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Biomedical subjects

E Mårtensson

Publications and source records attributed to E Mårtensson.

At least 19 recordsLinked to original sources
PubMed2001

Subcellular targeting analysis of SDR-type hydroxysteroid dehydrogenases.

Most mammalian hydroxysteroid dehydrogenases known thus far belong to the protein superfamilies of short-chain dehydrogenases/reductases (SDR) and aldo-keto reductases (AKR). Whereas members of the AKR family are soluble, cytoplasmic enzymes, SDR-type hydroxysteroid dehydrogenases are also located to other subcellular compartments, i.e. endoplasmic reticulum, mitochondria or peroxisomes. Differential localization might play an important role in influencing the reaction direction of hydroxy dehydrogenase/oxo reductase pathways by determining the available nucleotide cofactor pool. Targeting signals for different subcellular organelles in human hydroxysteroid dehydrogenases have been identified, however, in several enzymes localization signals remain to be determined.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2000

Type 1 11beta -hydroxysteroid dehydrogenase mediates glucocorticoid activation and insulin release in pancreatic islets.

Metabolic transformation of glucocorticoid hormones constitutes a determinant of their cell-specific effects. The most important reaction for this class of steroids is the reversible C11 keto/beta-hydroxyl conversion between receptor-binding 11beta-OH steroids and the nonbinding 11-oxo compounds, carried out by 11beta-hydroxysteroid dehydrogenases (11beta-HSDs). In this study, we determined the role of glucocorticoid conversion by 11beta-HSD in pancreatic islets and its function in the regulation of insulin release. Pancreatic islets isolated from ob/ob mice display type 1 11beta-hydroxysteroid dehydrogenase activity, i.e. in intact cells the reductive reaction prevails, leading from dehydrocorticosterone to corticosterone. Expression of type 1 11beta-HSD mRNA was detected by reverse transcriptase-polymerase chain reaction in islets isolated from ob/ob mice and also from human tissue. Incubation of beta-cells in the presence of 11-dehydrocorticosterone leads to a dose-dependent inhibition of insulin release, indicating cellular activation of 11-dehydrocorticosterone to the receptor ligand, further confirmed by reporter gene assays. Inhibition of 11beta-HSD activity by carbenoxolone reverses inhibition of insulin release. The presence of 11beta-HSD in islets supports the concept that reactivation of inert circulating hormone precursors in a cell-specific manner plays a major role in glucocorticoid physiology in rodents and man.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2000

Lack of quinone reductase activity suggests that amyloid-beta peptide/ERAB induced lipid peroxidation is not directly related to production of reactive oxygen species by redoxcycling.

Mitochondrial type II hydroxyacyl-CoA dehydrogenase (ERAB) has recently been shown to mediate amyloid-beta peptide (Abeta) induced apoptosis and neurodegeneration. The precise mechanism of cell death induction is unknown, however, Abeta inhibits ERAB activities and as a result of ERAB-Abeta interactions, enhanced formation of lipid peroxidation products occur. The possibility that ERAB mediates quinone reduction is therefore investigated, thus giving the potential of redoxcycling and production of reactive oxygen species, leading to lipid peroxidation. Recombinant human ERAB was produced in a bacterial expression system and enzymological properties were evaluated. Using several orthoquinones as substrates, no ERAB mediated quinone reductase activity was found either in the presence or absence of Abeta, suggesting that the observed in vivo lipid peroxidation is a result of other mechanisms than redoxcycling by quinones.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1999

Characterization of MK-801-induced behavior as a putative rat model of psychosis.

The objective of this study was to characterize the behavior induced by the N-methyl-D-aspartate receptor antagonist MK-801 (dizocilpine maleate) in rats as a model of psychosis. The temporal profile, dose dependence, age, and sex differences of the behavior are described. A gas chromatographic method for the analysis of MK-801 in plasma and brain was developed. Female rats showed 4 to 10 times more MK-801-induced behavior and displayed around 25 times higher serum and brain concentrations of MK-801 than male rats. Twenty-one neuroactive compounds, including a number of excitatory amino acid-active substances, were tested for the effect on MK-801-induced behavior. Neuroleptics blocked MK-801-induced behavior in a dose-dependent manner that correlated to their antipsychotic potency in humans. Adenosine receptor agonists and an N-methyl-D-aspartate receptor-associated glycine site antagonist showed putative antipsychotic effects. In conclusion, MK-801-induced behavior represents a rat excitatory amino acid hypofunction model of psychosis that appears to be of clinical relevance and may be of value in the search for new antipsychotic agents.

Aging↗
PubMed1996

Concentration-related pharmacodynamic effects of thioridazine and its metabolites in humans.

OBJECTIVE: To measure cardiac and other effects of thioridazine and relate these to the plasma concentration of the parent drug and its principal metabolites. METHODS: A double-blind, randomized-order crossover study involving nine healthy male subjects compared the effects of single doses of thioridazine (10 mg and 50 mg) with placebo. Plasma concentrations of thioridazine and its ring sulfoxide, side-chain sulfoxide, and side-chain sulfone metabolites were measured, together with effects on the ECG, blood pressure, salivary flow, and a batch of psychomotor tests for 72 hours after administration. RESULTS: Thioridazine, 50 mg, reduced standing systolic blood pressure (mean peak changes from baseline [95% CI] -32 mm Hg [-55, 10 mm Hg]; p < 0.01 versus placebo) and diastolic blood pressure (-14 mm Hg [-26, -2 mm Hg]; p < 0.05), increased standing heart rate (7 beats/min [-1, 16 beats/min]; p < 0.05), impaired psychomotor function, and prolonged the JT (20 ms1/2 [7, 34 ms1/2]; p < 0.05), QTa (22 ms1/2 [8, 36 ms1/2]; p < 0.05), and QTc (22 ms1/2 [11, 33 ms1/2]; p < 0.01) intervals, but had no effect on QT dispersion (-12 ms1/2 [-31, 6 ms1/2]). Thioridazine, 1.0 mg, also significantly increased QTc, but the effect was less marked (9 ms1/2 [-1, 19 ms1/2]; p < 0.05). Plasma thioridazine and metabolite concentrations did not correlate significantly with these effects. Maximum effects on QTc occurred after peak concentrations of thioridazine but before peak concentrations of the ring sulfoxide and side-chain sulfone metabolites. CONCLUSIONS: These data suggest that thioridazine has dose-related effects on ventricular repolarization and that the parent drug causes an important proportion of these effects, although its metabolites may also contribute.

Adult↗
PubMed1994

A long-term cross-over pharmacokinetic study comparing perphenazine decanoate and haloperidol decanoate in schizophrenic patients.

The purpose of the study was to investigate clinical and pharmacokinetic parameters concerning perphenazine decanoate (PD) and haloperidol decanoate (HD) with an interval of 3 weeks during a study period of 51 weeks. This was done by using the available drug preparations in chronic schizophrenic patients in a randomised, double-blind, cross-over, multicentre study. In addition, an elimination phase of 6 weeks was added, when no IM injections of the depot drugs were given. Twenty-nine patients in a stable neuroleptic maintenance phase entered the study. The patients were rated during the trial according to the CPRS-SCHZ and CGI scales, the UKU side effect scale and serum concentrations of the drugs and prolactin were monitored. There was no significant difference between the drugs in antipsychotic efficacy or side effects. Thus, the doses were equipotent with regard to the CPRS-SCHZ scores. However, the patients' global improvement rating was higher for PD (52%) than for HD (39%) (P > 0.05). The elimination of both drugs was very slow. No interaction effects between PD and HD were observed. The serum levels of HD were in most patients lower than those recommended for acute-subacute treatment. The mean doses were 117 mg (0.29 mmol), range 20-313 mg PD and 120 mg (0.32 mmol), range 20-350 mg HD. The serum concentrations in nmol/L of perphenazine and haloperidol (week 24) were 0.8-15.9 and 2.3-46.7, respectively.

Adult↗
PubMed1992

Severe amitriptyline overdose: relationship between toxicokinetics and toxicodynamics.

The clinical features and toxicokinetics of amitriptyline were studied in nine patients with severe amitriptyline poisoning. Amitriptyline and amitriptyline metabolites were studied in plasma, red blood cells, and cerebral spinal fluid. Eight patients were intubated and six required assisted ventilation. Two patients had ventricular arrhythmias, three patients convulsions and two were hypotensive. All complications developed within four hours of admission. Early in the course of the intoxication the QRS duration correlated with plasma, unbound and red blood cell nortriptyline concentration. The QRS duration also correlated with unbound but not the plasma amitriptyline concentration. The level of consciousness correlated with the plasma and unbound amitriptyline both in alpha and beta phase and with red blood cell amitriptyline in alpha phase. There was no correlation between nortriptyline concentration and level of consciousness. No correlation between coma grade or QRS duration and cerebral spinal fluid concentration of amitriptyline was found. There was no correlation between any hydroxymetabolite in blood or cerebral spinal fluid and QRS duration or coma grade. The beta half-life for amitriptyline was shorter for two patients with high concentrations of hydroxymetabolites. Although intubated, neither patient required assisted ventilation or developed complications. Because of the wide range of concentrations of amitriptyline and amitriptyline metabolites observed between individuals, it is not possible to predict outcome based on a single tricyclic antidepressant concentration.

Amitriptyline↗
PubMed1992

Amitriptyline and amitriptyline metabolites in blood and cerebrospinal fluid following human overdose.

The toxicokinetics of amitriptyline were studied in nine patients admitted to hospital in Matthew-Lawson Coma Scale grade III-IV after an estimated ingestion of 1-5 g amitriptyline. Gastric lavage was performed and 50 g activated charcoal were given orally. Venous blood samples were taken on admission and at 1, 2, 4, 8, and 24 h, and in some patients at 36 and 48 h after admission. Arterial blood samples were taken at 1, 4, 8, and 24 h after admission. Lumbar punctures were performed 1 h after admission in 8 patients and again 4 h later in 5 patients. A urine sample was screened for other drugs. The bound and unbound fraction of amitriptyline and its metabolites nortriptyline, E and Z forms of 10-OH-amitriptyline and nortriptyline were analyzed in plasma, whole blood, red blood cells, and cerebrospinal fluid using an HPLC technique. The T1/2 alpha and T1/2 beta for amitriptyline were 1.5 - 3.1 and 15 - 43 h respectively. The rate of elimination of amitriptyline was not dose-dependent. The arteriovenous differences in the total amitriptyline+nortriptyline concentration were maximal in patients admitted soon after intake of drugs. Amitriptyline concentrations in cerebrospinal fluid were quantitatively similar to the unbound amitriptyline concentration in blood. The highest cerebrospinal fluid amitriptyline concentration was 506 nmol/L. There were large individual differences in plasma, blood and cerebrospinal fluid concentrations between different individuals. Repeated quantitative analysis of amitriptyline and its metabolites is unlikely to contribute to the clinical management of most patients with amitriptyline overdose.

Adult↗
PubMed1987

Unbound plasma concentrations, total plasma concentrations, and red blood cell concentrations of thioridazine and its main metabolites: an in vitro study.

The relationships between, on the one hand, the unbound plasma concentrations of thioridazine and thioridazine metabolites and, on the other, the total plasma concentrations and the red blood cell concentrations were studied in vitro. The relationships between the unbound and total plasma concentrations were curvilinear, while those between the unbound concentrations and the red blood cell concentrations within a broad range were closer to rectilinear. Profound changes were seen in the relationship between unbound and total plasma concentrations at varying concentrations of alpha 1-acid glycoprotein, while the rectilinear relationship between the unbound plasma concentrations and the red blood cell concentrations remained essentially unchanged.

Adult↗
PubMed1987

Total plasma concentrations, red blood cell concentrations, and radioreceptor assay values compared with unbound plasma concentrations of thioridazine and thioridazine metabolites in psychiatric patients.

Neuroleptic drug concentrations at the receptor sites are likely to be reflected more closely by the unbound than by the total plasma concentrations. The aim of this study was to establish whether or not the unbound plasma concentrations of thioridazine and its main nonconjugated metabolites show a stronger correlation to the red blood cell (RBC) concentration than to the total plasma concentration of the drug. The total and unbound plasma concentrations and the RBC concentrations of thioridazine and its metabolites were therefore determined in thioridazine-treated patients. "Calculated unbound concentration values" were derived from the determined total concentrations of the drug, the concentrations of drug-binding proteins, and previously determined kappa values. Since the RBC concentrations showed the best correlation to the unbound plasma values, they may be a more accurate tool than the total plasma concentrations for monitoring thioridazine treatment. The determined unbound plasma concentrations were better correlated to the calculated unbound concentrations than to the total plasma concentrations. The total plasma concentrations, but neither the unbound plasma nor the RBC concentrations, were significantly correlated to the concentrations of the drug-binding protein alpha 1-acid glycoprotein. Radioreceptor assay values were strongly correlated to the weighted sum of the total and unbound plasma concentrations of thioridazine and its metabolites.

Adolescent↗
PubMed1986

Concentrations of thioridazine and thioridazine metabolites in erythrocytes.

The concentrations of thioridazine and its main metabolites in erythrocytes from 61 thioridazine-treated patients were determined by gas-liquid chromatography. The mean and range of the erythrocyte concentrations, expressed as percentage of the corresponding plasma concentrations, were: thioridazine, 5.1% (2.0-10.6); side-chain sulfoxide, 5.6% (1.6-10.4); side-chain sulfone, 3.3% (1.1-6.8); ring sulfoxide 2.7% (0.8-4.9). The erythrocyte and plasma concentrations were significantly correlated. The erythrocyte/plasma concentration ratios, all the erythrocyte concentrations, but none of the plasma concentrations except ring sulfoxide were significantly positively correlated to the dose of thioridazine. The erythrocyte/plasma concentration ratio was not correlated to age. In vitro experiments indicated no clinically relevant erythrocyte-mediated oxidation of thioridazine.

Adult↗
PubMed1986

Preparation of serum and plasma samples for determination of tricyclic antidepressants: effects of blood collection tubes and storage.

The effects were tested of eight common types of blood collection tubes and two types of "plasma separators" on the stability of the tricyclic antidepressants amitriptyline, imipramine, clomipramine, and their monodemethylated metabolites in venous blood samples. Although EDTA-containing Venoject lavender and Vacutainer lavender tubes seemed to give the most stable plasma samples, and Venoject red the most stable serum samples, the differences were too small to have practical consequences. Vacutainer royal blue collection tubes gave significant losses of greater than 20% of some of the substances. The tubes with serum separator gel or filter proved unsuitable, since they were responsible for losses of greater than 40%. The losses were not caused by redistribution between blood cells and plasma but occurred mainly as a result of contact between the contents and the caps of the tubes. Experiments with freezing, thawing, and storage of samples showed that freshly sampled blood could be stored at room temperature for 24 h in Venoject green tubes without significant losses. Serum samples could be stored at refrigerator temperature for 4 weeks without important losses. Freezing, thawing, and storage at -20 degrees C did not influence the serum or plasma concentrations.

Antidepressive Agents, Tricyclic↗
PubMed1985

Thioridazine toxicity--an experimental cardiovascular study of thioridazine and its major metabolites in overdose.

Thioridazine, thioridazine side chain sulfoxide, side chain sulfone and ring sulfoxide were each given to two dogs in incremental doses. Profound changes in cardiac output and blood pressure were seen only in the dogs receiving the ring sulfoxide. Although all four drugs increased the QRS and Q-Tc interval, ventricular arrhythmias and "torsades de pointes" were seen only in dogs receiving the ring sulfoxide. Total plasma concentrations of thioridazine ring sulfoxide were in the same range as those seen in some patients on thioridazine therapy although the free concentrations were higher. Thioridazine ring sulfoxide appears to be the most toxic metabolite of thioridazine.

Animals↗
PubMed1984

Determination of free fractions of tricyclic antidepressants.

The plasma protein binding of amitriptyline, imipramine, clomipramine, and their primary demethylated metabolites were studied by means of a method combining dialysis and gas chromatography. Equilibrium in dialysis of serum containing amitriptyline and its metabolite nortriptyline was attained in about 0.5 h with the drug dissolved in the serum compartment, and in about 2 h with the drug passing from the buffer to the serum compartment. The calculation of free fractions was influenced by variations with dialysis time in the volumes of serum and buffer. Increase of pH in serum increased the protein binding of the weakly basic drugs studied, and made the Donnan distribution effects more pronounced. At pH 7.4, the Donnan effect was negligible. Binding parameters for the 6 tricyclic antidepressant substances studied were estimated for the binding to alpha 1-acid glycoprotein and for total binding in serum. For alpha 1-acid glycoprotein, the k-values ranged from 1 X 10(5) to 8 X 10(5) M-1, and for pooled serum from 0.4 X 10(5) to 8 X 10(5) M-1. The determined number of binding sites on the alpha 1-acid glycoprotein was, on average 0.87 for the 6 substances. In serum, the binding capacity was 2-14 times the concentration of alpha 1-acid glycoprotein.

Antidepressive Agents, Tricyclic↗
PubMed1984

Lidocaine and amitriptyline interaction during experimental haemoperfusion.

Displacement of amitriptyline by lidocaine was studied during haemoperfusion (HP) in five beagle dogs. Clearance of amitriptyline during HP was 0.93, although the amount of amitriptyline removed was only 2% of the given dose. Lidocaine does therefore not improve amitriptyline yield during HP. Clearance of lidocaine during HP was 0.99. Almost 13% of the lidocaine given intravenously was removed by HP. Lidocaine did not improve myocardial performance during HP in amitriptyline-intoxicated dogs. At necropsy the highest concentrations of amitriptyline in this model were found in the brain and the lung. The amitriptyline/nortriptyline ratio was lowest in the liver and lung, suggesting that these two organs are major sites of metabolism.

Amitriptyline↗