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Biomedical subjects

T Andersson

Publications and source records attributed to T Andersson.

At least 127 records · Page 7Linked to original sources
PubMed1994

The effect of oral omeprazole on the disposition of lignocaine.

The effects of the gastric antisecretory drug, omeprazole, on the disposition of lignocaine were studied in 10 healthy male volunteers in a double-blind, randomised, placebo-controlled, two-period crossover trial. Omeprazole 40 mg or placebo was taken daily for one week before administration of lignocaine 1 mg.kg-1 (3.7 mumol.kg-1) given intravenously over 10 min. Venous concentrations of lignocaine and its metabolite monoethylglycinexylidine were measured in plasma with reversed phase liquid chromatography. The mean (95% CI) areas under the curve at infinity for lignocaine after pretreatment with omeprazole or placebo were 6.67 (4.90-8.45) mumol.h.l-1 and 6.14 (5.05-7.23) mumol.h.l-1, respectively (p = 0.44). The respective areas for monoethylglycinexylidine were 1.85 (1.25-2.45) mumol.h.l-1 and 1.79 (1.44-2.14) mumol.h.l-1 (p = 0.78). Similarly, omeprazole had no significant effect on the half-lives of lignocaine or methylglycinexylidine.

Administration, Oral↗
PubMed1994

Identification of human liver cytochrome P450 isoforms mediating secondary omeprazole metabolism.

1. The in vitro metabolism of omeprazole was studied in human liver microsomes in order to define the secondary metabolic pathways and identify the cytochrome P450 (CYP) isoforms responsible for the formation of the secondary metabolites of omeprazole. 2. The major secondary omeprazole metabolite was the hydroxysulphone, which was formed during incubation with both hydroxyomeprazole and omeprazole sulphone. A second metabolite, tentatively identified as pyridine-N-oxide omeprazole sulphone, was also formed during incubation with omeprazole sulphone. The formation kinetics of these two metabolites from omeprazole sulphone were biphasic suggesting the involvement of multiple CYP isoforms in each case. In contrast, the formation kinetics of hydroxysulphone from hydroxyomeprazole were linear. 3. Inhibition studies, performed with omeprazole sulphone as substrate at concentrations at which the high affinity activities predominated, with a series of isoform selective inhibitors as well as with an anti-CYP2C3 antibody suggested a dominant role of S-mephenytoin hydroxylase in the formation of hydroxysulphone from omeprazole sulphone. By contrast, CYP3A activities were predominant in the formation of hydroxysulphone from hydroxyomeprazole as well as in the formation of pyridine-N-oxide omeprazole sulphone from omeprazole sulphone.

Cytochrome P-450 Enzyme System↗
PubMed1994

Diazepam metabolism by human liver microsomes is mediated by both S-mephenytoin hydroxylase and CYP3A isoforms.

1. The primary metabolism of diazepam was studied in human liver microsomes in order to investigate the kinetics and to identify the cytochrome P450 (CYP) isoforms responsible for the formation of the main diazepam metabolites, temazepam and N-desmethyldiazepam. 2. The formation kinetics of both metabolites were atypical and consistent with the occurrence of substrate activation. A sigmoid Vmax model equivalent to the Hill equation was used to fit the data. The degree of sigmoidicity was greater for temazepam formation than for N-desmethyldiazepam formation, so that the ratio of desmethyldiazepam:temazepam formation increased as the substrate (diazepam) concentration decreased. 3. alpha-Naphthoflavone activated both reactions but with a greater effect on temazepam formation than on N-desmethyldiazepam formation. In the presence of 25 microM alpha-naphthoflavone the kinetics for both pathways were approximated by Michaelis-Menten kinetics. 4. Studies with a series of CYP isoform selective inhibitors and with an inhibitory anti-CYP2C antibody indicated that temazepam formation was carried out mainly by CYP3A isoforms, whereas the formation of N-desmethyldiazepam was mediated by both CYP3A isoforms and S-mephenytoin hydroxylase.

Aryl Hydrocarbon Hydroxylases↗
PubMed1994

In vitro proguanil activation to cycloguanil by human liver microsomes is mediated by CYP3A isoforms as well as by S-mephenytoin hydroxylase.

1. The activation of proguanil to cycloguanil by human liver microsomes was studied to define the cytochrome P450 (CYP) isoforms involved in this reaction. 2. Apparent Km values for proguanil ranged from 35 microM to 183 microM with microsomes from four human livers. 3. There was a 6.3-fold range of activity with microsomes from seventeen human livers. Rates of proguanil activation correlated significantly with CYP3A activities (benzo[a]pyrene metabolism, caffeine 8-oxidation and omeprazole sulphone formation) and CYP3A immunoreactive content. There was also a highly significant correlation with rates of hydroxyomeprazole formation. Correlations with activities selective for CYP1A2, CYP2C9/10 and CYP2E1, and with immunoreactive CYP1A2 content were not significant. 4. Proguanil activation was inhibited by R,S-mephenytoin, troleandomycin and by inhibitory anti-CYP3A antiserum and anti-CYP2C IgG and was activated by alpha-naphthoflavone. Inhibitors selective for CYP1A2, CYP2E1, CYP2A6 or CYP2C9/10 had little or no effect on proguanil activation. The extents of inhibition by R,S-mephenytoin, troleandomycin and the two antibodies varied with the immunoreactive CYP3A content of the microsomes used. 5. It is concluded that proguanil activation to cycloguanil by human liver microsomes is mediated both by S-mephenytoin hydroxylase and isoforms of the CYP3A subfamily. This has implications for the use of proguanil as an in vivo probe for the S-mephenytoin poor metaboliser phenotype.

Aryl Hydrocarbon Hydroxylases↗
PubMed1994

Photodynamic therapy of non-melanoma malignant tumours of the skin using topical delta-amino levulinic acid sensitization and laser irradiation.

Eighty basal cell carcinomas (BCCs) in 21 patients, 10 lesions of Bowen's disease in three patients, and four lesions of cutaneous T-cell lymphoma in two patients, were treated with photodynamic laser therapy (PDT), using topical application of the haem precursor delta-amino levulinic acid (ALA). The diagnoses were confirmed histologically prior to treatment. Fifty-five of the BCCs were superficial lesions, and 25 were nodular. Of the 80 BCCs, 39 (49%) were located on the trunk, 36 (45%) on the head and neck region, four (15%) on the leg and one on the arm. The two principal locations of the 10 Bowen's disease lesions were the leg (50%) and the trunk (40%). The T-cell lymphoma lesions were located on the shoulder and on the arm. A water-in-oil based cream containing 20% ALA was applied to the lesions, with a margin of about 10-20 mm beyond the visible tumour border, 4-6 h before the laser procedure. During this period of time the highly fluorescent and photodynamically active substance protoporphyrin IX (Pp IX) is synthesized via the haem cycle. Laser-induced fluorescence (LIF) was used for real-time monitoring of the Pp IX distribution in the tumour and in the normal surrounding skin, before and after treatment in all patients. Before laser treatment the Pp IX distribution demonstrated by LIF showed a demarcation between tumour and normal skin of about 15:1 for BCC and Bowen's disease, and 5:1 for T-cell lymphomas.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Topical↗
PubMed1994

Diagnostics of malignant lymphomas with ultrasound guided 1.2 mm biopsy-gun.

In a retrospective analysis of 129 ultrasound-guided biopsy-gun biopsies (USGB) from patients with known or suspected malignant lymphoma, a histopathological diagnosis was obtained in 101 (78%) instances and no further procedures for histological verification were required. In the 28 cases with initially non-diagnostic results, 14 new USGBs were performed and a diagnosis was obtained in 11. Thus, a total success rate of 87% was achieved. The correct diagnosis was confirmed with either surgery, autopsy, or radiological or clinical follow-up (median 40 months). The diagnoses were categorised as Hodgkin's disease and high-grade or low-grade non-Hodgkin's lymphoma. Further subtyping of the lymphoma was possible in a few cases only. Immunohistochemistry was utilised only in a minor proportion of the cases (25/129), but refined the diagnosis in several instances. The biopsy-gun method was safe and minor adverse effects were seen in two patients only.

Adolescent↗
PubMed1994

Ultrasound monitored laser-induced local hyperthermia in the liver. An experimental study on pigs.

Ultrasound (US) was used to monitor the size of tissue necrosis generated by Nd-YAG laser-induced local interstitial hyperthermia and tissue coagulation in 8 normal pig livers. Four treatments were done in each liver with 4 different energy settings. The size of the tissue necrosis measured on specimens was compared to the size measured on US. The laser energy caused a round tissue necrosis with some charring in the centre surrounded by a zone of white necrosis and a thin border of hyperaemia. A good correlation was found between the true and US-measured size of the necrosis diameters. It therefore seems possible to safely guide and monitor local laser hyperthermia in the liver with real-time US. The water-cooled quartz fibre used in this study has, however, some limitations.

Aluminum Oxide↗
PubMed1993

High-performance liquid chromatographic assay for human liver microsomal omeprazole metabolism.

Assays for the measurement of omeprazole metabolites in plasma and urine have been reported, but when applied to the determination of omeprazole metabolites formed by human liver microsomal incubations there were obvious limitations in sensitivity. The present high-performance liquid chromatographic (HPLC) assay, which comprises extraction, evaporation and reconstitution, is several-fold more sensitive with a limit of detection of approximately 2 pmol (2 nM in incubate) for omeprazole sulphone and 25 pmol (25 nM in incubate) for hydroxyomeprazole. Extraction efficiency is essentially quantitative and is highly reproducible (coefficient of variation = 2.1% for both metabolites). The assay is linear over a wide range of concentrations and the formation of the metabolites is linear with respect to both time (to 15 min) and protein concentration (to 1.5 mg/ml). Two minor metabolites, one of which was identified tentatively as 5-O-desmethylomeprazole, were also formed by human liver microsomes and could be determined by this method. Preliminary studies of the formation of omeprazole sulphone and hydroxyomeprazole showed that the formation kinetics in human liver microsomes were biphasic for both metabolites, suggesting that at least two different cytochrome P450 isoforms are involved in their formation.

Aryl Hydrocarbon Hydroxylases↗
PubMed1993

Stimulus-induced dissociation of alpha subunits of heterotrimeric GTP-binding proteins from the cytoskeleton of human neutrophils.

Previous studies on the mechanism responsible for terminating the generation of second messengers induced by chemotactic factor-receptor complexes have, on one hand, suggested a direct role of a GTP-binding protein(s) (G protein), and, on the other hand, proposed that there is a lateral segregation of the ligand-receptor complexes into G protein-depleted domains of the plasma membrane. In the present investigation, which addresses these apparently contradictory findings, we found that a substantial part of the alpha subunits of the Gn protein (Gn alpha) in unstimulated neutrophils were associated with a cytoskeletal fraction and that release of these subunits occurred upon stimulation with the chemotactic factor fMet-Leu-Phe. An identical Gn alpha release could also be induced by direct activation of G proteins with guanosine 5'-[gamma-thio]triphosphate or AIF4-. In contrast, the alpha subunits of the stimulatory G protein (Gs alpha) also found associated with the cytoskeletal fraction of unstimulated cells were not released by fMet-Leu-Phe stimulation. However, they were effectively released by direct G-protein activation with guanosine 5'-[gamma-thio]triphosphate. In addition, inhibition of the fMet-Leu-Phe-stimulated modulation of the actin network by pertussis toxin did not affect the fMet-Leu-Phe-induced release of Gn alpha from the cytoskeletal fraction. These observations indicate that fMet-Leu-Phe-induced activation of neutrophils involves a specific dissociation of Gn alpha from the cytoskeleton and that this release is not a consequence of the well-known effect of fMet-Leu-Phe on the cytoskeleton of neutrophils. The present data contribute ideas concerning the transducing properties of G proteins in cellular signaling and seem to reconcile the apparently contradictory concepts of how the cytoskeleton participates in the termination of the chemotactic-factor-induced generation of second messengers in human neutrophils.

Cell Membrane Permeability↗
PubMed1993

Signaling properties of CR3 (CD11b/CD18) and CR1 (CD35) in relation to phagocytosis of complement-opsonized particles.

Human neutrophils preincubated with antibodies against complement receptor type 1 (CR1) (anti-CD35) and/or complement receptor type 3 (CR3) (anti-CD11b or anti-CD18) exhibited a reduced ability to engulf complement-opsonized yeast particles, whereas cellular adhesion of these particles was reduced only in the presence of anti-CD35 antibodies. These data support the idea that CR1 primarily promotes the adhesion of particles and CR3 mediates the subsequent engulfment. However, the effects of anti-CR1 and anti-CR3 antibodies on particle-induced diglyceride production correlate with the effects of these antibodies on the cellular uptake of the particles. Hence, it seems reasonable to suggest that CR1 also participates in mediating the signal(s) that induce particle uptake. This idea is further supported by the findings that cross-linking surface-bound anti-CD11b, anti-CD18 as well as anti-CD35 antibodies results in activation of phospholipase D (PLD), a signal closely associated with phagocytosis of complement-opsonized yeast particles in human neutrophils. The signaling property of CR1 was further revealed by the observation that cross-linking of surface-bound anti-CD35 triggered a rapid and transient mobilization of intracellular Ca2+, a signal most likely involved in the phagosome-lysosome fusion that occurs after the uptake of a particle. Pretreatment with PMA, which positively modulates CR-mediated engulfment of particles, was found to potentiate the CR3- and CR1-induced activation of PLD but impair the activation of phospholipase C, giving added support to the idea that PLD activation is the principal signal for the engulfment process. The activation of PLD was also increased by stimulating the cells with anti-CD18 or anti-CD35 antibodies prefixed on Staphylococcus aureus particles, instead of cross-linking cellular-bound antibodies, suggesting that the form of ligand presentation is a critical parameter of phagocytic signaling. Taken together, the present results demonstrate that both CR1 and CR3 can initiate transmembrane signaling in human neutrophils and, in particular, activation of PLD. This activation was also further recognized as an important signal regulating the engulfment of complement-opsonized particles.

Complement System Proteins↗
PubMed1993

Measles virus-induced hippocampal neurodegeneration in the mouse: a novel, subacute model for testing neuroprotective agents.

The hamster neurotropic (HNT) strain of measles virus causes non-inflammatory encephalopathy in Balb/c mice, associated with neurodegeneration in hippocampal CA1 and CA3 regions. This loss of pyramidal cells can be prevented by twice daily systemic treatment with 1 mg/kg dizocilpine (5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclo-hepten-5,10-imine maleate; MK-801) for 7 days. By varying the MK-801 treatment protocol, we now found that drug administration during the last 4 days prior to sacrifice (i.e. days 4-7 post inoculation, p.i.) is essential for neuroprotection. In contrast, MK-801 treatment during the first days (days 0-4 p.i.) did not prevent the neuronal necrosis. These data suggest that the concentration of an excitotoxic factor in the mouse brain increases after virus inoculation, reaching toxic levels by days 4-5 p.i. This novel 'subacute' mouse model of neurodegeneration therefore constitutes an attractive tool for mechanistic and interventional studies in excitotoxicity research.

Animals↗
PubMed1993

Electroneurography index: a standardized neurophysiological method to assess peripheral nerve function in patients with polyneuropathy.

An index based on 12 electrophysiological parameters (conduction velocities, F-latencies, and amplitudes) was constructed to obtain an overall estimation of peripheral nerve conduction. The index was expressed as the mean deviation (in SD) compared to controls standardized for age or height. The stability of the index was tested by repeated examinations during intervals of several months in healthy subjects. The use of a compound index enabled detection of slight impairments of nerve conduction. The relatively low interrecording variability of the index makes it suitable to follow the progression of a polyneuropathy.

Adolescent↗
PubMed1993

Pituitary as a target organ for toxic effects of P4501A1 inducing chemicals.

We report here that cytochrome P4501A1 in the male rainbow trout pituitary is highly inducible by beta-naphthoflavone. Pituitary cells containing inducible P4501A1 were identified by double immunostaining as gonadotrophs containing gonadotropin II. Thus, the pituitary gonadotrophs may be target cells for polyaromatic hydrocarbons. Elevated plasma levels of gonadotropin II (GTH II) and testosterone in the induced fish indicated that the functioning of the pituitary was disturbed. Because GTH II regulate the final stage of sexual maturation the results implies that exposure to P4501A1 inducing compounds may disturb this development stage.

Animals↗
PubMed1993

Beta 2 integrin engagement triggers actin polymerization and phosphatidylinositol trisphosphate formation in non-adherent human neutrophils.

Beta 2 integrins are involved in the adhesion of leukocytes to other cells and surfaces. Although adhesion is required for cell locomotion, little is known regarding the way beta 2 integrin-receptors affect the actin network in leukocytes. In the present study filamentous actin (F-actin) levels in non-adherent human neutrophils have been measured by phalloidin staining after antibody cross-linking of beta 2 integrins. Antibody engagement of beta 2 integrins resulted in a rapid and sustained (146 and 131% after 30 and 300 s, respectively) increase in the neutrophil F-actin content. This is in contrast to stimulation with N-formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLP), which causes a prompt and pronounced but rapidly declining rise in F-actin (214 and 127% after 15 and 300 s, respectively). Priming neutrophils with 1 nM PMA, a low concentration that did not influence the F-actin content per se, increased the magnitude of the beta 2 integrin-induced response but had no effect on the kinetics (199% after 30 s and 169% after 300 s). Removal of extracellular Ca2+ only marginally affected the beta 2 integrin-induced F-actin response for cells that were pretreated with PMA whereas the response for nonprimed cells was reduced by half. This suggests that even though extracellular Ca2+ has a modulatory effect it is not an absolute requirement for beta 2 integrin-induced actin polymerization. beta 2 integrin engagement did not affect the resting cellular level of cAMP arguing against a role of cAMP in beta 2 integrin-induced actin assembly.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗
PubMed1993

Identification of human liver cytochrome P450 isoforms mediating omeprazole metabolism.

1 The in vitro metabolism of omeprazole was studied in human liver microsomes in order to define the metabolic pathways and identify the cytochrome P450 (CYP) isoforms responsible for the formation of the major omeprazole metabolites. 2 The four major metabolites identified in vitro, in tentative order of importance, were hydroxyomeprazole, omeprazole sulphone, 5-O-desmethylomeprazole, and an unidentified compound termed metabolite X. Omeprazole pyridone was also detected but could not be quantitated. Incubation of hydroxyomeprazole and omeprazole sulphone with human microsomes resulted in both cases in formation of the hydroxysulphone. The kinetics of formation of the four primary metabolites studied were biphasic suggesting the involvement of multiple CYP isoforms in each case. Further studies used substrate concentrations at which the high affinity activities predominated. 3 Formation of the major metabolite, hydroxyomeprazole, was significantly correlated with S-mephenytoin hydroxylase and with benzo[a]pyrene metabolism and CYP3A content. Inhibition studies with isoform selective inhibitors also indicated a dominant role of S-mephenytoin hydroxylase with some CYP3A contribution in the formation of hydroxyomeprazole. Correlation and inhibition data for the sulphone and metabolite X were consistent with a predominant role of the CYP3A subfamily in formation of these metabolites. Formation of 5-O-desmethylomeprazole was inhibited by both R, S-mephenytoin and quinidine, indicating that both S-mephenytoin hydroxylase and CYP2D6 may mediate this reaction in human liver microsomes and in vivo. 4 The Vmax/Km (indicator of intrinsic clearance in vivo) for hydroxyomeprazole was four times greater than that for omeprazole sulphone. Consistent with findings in vivo, the results predict that omeprazole clearance in vivo would be reduced in poor metabolisers of mephenytoin due to reduction in the dominant partial metabolic clearance to hydroxyomeprazole.

Analysis of Variance↗
PubMed1993

Pharmacokinetics of [14C]omeprazole in patients with liver cirrhosis.

The pharmacokinetics of omeprazole and its metabolites following single doses were studied in 8 patients with liver cirrhosis. Each patient participated in 2 experiments in which [14C]omeprazole was administered either intravenously (20mg) or in an oral solution (40mg) in a randomised crossover design. Plasma concentrations of omeprazole and 2 of its identified metabolites, as well as total radioactivity were followed for 24h; urinary excretion was followed for 96h. The mean elimination half-life of omeprazole in the patients with cirrhosis was 2.8h and the mean total plasma clearance was 67 ml/min (4.02 L/h); corresponding values from separate studies in young healthy volunteers were 0.7h and 594 ml/min (35.64 L/h). The mean systemic availability was nearly 100% in the patients with cirrhosis whereas the previously reported value in young volunteers was only 56%. Almost 80% of a given dose was excreted as urinary metabolites in both patients and young volunteers. It is concluded that, as the hepatic clearance of omeprazole was substantially reduced in these patients, the dose of omeprazole needed for a certain degree of acid suppression is lower in patients with liver cirrhosis.

Administration, Oral↗
PubMed1993

A study of the interaction between omeprazole and cyclosporine in renal transplant patients.

1. To determine any interaction between omeprazole and cyclosporine A (CsA) 10 male patients with 1-7 year renal transplants and stable renal function, participated in this randomised blind cross-over trial with omeprazole, 20 mg, and placebo treatment once daily for 2 consecutive weeks each. 2. Blood samples for measurement of trough concentrations of CsA were obtained twice a week during the 4 study weeks, and during the 2 weeks before and after the study. Unchanged CsA concentrations were measured by h.p.l.c. and using a monoclonal antibody r.i.a., and drug plus metabolites were measured by a polyclonal antibody f.p.i.a. In addition, one of the metabolites, M17, was assayed separately by h.p.l.c. 3. The mean whole blood trough CsA concentration during omeprazole treatment was 102 (95% confidence interval, 84-122) micrograms l-1 determined by h.p.l.c. and 81 (65-100) micrograms l-1 determined by r.i.a. Corresponding values during placebo treatment were 100 (79-127) micrograms l-1 and 95 (75-120) micrograms l-1. The ratios between omeprazole and placebo treatments were 1.01 (0.84-1.22) (h.p.l.c.) and 0.85 (0.67-1.08) (r.i.a.). Assuming that a change of < 30% in CsA blood concentrations is of no clinical significance, these results show that there was no clinically or statistically significant influence of omeprazole on CsA concentrations. Neither CsA concentrations determined by f.p.i.a. nor determination of M17 by h.p.l.c. indicated any effect of omeprazole on the metabolism of CsA. 4. It is concluded that omeprazole (20 mg daily) does not significantly interfere with CsA metabolism in stabilised renal transplant patients and may be used safely without extra monitoring of blood CsA concentrations.

Adult↗