PubMed Health⌕ Search

Biomedical subjects

L Ståhle

Publications and source records attributed to L Ståhle.

At least 19 recordsLinked to original sources
PubMed2004

Evidence that plasma concentration rather than dose per kilogram body weight predicts ribavirin-induced anaemia.

Ribavirin in combination with interferon alpha-2 or pegylated interferon is the standard treatment for chronic hepatitis C. The current dosage recommendations for ribavirin are based on body weight (bw). Ribavirin is mainly eliminated by the kidneys and we have recently shown that ribavirin plasma concentrations are determined primarily by renal function. It is therefore reasonable to hypothesize that side-effects of ribavirin, i.e. anaemia, should be more closely related to plasma concentrations of ribavirin than to the dose per kg bw. A total of 108 consecutive patients eligible for treatment of chronic hepatitis C were studied. Ribavirin concentrations in plasma were measured by high-performance liquid chromatography (HPLC)-UV after solid-phase extraction in trough samples taken 4, 8 and 12 weeks after the treatment commenced. A total of 213 samples were obtained and the change in the haemoglobin level and the creatinine concentration was measured in addition to ribavirin. The dose of ribavirin per kg bw did not correlate with the drop in haemoglobin level induced by ribavirin. The concentration of ribavirin was non-linearly related to the drop in the haemoglobin level as revealed by fitting a standard Hill equation type dose-response curve. The half maximal drop in haemoglobin was obtained at 4.4 microm. The results from this study suggest that the anaemia induced by ribavirin depends primarily on the concentration of ribavirin, and not on the dose per kg bw. This lends further support to the idea that ribavirin should be dosed according to renal function.

Adult↗
PubMed2001

Ribavirin treatment in dialysis patients with chronic hepatitis C virus infection--a pilot study.

Standard treatment for chronic hepatitis C is with interferon (IFN)-alpha and ribavirin for 6-12 months. In dialysis patients only interferon therapy is currently used due to the lack of knowledge concerning ribavirin dosage and side-effects. The aim of this study was to investigate if ribavirin can be added to interferon when treating dialysis patients with hepatitis C. Five patients on haemodialysis and one patient on peritoneal dialysis with chronic hepatitis C, five with genotype 1 and one with genotype 4, were given interferon-alpha2b 3 MU thrice weekly for 4 weeks, whereafter ribavirin 200-400 mg was added, for an intended total treatment period of 28 weeks. Ribavirin plasma concentrations were monitored, using HPLC. Four patients completed the treatment. One patient suffered marked side-effects from interferon and therapy was terminated. One patient developed heart failure and died after 14 weeks of treatment but the death was not considered treatment related. Based on plasma concentrations, ribavirin doses were frequently adjusted initially. The target concentration (10-15 micromol/L) was reached with average daily doses of 170-300 mg ribavirin. Ribavirin induced anaemia was managed with high doses of erytropoietin (20 000-30 000 IU/week). Five of six patients became hepatitis C virus (HCV)-RNA negative during treatment, but four relapsed post-treatment; one is HCV-RNA negative. Hence ribavirin, in combination with IFN-alpha, can be used to treat dialysis patients with HCV. However, this requires reduced ribavirin doses and close monitoring of ribavirin plasma concentrations and haemoglobin. Ribavirin-induced anaemia can be managed with high doses of erythropoeitin.

Adult↗
PubMed2001

Distribution of valproate to subdural cerebrospinal fluid, subcutaneous extracellular fluid, and plasma in humans: a microdialysis study.

We sought to study the time course of the distribution of valproate (VPA) to subdural cerebrospinal fluid (CSF) in relation to subcutaneous extracellular fluid (ECF) and plasma after a single oral dose and to study the distribution to these three compartments under steady-state conditions. Microdialysis was used to estimate unbound VPA concentrations in subdural CSF and subcutaneous ECF, and blood samples were drawn for estimation of total and unbound VPA plasma concentrations in four patients with drug-resistant partial epilepsy undergoing presurgical evaluation with subdural EEG monitoring. Three patients were given a single oral dose of VPA, and one patient was receiving regular VPA treatment. VPA was analyzed by gas chromatography with flame ionization detection. The distribution of VPA to subdural CSF was rapid (Tmax, 3.5 h in two patients and 5.5 h in one patient) and subject to a minor delay in all three patients compared with that in the subcutaneous tissue ECF (Tmax, 2.5 h in all three patients), which in turn exhibited no evidence of a distribution delay compared with plasma. Subdural CSF levels of VPA were slightly lower than subcutaneous ECF levels (mean ratio, 0.78) and unbound plasma levels (mean ratio, 0.91). VPA rapidly enters the subdural CSF in unbound concentrations marginally lower than those obtained in subcutaneous ECF and plasma. These findings provide a pharmacokinetic rationale for acute administration of VPA. The good correlation between VPA concentrations in subcutaneous ECF and subdural CSF indicates that estimation of unbound VPA concentrations in subcutaneous tissue using microdialysis sampling has the potential to be useful for monitoring purposes.

Administration, Oral↗
PubMed2001

Quantitative pharmacogenetics of nortriptyline: a novel approach.

OBJECTIVE: To quantitatively model nortriptyline clearance as a function of the cytochrome P450 (CYP) 2D6 genotype and to estimate the contribution of genotype to the interindividual variability in steady-state plasma concentration and metabolic clearance. DESIGN: Modelling study using data from two previously published studies. PARTICIPANTS: 20 healthy volunteers receiving single oral doses of nortriptyline and 20 patients with depression on steady-state oral treatment. METHODS: A total of 275 nortriptyline plasma concentrations were analysed by standard nonlinear regression and nonlinear mixed effect models. The pharmacokinetic model was a 1-compartment model with first order absorption and elimination. All participants had previously been genotyped with respect to the CYP2D6 polymorphism. RESULTS: A model in which the intrinsic clearance is a linear function of the number of functional CYP2D6 genes and hepatic blood flow is fixed to 60 L/h gave the closest fit of the pharmacokinetic model to the data. Stable estimates were obtained for population pharmacokinetic parameters and interindividual variances. Assuming 100% absorption, the model allows systemic clearance and bioavailability to be estimated. Bioavailability was found to vary between 0.17 and 0.71, depending on the genotype. Using the frequency distribution of CYP2D6 genotype with the above results we estimate that, in compliant Swedish individuals on nortriptyline monotherapy, the number of functional CYP2D6 genes could explain 21% of the total interindividual variance in oral clearance of nortriptyline and 34% of that in steady-state plasma concentrations. CONCLUSION: Nonlinear mixed-effects modelling can be used to quantify the influence of the number of functional CYP2D6 genes on the metabolic clearance and plasma concentration of drugs metabolised by this enzyme. Gene dose has a significant impact on drug pharmacokinetics and prior knowledge of it may aid in predicting plasma concentration of the drug and thus tailoring patient-specific dosage regimens.

Adolescent↗
PubMed2000

On mathematical models of microdialysis: geometry, steady-state models, recovery and probe radius.

Commonly used methods for microdialysis recovery measurement are reviewed and the zero flow and no net flux methods are suggested as the most robust in practice. Six different mathematical models of microdialysis assumptions are investigated and compared for varying dialysis probe radius. One transmitter (dopamine), three metabolites (DOPAC, HVA and 5HIAA) and two drugs (caffeine and theophylline) were studied. Histology and functional response to a drug were measured. Deficiencies were demonstrated for several of the models, the one best explaining experimental data includes both passive diffusion and active tissue regulation in a cylindrical symmetric geometry. The recovery decreased with decreasing probe radius but smaller probes caused less tissue injury. It is concluded that a mathematical model of microdialysis must include diffusional and physiological processes in order to accurately account for experimentally observed phenomena. The experiments also demonstrated that, for small brain nuclei, the size of the nucleus may influence the recovery.

Animals↗
PubMed2000

Interaction between nelfinavir and tacrolimus after orthoptic liver transplantation in a patient coinfected with HIV and hepatitis C virus (HCV).

A 49-year old male patient with severe hemophilia A, coinfected with HIV and HCV, who underwent orthoptic liver transplantation because of hepatitis C cirrhosis is presented. We describe a strong interaction between nelfinavir and tacrolimus postoperatively, that caused a reduction of the dose of tacrolimus by a factor 70 compared with normal, to achieve therapeutic blood concentrations and to avoid toxic side effects. We suggest that nelfinavir inhibits the metabolism of tacrolimus because both compounds are well-known substrates for the cytochrome P450 isoenzyme CYP 3A4. The nelfinavir serum concentrations were not affected by the institution of tacrolimus. Although the interaction dramatically changed the tacrolimus dose-concentration relationship, the situation was manageable by frequent monitoring of blood concentrations of tacrolimus.

Drug Interactions↗
PubMed2000

Determination of ribavirin in serum using highly selective solid-phase extraction and high-performance liquid chromatography.

A rapid assay for determination of ribavirin in serum using solid-phase extraction (SPE), high-performance liquid chromatography (HPLC), and UV-detection was developed. The SPE uses phenylboronic acid columns with an approximately 100% recovery for ribavirin. The concentration-peak area relation was linear (r > 0.995), from 1 to 64 microM in 100 microL serum. The limit of detection was 0.1 microM. The intraassay CV was 3.2% at treatment levels (9.7 microM) and 11.5% at 0.4 microM. The method is used to monitor patients undergoing ribavirin treatment for hepatitis C (HCV). Samples from HCV-infected patients with and without renal dysfunction have been analyzed without interference of endogenous compounds. It is concluded that the method is useful for routine therapeutic drug monitoring.

Antiviral Agents↗
PubMed2000

Rapid and simple determination of indinavir in serum, urine, and cerebrospinal fluid using high-performance liquid chromatography.

A method for analysis of indinavir in serum, cerebrospinal fluid, and urine was developed. The method is based on liquid-liquid extraction followed by high performance liquid chromatography with UV detection. The method has a shorter analysis time than previously published methods, and it is sensitive enough to measure levels in all three fluids under routine clinical conditions. The method is linear up to 32 micromol/L, the limit of detection is 0.01 micromol/L, and recovery of the method is 86%. The interassay coefficient of variation at 2.0 micromol/L was 2.8%, and no internal standard is needed. Over 700 clinical samples have been analyzed by this method, and concomitant antiviral drugs do not interfere with the assay. Paroxetin and dipyridamol are the only two compounds encountered to elute with retention times similar to that of indinavir. Examples of chromatograms and a pharmacokinetic curve are given. The method is well suited for routine therapeutic drug monitoring as well as for pharmacokinetic studies for research purposes.

Anti-HIV Agents↗
PubMed2000

Plasma levels of 24S-hydroxycholesterol reflect the balance between cerebral production and hepatic metabolism and are inversely related to body surface.

We have previously presented evidence that most of the 24S-hydroxycholesterol present in the circulation originates from the brain and that most of the elimination of this oxysterol occurs in the liver. Plasma 24S-hydroxycholesterol levels decline by a factor of about 5 during the first decades of life. The concentration of the enzyme cholesterol 24S-hydroxylase in the brain is, however, about constant from the first year of life, and reduced enzyme levels thus cannot explain the decreasing plasma levels during infancy. In the present work we tested the hypothesis that the plasma levels of 24S-hydroxycholesterol may reflect the size of the brain relative to the capacity of the liver to eliminate the substance. It is shown here that the age-dependent changes in absolute as well as cholesterol-related plasma level of 24S-hydroxycholesterol closely follow the changes in the ratio between estimated brain weight and estimated liver volume. The size of the brain is increased only about 50% whereas the size of the liver is increased by about 6-fold after the age of 1 year. Liver volume is known to be highly correlated to body surface, and in accordance with this the absolute as well as the cholesterol-related plasma level of 24S-hydroxycholesterol was found to be highly inversely correlated to body surface in 77 healthy subjects of varying ages (r(2) = 0.74). Two chondrodystrophic dwarves with normal size of the brain but with markedly reduced body area had increased levels of 24S-hydroxycholesterol when related to age but normal levels when related to body surface. It is concluded that the balance between cerebral production and hepatic metabolism is a critical determinant for plasma levels of 24S-hydroxycholesterol at different ages and that endocrinological factors are less important. The results are discussed in relation to the possibility to use 24S-hydroxycholesterol in the circulation as a marker for cholesterol homeostasis in the brain.

Adolescent↗
PubMed1999

Indinavir-based treatment of HIV-1 infected patients: efficacy in the central nervous system.

OBJECTIVE: To study the pharmacokinetic properties and clinical efficacy of the HIV-1 protease inhibitor (PI) indinavir in the central nervous system (CNS). DESIGN: Twenty-five consecutive HIV-1 infected patients on combination therapy that included indinavir, had cerebrospinal fluid (CSF) and plasma samples taken on 32 different occasions, at different times after indinavir administration. CSF and viral load data obtained from these treated patients were compared with those from 36 untreated HIV-1 infected patients of similar immunological and demographic pre-treatment status. METHODS: Concentrations of indinavir were measured in CSF and plasma by high-pressure liquid chromatography with ultraviolet light detection and the data were used in pharmacokinetic modelling. RESULTS: The concentration of indinavir in plasma varied with time over a dose interval by about two orders of magnitude, whereas the concentration in CSF was relatively stable. The median concentration of indinavir in CSF was 210 nmol/l, which is above the 95% inhibitory concentration in vitro. Findings from the pharmacokinetic modelling indicate that indinavir is actively transported out of the CSF (P <0.001 compared with a passive transport-only model). In the PI-treated group there was a reduction in viral load to below 50 copies/ml in most subjects and a normalization of the CSF cell content and IgG-index. CONCLUSIONS: This study has shown that one PI, indinavir, is present in the CSF at therapeutic concentrations, and is likely to contribute to the antiretroviral activities observed within the CNS.

Adult↗
PubMed1999

[Volume kinetics--a new method to control intravenous fluid infusion].

The body's handling of fluid given by intravenous infusion can be analysed and simulated by means of volume kinetics, in which pharmacokinetic principles are applied to dilution-time profiles obtained during fluid therapy. In volume kinetics, the emphasis is on the distribution of fluid to body fluid spaces which accordingly become expanded. These spaces do not always correspond to known anatomical or physiological fluid compartments. The time course of the effect of volume fluid distribution to these spaces may be investigated by means of computer-assisted simulation, or a nomogram based on values for volume kinetic variables obtained from infusion experiments.

Computer Simulation↗
PubMed1999

[Mammographic screening does not reduce breast cancer mortality].

The outcome of a Swedish mammographic screening programme has been studied by analysis of official health statistics for 1987-96. The study series comprised 605,260 women (70 per cent of those aged 50-69 years at inclusion in the mammography programme), representing 4,908,176 woman-years, 1,932,353 mammographies, and 6,713 deaths due to breast cancer. The observed number of deaths was 55 (0.8%) less than would have been expected had the screening not been performed (ns), whereas findings in the Two County Council study suggest that the reduction in mortality should have been 28 per cent (n = 739) for the group and period studied. Thus, the cost of saving a single life was estimated to have been SEK 18-25 million (approximately GBP 1.3(1.8 m. USD 2.36(3.17 m).

Aged↗