalcitabine (2',3'-dideoxycytidine) and BEA005 (2', 3'-dideoxy-3'-hydroxymethylcytidine) in rats, studied by microdialysis.

Microdialysis was applied to sample the unbound drug concentration in the extracellular fluid in brain and muscle of rats given zalcitabine (2',3'-dideoxycytidine; n = 4) or BEA005 (2', 3'-dideoxy-3'-hydroxymethylcytidine; n = 4) (50 mg/kg of body weight given subcutaneously). Zalcitabine and BEA005 were analyzed by high-pressure liquid chromatography with UV detection. The maximum concentration of zalcitabine in the dialysate (Cmax) was 31.4 +/- 5. 1 microM (mean +/- standard error of the mean) for the brain and 238. 3 +/- 48.1 microM for muscle. The time to Cmax was found to be from 30 to 45 min for the brain and from 15 to 30 min for muscle. Zalcitabine was eliminated from the brain and muscle with half-lives 1.28 +/- 0.64 and 0.85 +/- 0.13 h, respectively. The ratio of the area under the concentration-time curve (AUC) (from 0 to 180 min) for the brain and the AUC for muscle (AUC ratio) was 0.191 +/- 0.037. The concentrations of BEA005 attained in the brain and muscle were lower than those of zalcitabine, with Cmaxs of 5.7 +/- 1.4 microM in the brain and 61.3 +/- 12.0 microM in the muscle. The peak concentration in the brain was attained 50 to 70 min after injection, and that in muscle was achieved 30 to 50 min after injection. The half-lives of BEA005 in the brain and muscle were 5.51 +/- 1.45 and 0.64 +/- 0.06 h, respectively. The AUC ratio (from 0 to 180 min) between brain and muscle was 0.162 +/- 0.026. The log octanol/water partition coefficients were found to be -1.19 +/- 0.04 and -1.47 +/- 0.01 for zalcitabine and BEA005, respectively. The degrees of plasma protein binding of zalcitabine (11% +/- 4%) and BEA005 (18% +/- 2%) were measured by microdialysis in vitro. The differences between zalcitabine and BEA005 with respect to the AUC ratio (P = 0.481), half-life in muscle (P = 0.279), and level of protein binding (P = 0.174) were not statistically significant. The differences were statistically significant in the case of the half-life in the brain (P = 0.032), clearance (P = 0.046), volume of distribution (P = 0.027) in muscle, and octanol/water partition coefficient (P = 0.019).

Animals↗

PubMed1998

Cholesterol homeostasis in human brain: turnover of 24S-hydroxycholesterol and evidence for a cerebral origin of most of this oxysterol in the circulation.

We have previously demonstrated that the brain contains about 80% of the 24S-hydroxycholesterol in the human body and that there is a net flux of this steroid from the brain into the circulation (Lütjohann, D. et al. 1996. Proc. Natl. Acad. Sci. USA. 93: 9799-9804). Combining previous data with new data on 12 healthy volunteers, the arteriovenous difference between levels of this oxysterol in the internal jugular vein and in a peripheral artery was found to be -10.2 +/- 2.8 ng/ml (mean +/- SEM) corresponding to a net flux of 24S-hydroxycholesterol from the brain of about 6.4 mg/24 h. The arteriovenous difference between levels of 24S-hydroxycholesterol in the hepatic vein and a peripheral artery of 12 other volunteers was found to be 7.4 +/- 2.2 ng/ml, corresponding to a hepatic uptake of about 7.6 mg/24 h. The concentrations of 24S-hydroxycholesterol in the renal vein were about the same as those in a peripheral artery, indicating that a renal elimination is not of importance. Intravenously injected deuterium-labeled racemic 24-hydroxycholesterol was eliminated from the circulation of two human volunteers with half-lives of 10 h and 14 h, respectively. A positive correlation was found between the levels of circulating cholesterol and 24S-hydroxycholesterol. The results are consistent with a cerebral origin of most of the circulating 24S-hydroxycholesterol and suggest that the liver is the major eliminating organ. It is concluded that conversion into 24S-hydroxycholesterol is a quantitatively important mechanism for elimination of cholesterol from human brain. The possibility is discussed that circulating levels of 24S-hydroxycholesterol can be used as a marker for pathological and/or developmental changes in the brain.

Adult↗

PubMed1998

Luminometric single step urea assay using ATP-hydrolyzing urease.

An automatic enzyme kinetic luminometric method for determination of small quantities of urea in biological fluids and in microdialysates is presented. The method is based on the ATP-hydrolyzing urease reaction [urea amidohydrolase (ATP-hydrolyzing); EC 3.5.1.45], monitored by a luciferin-luciferase ATP reaction. The assay range is 100 pmol to 50 nmol with a detection limit of 5 micromol/L in the sample, compared with detection limits of 0.1 mmol/L in earlier spectrophotometric methods. To reduce the non-urea-dependent ATPase activity (v(blank)) and to increase the urea-dependent activity, 1,2-propanediol was included. Assay conditions were optimized by multivariate analysis. Recoveries of urea added to blood dialysate and plasma were 96-103%. No analytical interference of common metabolites, drugs, or other additives was observed. The total CVs (6 days and six concentrations, 1.2-21.8 mmol/L) were 3.6-8.5%. The results obtained with the present assay were highly correlated for dialysate (r = 0.979) and for plasma (r = 0.978) with those obtained by a spectrophotometric kit method with slopes of 1.02-1.03 and intercepts of 0.08-0.23 mmol/L.

Adenosine Triphosphate↗

PubMed1997

Factors that influence microdialysis recovery. Comparison of experimental and theoretical microdialysis recoveries in rat liver.

Inhibition of metabolic processes was used to assess the possible change in the recovery of material from a microdialysis probe implanted in vivo in rat liver. Phenacetin and antipyrine were perfused through a microdialysis probe implanted in the liver. Inhibition of phenacetin and antipyrine metabolism was achieved through an iv bolus dose of the cytochrome P450 suicide substrate 1-aminobenzotriazole (1-ABT). 1-ABT inhibited phenacetin clearance by 90%, thus also inhibiting metabolism by 90%. There was no statistical difference in the recovery of phenacetin and antipyrine across the microdialysis membrane in the liver between the control and metabolically inhibited animals. Partial differential equations were developed that describe the transport of analyte from the microdialysis probe and solved by an implicit finite-difference method to aid in the understanding of the above-mentioned microdialysis experiments. Predictions of microdialysis recovery obtained from the numerical model are compared with those found experimentally. The model could predict trends in the data, but not the actual experimental values. This suggests that predictions from this microdialysis model are essentially heuristic and as presently formulated can be used only to show mechanisms that affect recovery, but they cannot be used to accurately predict recovery. Prediction of actual recovery requires knowledge of the values of the parameters that describe chemical properties such as the in vivo diffusion coefficient, metabolism rate constant, and capillary exchange rate constant. For microdialysis experiments performed in the liver, capillary exchange and the rate of liver blood flow appear to be the dominant processes that facilitate net transport from a microdialysis probe rather than metabolic processes. These results indicate that microdialysis recoveries measured after inhibition of a concentration-dependent kinetic process via pharmacological challenge will change only when the kinetic process that is being challenged is large compared to the contribution of all concentration-dependent kinetic processes, including other metabolism routes, capillary exchange, or uptake that remove the analyte from the tissue space. It is concluded that the microdialysis recovery of a substance from the liver is not generally affected by liver metabolism.

Animals↗

PubMed1997

Modelling the volume of expandable body fluid spaces during i.v. fluid therapy.

We have developed mathematical models to represent the changes in volume of fluid spaces associated with i.v. administration of a crystalloid solution. Input data for parameter estimations were dilution of blood, measured as reduction of blood haemoglobin concentration. The models were based on the assumption that the body strives to maintain volume homeostasis of fluid spaces and that the rate of restoration is a function of deviation from resting volume. Two models were derived; the first had a single fluid space into which fluid was administered and from which fluid left, the other model had a second fluid space communicating with the first. These models may be useful in the description and analysis of the effects of i.v. fluid therapy.

Adult↗

PubMed1997

Volume kinetics of Ringer's solution in female volunteers.

The kinetics of crystalloid solutions in humans have not been adequately described previously. Therefore, we measured blood haemoglobin concentration during and for 120 min after i.v. infusion of 25 ml kg-1 of Ringer's acetate solution over 15, 30, 45 and 80 min, and 12.5 ml kg-1 over 30 min in six adult female volunteers. The dilution-time profiles were analysed according to a new kinetic model adapted for fluid spaces. Volume expansion produced by Ringer's solution approached steady state in an exponentially decaying manner when plasma volume had increased by approximately 550 ml. The size of the fluid space expanded by Ringer's solution was only 4.8 litre (95% confidence interval 3.8-5.8 litre) except for the fastest infusion, where it averaged 9.0 litre. The rate of fluid elimination could be predicted as the product of plasma dilution and a constant averaging 95 (95% confidence interval 68-122) ml min-1.

Adult↗

PubMed1996

Monitoring free extracellular valproic acid by microdialysis in epileptic patients.

This report describes the first experiences with monitoring of valproic acid pharmacokinetics in patients with epilepsy by subcutaneous microdialysis. We could demonstrate good correspondence between total concentration in plasma and free concentration in plasma and dialysate. In this study the dialysate concentrations were not corrected for in vivo recovery because the aim was to explore the possibilities of the method in routine clinical work rather than to estimate absolute concentrations in extracellular fluid. In one patient, microdialysis was continued for 3 days without problems. The dialysis probe with a small portable pump could be carried without any notable interference with daily activities of patients in the ward. No side effects were noted. The results encourage further studies along two lines: to investigate the free-concentration effect relation for valproic acid and to monitor drug concentration under nonhospital conditions in order to study the interaction between daily activities and drug concentration.

Adult↗

PubMed1995

Use of multivariate characterization, design and analysis in assay optimization.

A procedure is proposed for utilizing information from previous work on development of LC assays in order to facilitate the analysis of novel compounds related to those previously analysed. The procedure employs a multivariate method from the field of chemometrics, partial least squares analysis (PLS) to combine quantitative information on the chemical properties of a compound with a quantitative description of the column and the mobile phase and then to use this information to form a regression model for the retention time. A test of the procedure was made by using data on nucleoside analogues studied in our laboratory. Data obtained from chromatographic studies of seven compounds tested in a total of 28 combinations of columns and mobile phases (3-5 per compound) were used to calculate a PLS model. The model was then used to predict retention times of nine other substances and the results were compared with experimental data. The predictions were (115 +/- 82%) (95% confidence interval) of the experimentally observed retention times. The results are encouraging and the method will be subject to further and extended investigations.

Chemical Phenomena↗

PubMed1994

Zidovudine and alovudine as cross-wise recovery internal standards in microdialysis experiments?

The study investigates the recovery over the dialysis membrane in microdialysis probes of two thymidine analogues, alovudine and zidovudine, in both the brain and white (epididymal) adipose tissue. There were no significant differences in recovery between the two compounds in neither tissue, but when dialysis probes are perfused with both compounds simultaneously the recovery of alovudine in the brain is reduced from 10.6% to 8.7% with 4-mm long, 0.5-mm diameter probes perfused at 1 microL/min. It is concluded that the substances can be used as internal standards cross-wise in adipose tissue while they are less suitable in the brain.

Adipose Tissue↗

PubMed1993

Zero and first moment area estimation from microdialysis data.

The calculation of classical pharmacokinetic parameters from microdialysis data has been described in a previous paper. In this paper I have derived methods for calculating AUMC and AUC from the time-integral type of data that are generated in microdialysis pharmacokinetics experiments. The method derived to estimate AUC is elementary, but is given a theoretical basis using principles of mathematical real analysis, clearly stating ths assumptions. The method derived to estimate AUMC is a numerical approximation method based on the linear trapezoidal method. A simulation study was performed to evaluate the precision of the methods and to compare them with corresponding methods for analysis of blood sample data. The estimates from the presently derived methods have a small bias and a small variance. In the simulation study I investigated the influence of model parameters, number of samples, size of statistical error, and the size of the AUC beyond the last sample. Finally, I have given numerical examples from real data to illustrate the use of the method.

Humans↗