Search PubMed⌕ Search

Biomedical subjects

B M Frey

Publications and source records attributed to B M Frey.

At least 55 records · Page 3Linked to original sources
PubMed1995

Furosemide inhibits 11 beta-hydroxysteroid dehydrogenase in vitro and in vivo.

11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) protects the non-selective renal mineralocorticoid receptor from the endogeneous glucocorticoid cortisol. Thus, drugs inhibiting 11 beta-OHSD might enhance urinary loss of potassium. In an attempt to find drugs inhibiting 11 beta-OHSD, 23 commonly used agents known to interfere with the potassium metabolism have been screened for inhibitory effect on 11 beta-OHSD. Furosemide appeared as the only inhibitor. Its inhibition constant (Ki) was 19.5 microM when kidney and 21.3 microM when liver microsomes were used as a source of 11 beta-OHSD. The type of inhibition was competitive. For confirmation that furosemide specifically inhibits 11 beta-OHSD, the complementary DNA (cDNA) of 11 beta-OHSD was transfected into COS-1 cells devoid of spontaneous expression of 11 beta-OHSD. In these cells, oxidation of corticosterone (Ki = 17.4 microM) and reduction of dehydrocorticosterone (Ki = 12.5 microM) was inhibited by furosemide. To establish whether this inhibition also occurs in vivo, the 11 beta-hydroxysteroid prednisolone was administered with and without furosemide to rats. The concentration ratio of prednisolone to its 11-ketometabolite prednisone increased in kidney and liver tissue after furosemide administration, indicating inhibition of 11 beta-OHSD. These data suggest that furosemide modulates in vivo the access of 11 beta-OH glucocorticoids to their target organs.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1994

[Simultaneous occurrence of breast carcinoma and malignant lymphoma. Case observations and literature review].

Based on the observation of 5 patients with simultaneous breast cancer and malignant lymphoma, we discuss the phenomenon of synchronicity of two different tumors in the same individual. Synchronicity of malignancy is rare and could point to a genetic predisposition (family history) or common environmental influence in generating cancer. In elderly patients, the appearance of multiple tumors may coincide by chance. In the case of synchronous or metachronous tumors it is essential to examine the new tumor manifestation by biopsy. In view of the therapeutic and prognostic implications, the second tumor should not be confused with a progression of the known primary malignancy.

Adult↗
PubMed1994

Pharmacology of 11 beta-hydroxysteroid dehydrogenase.

In clinical practice synthetic glucocorticoids are mainly used as therapy for inflammatory disorders and in suppressing immunological responses to transplanted allografts. The presence of an 11 beta-hydroxyl (11 beta-OH) group is mandatory for the antiinflammatory effects of glucocorticosteroids. The interconversion of the 11 beta-OH into the corresponding 11-keto group and vice versa by 11 beta-OH-steroid dehydrogenase might thus play a pivotal role for the efficacy of these steroids. Estimates of the apparent capacity to interconvert these steroids have been derived from plasma and tissue concentration measurements. Such estimates reveal that the interconversion process is concentration dependent and tissue specific. It remains to be established whether modulating that process might allow the immunosuppressive effect to be targeted within certain organs, thereby increasing the ratio between therapeutic and side effects of glucocorticoid administration.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1994

11 beta-Hydroxysteroid dehydrogenase accounts for low prednisolone/prednisone ratios in the kidney.

The purpose of the present investigation was to establish whether the ratio of the biologically active prednisolone to its inactive metabolite prednisone is determined by the 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD). The concentration ratios of prednisolone/prednisone assessed by HPLC 60 min after ip administration of prednisolone to rats were 0.8 in kidney, 5.5 in lung, 5.7 in spleen, 6.3 in heart, 7.1 in plasma, and 43 in liver. When prednisolone was injected together with glycyrrhetinic acid, an inhibitor of the 11 beta-OHSD, the ratios of prednisolone/prednisone in plasma and all tissues increased more than 10-fold. The plasma concentrations of glycyrrhetinic acid required to exhibit apparent half-maximal inhibitory effect of the 11 beta-OHSD were more than 7-fold higher for renal than for all other tissues. Thus, the 11 beta-OHSD accounts for low prednisolone/prednisone concentration ratios in renal tissue and, therefore, has to be considered a relevant determinant for the local intrarenal immunosuppressive effect of 11 beta-hydroxysteroids such as prednisolone.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1994

Kinetics and dynamics of orally administered 18 beta-glycyrrhetinic acid in humans.

18 beta-Glycyrrhetinic acid (GRA) represents a major metabolite of glycyrrhizic acid (glycyrrhizin), an important constituent of licorice and licorice root, and is a potent inhibitor of 11 beta-hydroxysteroid dehydrogenase (11 beta OHSD). Different oral doses of GRA (500, 1000, or 1500 mg) were administered to healthy volunteers in order to study its kinetics and dynamics. In agreement with the lipophilic nature of GRA, with a biphasic decay of the plasma concentration-time curve at doses greater than 500 mg. The mean (+/-SEM) half-life of the second elimination phase was 11.5 +/- 1.2 h after 1000 mg GRA and 38.7 +/- 10.5 h after 1500 mg GRA (P < 0.05). The peak plasma concentration and the area under the plasma concentration-time curve (AUC) increased with increasing GRA doses. Urinary elimination of GRA and GRA glucuronides over 24 h was less than 1% of the dose administered. The dynamics of GRA were assessed by measuring the activity of the 11 beta OHSD in vivo, as reflected by the cortisol and cortisone concentrations in plasma. With increasing doses of GRA, the cortisone concentration declined, and the cortisol/cortisone ratio increased. Both peak plasma concentration and AUCs of GRA correlated with changes in the AUC values of cortisone. Based on the single dose kinetics, the kinetic/dynamic analysis of the data revealed that after multiple doses of 1.5. g GRA/day, the 11 beta OHSD might be constantly inhibited, whereas at daily doses of 500 mg or less, such an inhibition might occur only transiently.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1994

Renal handling of prednisolone/prednisone: effect of steroid dose and 11 beta-hydroxysteroid dehydrogenase.

UNLABELLED: The purposes of this study were: (1) to determine under steady-state conditions whether the renal clearance of prednisolone is concentration dependent, and (2) to establish whether the urinary excretion of prednisolone and its biologically inactive 11-dehydro metabolite prednisone depend upon the activity of 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD). For that purpose 10 healthy volunteers were infused to steady state over a 13-h period either at a low (11 micrograms/h x kg) or a high (70 micrograms/h x kg) rate with prednisolone on two occasions, once without and once with administration of glycyrrhetinic acid, an inhibitor of 11 beta-OHSD. Prednisolone and prednisone were measured by high-pressure liquid chromatography. Mean renal clearance values of total or unbound prednisolone were several times higher during the high than the low infusion rate. The fractional renal clearance of unbound prednisolone during the high, but not during the low infusion rate exceeded 1. This indicates that in addition to unbound prednisolone, protein-bound prednisolone is excreted in urine at high plasma concentrations. Inhibition of 11 beta-OHSD increased the urinary ratios of prednisolone/prednisone in all subjects. CONCLUSIONS: (1) The renal clearance of prednisolone is concentration dependent; (2) there must be tubular secretion and/or glomerular filtration of prednisolone bound to plasma proteins; (3) the urinary excretion of prednisolone/prednisone is modulated by the activity of 11 beta-OHSD.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1993

[Therapeutic plasmapheresis--a critical review in the light of the current literature].

For centuries it has been the dream of many physicians to cure illnesses by eliminating disease provoking substances which are thought to circulate in the human body. Technical developments during the past 20 years have made therapeutic plasma exchange (TP) a useful procedure for clinical application. Because of the lack of well controlled studies the true benefit of the method remains speculative in many clinical situations. Since the report of the American Medical Association (AMA) Panel on Therapeutic Plasmapheresis in 1985 several controlled studies on this subject have been published in recent literature; they are reviewed in this article. In summary, TP seems justified only in some area and well defined situations such as thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, acute and severe myasthenia gravis, severe Guillain-Barré-syndrome, hyperviscosity syndromes such as hyper- and paraproteinemia, and in several intoxications and metabolic disorders such as Refsum disease or hereditary hyperlipidemia type IIa.

Adult↗
PubMed1993

Presence of lipocortins I and IV, but not II and VI, in human platelets.

The present investigation revealed the presence of lipocortins I and IV, but not lipocortins II and VI, in human platelets. Lipocortin I was found in the Triton-soluble fraction of both resting and thrombin-activated platelets and was not covalently bound to skeletal components. Without detergents, when resting platelets were lysed and fractionated in the absence of Ca2+, lipocortin I was found only in the cytosolic fraction, whereas, in the presence of Ca2+, lipocortin I was associated only with the crude particulate and not with the membrane nor the cytosolic fractions.

Annexin A1↗
PubMed1993

Glucocorticoid deficiency increases phospholipase A2 activity in rats.

An important mechanism for the antiinflammatory effect of pharmacological doses of glucocorticoids is the inhibition of arachidonic acid release from phospholipids by phospholipase A2 (PLA2). As a corollary, one might predict that low endogenous concentrations of glucocorticoids favor inflammatory disease states. Indeed, clinical and experimental observations revealed an association between glucocorticoid deficiency and disease states caused by immunological and/or inflammatory mechanisms. The purpose of the present investigation was to study the regulation of PLA2 mRNA, protein, and enzyme activity in adrenalectomized (ADX) rats where glucocorticoid concentrations were below physiological levels. The mRNA of group I and II PLA2 were measured by PCR. Group II PLA2 mRNA was increased by 126 +/- 9% in lung tissue of ADX rats, whereas group I PLA2 was increased only by 27 +/- 1.5%. The increase in group II mRNA in ADX rats was reflected by a corresponding increase of group II PLA2 protein (70-100%) in lung, spleen, liver, and kidney. This increase was reversed by the administration of exogenous corticosterone. After ADX, the percentage increase in total PLA2 activity was higher than that of mRNA or PLA2 protein, suggesting that the activity of the enzyme was modulated by inhibitors or activators. The concentration of lipocortin-I, an inhibitor of PLA2 enzyme was strongly correlated with the activity of PLA2 in the tissues (lung, spleen, liver, and kidney). In all these tissues, the concentrations of lipocortin-I declined after ADX. Thus upregulation of PLA2 enzyme and downregulation of lipocortin-I might account for the enhanced inflammatory response in hypoglucocorticoid states.

Adrenalectomy↗
PubMed1993

[Mechanism of action of immunosuppressive agents].

In addition to T and B cells, accessory cells such as macrophages are necessary for an immune response to occur. At present it is probably reasonable to regard collaborative immune response as a series of interrelated processes in which antigen-specific recognition is performed and in which various nonspecific mediators function as modifiers to regulate the intensity and quality of the response. According to this model, immunosuppressive drugs interfere at different stages and levels of the immune response. Glucocorticoids inhibit preferentially the activities of monocytes and T-helper cells as well as lymphokine production. Cyclosporin effectively inhibits the production of interleukin-2 and influences selectively the action of the T lymphocytes. Azathioprine, cyclophosphamide and methotrexate decrease the proliferative response of all the cells involved in the immune response. The immunosuppressive activity of chloroquine is still not well established, but the drug seems to have inhibitory effect on thromboxane and interleukin-2 production. Whole populations of lymphoid elements are destroyed by administering antibodies against surface determinants of these lymphoid elements. Antiidiotypic antibodies, present in intravenous immunoglobulin preparations from pools of donors, are capable of eliminating circulating (auto-)antibodies by binding to the idiotypic region of a specific disease-associated antibody.

Autoantibodies↗
PubMed1992

Microsomal liver function declines steadily after kidney grafting: a three to five year follow-up.

We have previously shown that the functioning hepatocyte mass (galactose elimination capacity, GEC) and microsomal liver functions (non-renal clearances of unbound prednisolone and cyclosporin A) are impaired in renal allograft recipients (N = 28) one month and one year after successful transplantation. To assess the natural history of these hepatic functional derangements, we reinvestigated 21 patients with stable renal function three to five years following grafting. GEC remained with 6.07 +/- 0.86 mg/min x kg significantly (P less than 0.001) below that in healthy controls (7.52 +/- 0.78 mg/min x kg), but did not significantly change during follow-up (5.93 +/- 0.96 and 6.26 +/- 0.94 mg/min x kg at 1 year and 1 month, respectively). In contrast, the non-renal clearance of unbound prednisolone declined steadily during follow-up averaging 4.98 +/- 0.71 ml/min x kg at three to five (compared to 5.83 +/- 1.51 and 6.80 +/- 1.73 ml/min x kg at one year and one month, respectively). These values were lower (P less than 0.01) than those observed in healthy control subjects (7.56 +/- 1.59 ml/min x kg). The total body clearance of cyclosporin A decreased similarly with time averaging 4.5 +/- 1.2 ml/min x kg at three to five years (compared to 4.9 +/- 1.2 and 5.9 +/- 2.1 ml/min x kg at 1 year and 1 month, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1992

Lactate mapping in ischemic rat kidneys using 1H spectroscopic imaging.

RATIONALE AND OBJECTIVES: Biochemical studies have shown that during renal ischemia, lactate is built up predominantly in the medulla and less in the cortex. The authors intend to confirm such a difference in lactate concentration between these two zones of the kidney by means 1H magnetic resonance (MR) spectroscopy. METHODS: In 10 rats, the authors used four-dimensional (n = 4) and three-dimensional (n = 6) spectroscopic imaging to investigate the left kidney after occlusion of the renal artery. RESULTS: By this technique, a map of the intrarenal lactate distribution was obtained during ischemia. It was determined that lactate concentration is indeed higher in the medulla than in the cortex, as verified by chemical analysis (17 +/- 4 versus 9 +/- 4 mumol/g). CONCLUSIONS: By correlating biochemical and morphologic information, localized MR spectroscopy combined with imaging is a powerful tool for investigating pathophysiologic mechanisms.

Animals↗
PubMed1992

Adrenalectomy decreases lipocortin-I messenger ribonucleic acid and tissue protein content in rats.

Clinical and experimental observations revealed that glucocorticoid-deficient states are associated with an enhanced inflammatory response. The antiinflammatory response of pharmacological doses of glucocorticoids has been tentatively attributed to the induction of lipocortin-I. To determine whether glucocorticoid deficiency causes lipocortin-I down-regulation, the expression of lipocortin-I mRNA and protein was quantified in rats with and without adrenalectomy (ADX). The mRNA of lipocortin-I was quantified by polymerase chain reaction, using a constant amount of modified lipocortin-I cDNA transcript as an internal standard. The lipocortin-I mRNA was decreased by 56 +/- 14% in lung tissue of ADX rats. This down-regulation of lipocortin-I mRNA was not due to a nonspecific effect of ADX, since the mRNA levels of other proteins (c-fos, c-myc, c-erbA beta, and metallothionein-II) remained unchanged. The decrease in lipocortin-I mRNA in ADX rats was reflected by a corresponding decrease in tissue (lung, spleen, liver, and kidney) lipocortin-I protein content, as assessed by quantitative Western blot analysis. Thus, ADX causes a decline in lipocortin-I message and protein, an observation compatible with the increased susceptibility to inflammatory reactions in glucocorticoid deficiency.

Adrenalectomy↗
PubMed1992

Pharmacokinetics/pharmacodynamics of ketoconazole-prednisolone interaction.

Ketoconazole is commonly used in patients with fungal infections during immunosuppressive therapy with prednisolone. Ketoconazole inhibits mixed function oxidases, enzymes responsible for the catabolism of prednisolone, and might, by that mechanism, increase prednisolone concentrations and thus, the immunosuppressive effect of prednisolone. On the other hand, ketoconazole has been found to bind to the glucocorticoid receptor and, thereby, to function as a glucocorticoid antagonist in cultured cell preparations. In order to establish whether ketoconazole enhances or attenuates the immunosuppressive effect of prednisolone, the influence of ketoconazole on the kinetics of prednisolone and on the delayed hypersensitivity response was assessed in mice. Ketoconazole increased prednisolone concentrations, measured by high pressure liquid chromatography, in mice given a single dose of prednisolone or a continuous prednisolone treatment for 17 days. At four different doses of prednisolone administered for 17 days, the glucocorticoid therapy-associated inhibition of the delayed hypersensitivity response to keyhole limpet hemocyanin was enhanced by ketoconazole. Thus, coadministration of ketoconazole with prednisolone increases the exposure to the steroid and enhances the immunosuppressive effect.

Animals↗
PubMed1991

Expression of human recombinant lipocortin I in a wheat-germ cell-free system and Xenopus oocytes. Lipocortin is not secreted.

Lipocortin I has been presumed to be synthesized and secreted in response to glucocorticoids yet the amino acid sequence of lipocortin I reveals no signal sequence typically necessary for proteins to enter the secretory pathway. The translocation of lipocortin I across membranes was analyzed in a cell-free system and in Xenopus oocytes. Based on the published sequence, the cDNA of human lipocortin I was cloned and expressed in Escherichia coli. Lipocortin I was purified and used to raise monoclonal antibodies. To test whether lipocortin I is secreted in vitro, transcribed lipocortin mRNA was translated in a wheat germ cell-free system in the absence and presence of microsomal membranes. Prolactin mRNA was used as a control for translocation of newly synthesized protein into membrane vesicles. Prolactin, but not lipocortin I, was translocated into the membranes. To test for secretion of lipocortin I in vivo, Xenopus oocytes were co-injected with transcripts encoding lipocortin I and prolactin, with and without the signal sequence. Prolactin with the signal sequence was released into the medium. However, neither prolactin without a signal sequence nor lipocortin I was released. Carbonate extraction, using an integral transmembrane protein as control, revealed no evidence for membrane integration of lipocortin I. Thus lipocortin I is not a secreted protein.

Animals↗
PubMed1991

Prednisolone concentrations in cerebrospinal fluid after different prednisolone prodrugs.

The concentration-time curves of prednisolone in cerebrospinal fluid (CSF) and plasma were measured following an equimolar i.v. bolus dose of prednisolone phosphate (five patients) and prednisolone phthalate (four patients). Independent of the prodrug administered, the value of the AUC (0.360 min) in CSF was more than three times lower than the corresponding value in plasma. The AUCs of unbound prednisolone in plasma were higher after prednisolone phosphate, than after prednisolone phthalate (68.1 +/- 15.7 vs 19.0 +/- 5.2 micrograms ml-1 min, P less than 0.001). Similarly, the AUCs of prednisolone were higher in the CSF after prednisolone phosphate, than after prednisolone phthalate (17.6 +/- 2.8 vs 3.3 +/- 1.0 micrograms ml-1 min, P less than 0.0001). The results indicate that the concentrations of prednisolone in CSF are much lower than the unbound concentrations in plasma and that therapeutic inequivalence should be expected when the two prodrugs are given in equimolar doses.

Aged↗
PubMed1990

Pharmacokinetics and chronic toxicity of cyclosporine A in genetic hydroxylation-deficient dark Agouti rats.

Since oxidation plays a key role in the metabolism of cyclosporine A (CsA), the pharmacokinetics and the toxicity of CsA was investigated in female dark Agouti rats exhibiting a deficiency for debrisoquine hydroxylation and for dextromethorphan demethylation. When compared with Wistar rats (n = 10), dark Agouti rats (n = 10) had a higher mean clearance (4.8 ml/min per kg vs. 3.3 ml/min per kg) and a lower mean residence time (606 min vs. 1361 min) after intravenous dosing of CsA. The systemic availability of subcutaneous CsA was close to 100%. The steady state CsA concentrations assessed by HPLC in whole blood after subcutaneous dosing of 20 mg/kg per day for 23 days (n = 10) were about 1000 ng/ml in dark Agouti rats. When compared with dark Agouti rats treated with cremophore (n = 10) or not treated at all (n = 12), dark Agouti rats on chronic subcutaneous CsA plus cremophore for 23 days (n = 10) had no difference in kidney histology but had slightly increased liver fatty changes. Rats on CsA and/or cremophore had a decreased uric acid clearance and evidence of hypoaldosteronism. The urinary ratio of debrisoquine/4-hydroxydebrisoquine decreased in rats on CsA, whereas the O-demethylation and N-demethylation of liver obtained from rats on cremophore was impaired. Thus, dark Agouti rats show no difference in the metabolism of CsA and when given CsA for 23 days show drug-induced functional but no relevant structural light microscopic changes in the kidney, and functional and slight structural changes in the liver.

Animals↗