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Biomedical subjects

F J Frey

Publications and source records attributed to F J Frey.

At least 91 records · Page 5Linked to original sources
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

[Quantitative assessment of the quality of life of patients with a kidney transplant].

Actually three methods are offered for the treatment of patients with chronic renal failure: 1. Hemodialysis, 2. chronic peritoneal dialysis for outpatients (CAPD) and 3. Transplantation of a kidney. In order to define the optimal therapy for these patients not only economic factors but also quantitative evaluation of life quality has to be taken into account. To this end a questionnaire called "Sickness Impact Profile", that covers most of the relevant features of life and is well established in the Anglo-Saxon countries, was translated into German language and tested in 34 hemodialysis-patients, 25 CAPD-patients and 29 patients with kidney transplant, in order to investigate the applicability. Results showed that the German issue can successfully be applied to Swiss patients with renal failure and lead to the conclusion that--in accordance to results of similar studies in the USA--life quality in patients with kidney transplant is better than in patients treated with hemodialysis or CAPD.

Activities of Daily Living↗
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

[Immunosuppressive therapy of glomerulonephritis--controlled studies].

Glucocorticoids, cytostatic agents and cyclosporin are frequently employed in the treatment of glomerular diseases of immunologic origin. In order to assess the efficacy of these drugs, we retrieved--with the help of a Medline-based search--and analysed all controlled studies published since 1966 dealing with immunosuppressive therapy of glomerulonephritis. Of the 34 identified controlled studies, only 27 had a prospective and randomized design. In patients with minimal-change glomerulonephritis, proteinuria decreases and disappears during therapy with prednisone. A comparable effect can be obtained with cyclosporin. Occasionally, there is a relapse of proteinuria after cessation of the immunosuppressive therapy in some patients. These relapses can be controlled with a chlorambucil-based regimen. Chlorambucil may be successfully utilized in the treatment of focal-segmental glomerulosclerosis, a form of glomerulonephritis which is more refractory to glucocorticoid therapy and is probably pathogenetically related to minimal-change glomerulonephritis. Patients with membranous glomerulonephritis and a nephrotic syndrome seem to benefit from an alternate month prednisone and chlorambucil regimen. However, an indiscriminate treatment of all patients with this regimen is not legitimate, because some patients would be overtreated as the disease may undergo spontaneous remission. There are no well-documented valuable therapies for the IgA-associated glomerulonephritis and the membranoproliferative glomerulonephritis. The combination of prednisone with cytotoxic substances, particularly cyclophosphamide and azathioprine, seem to remarkably improve the renal prognosis of the diffuse proliferative lupus glomerulonephritis. The efficacy of cyclophosphamide and prednisone with or without plasma exchange in the treatment of the rapidly progressive glomerulonephritis due to other systemic diseases (M. Wegener, panarteritis nodosa, Goodpasture syndrome) is a widely accepted therapeutic modality, although controlled studies are lacking. Immunosuppressive therapy of glomerulonephritis bears notable risks and sometimes questionable efficacy. Thus, before prescribing any immunosuppressive therapy, it is mandatory to evaluate in every single patient the prognostic factors of the underlying disease, the probability of the onset of severe side effects and the possible acceptance of a renal replacement therapy, including renal transplantation.

Autoimmune Diseases↗
PubMed1992

[Glucocorticoids and infection].

Glucocorticosteroids are the most commonly used immunosuppressive agents. In the following review important mechanisms of action of glucocorticoids on the immunological network are summarized, the relationship between duration of therapy, daily dose and incidence of infections is analysed, and evidence is presented that in some infectious diseases glucocorticoids may even be beneficial. The association between corticosteroid therapy and subsequent infections was calculated by pooling the data from 73 controlled clinical trials (meta-analysis). The rate of infectious complications was not increased in patients given a daily dose of less than 10 mg or a cumulative dose of less than 700 mg prednisone. With increasing doses the occurrence rate of infectious complications increased in patients given corticosteroids as well as in patients given placebo, a finding which suggests that not only the corticosteroid but also the underlying disease state accounts for the steroid-associated infectious complications observed in clinical practice. To analyze the effect of glucocorticoids prescribed as adjuvants in patients with infectious diseases, an analysis of the controlled trials was performed. Some patients with pulmonary tuberculosis or constrictive pericarditis have a better outcome when they are given prednisone. On the other hand, there is no evidence that patients with septic shock or ARDS derive advantage from glucocorticoid therapy. At present there is controversy as to whether patients with bacterial meningitis should be treated with glucocorticosteroids. Patients with hepatitis B should not be treated with glucocorticoids, whereas elderly patients less frequently show postherpetic neuralgia when given glucocorticosteroids. Patients with cerebral malaria should not be given glucocorticosteroids. Aids patients with pneumocystis carinii pneumonia have a higher survival rate when treated with glucocorticosteroids than with placebo.

Clinical Trials as Topic↗
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

Fleroxacin clinical pharmacokinetics.

Fleroxacin is a new member of the class of fluoroquinolones. The drug has good activity (i.e. minimum inhibitory concentrations at less than 2 mg/L against 90% of strains) against a wide range of Gram-positive and Gram-negative bacteria. High performance liquid chromatography is used to determine concentrations of fleroxacin and its metabolites in biological fluids. Absorption of orally ingested drug is rapid as the peak plasma concentration of approximately 5 mg/L is reached in 1 to 2h after a single dose of 400mg. The systemic availability is close to 100%. Fleroxacin is poorly bound to plasma proteins (23%) and exhibits excellent tissue distribution. Renal clearance accounts for 60 to 70% of elimination. The drug is metabolised to form antimicrobially active N-demethyl-fleroxacin and inactive N-oxide-fleroxacin. In multiple dose studies the accumulation ratio of a once-daily dosage regimen is about 1.3, as predicted from the elimination half-life of 10 to 12h. Compared with ciprofloxacin, fleroxacin has a greater systemic availability and a longer half-life. Fleroxacin concentrations are higher in elderly patients, but further studies are needed to establish whether a dosage reduction should be recommended for this age group. In patients with renal disease dosage adjustment is recommended since a decreased renal clearance of fleroxacin leads to a significant prolongation of the elimination half-life. Fleroxacin is only poorly eliminated by peritoneal dialysis or haemodialysis. The most important drug-drug interaction is a decrease in systemic availability of fleroxacin after ingestion of aluminium- or magnesium-containing antacids. There is no evidence of a significant interaction between fleroxacin and theophylline. Only limited data are available on adverse reactions of fleroxacin. The most important adverse effects appear to be photosensitivity and a dose-dependent incidence of central nervous system reactions including sleep disorders.

Adult↗
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↗
PubMed1991

Autoimmune adrenalitis, asthma and membranoproliferative glomerulonephritis.

We report the first case of membranoproliferative glomerulonephritis in a patient with chronic adrenal insufficiency due to autoimmune adrenalitis. In addition, this patient developed extrinsic asthma. The pathogenic implications of autoimmune adrenalitis with a long lasting hypocortisolemic state and the appearance of immunologically mediated diseases are discussed.

Addison Disease↗
PubMed1990

[Cyclosporin in autoimmune diseases].

The efficacy of cyclosporine (Sandimmun) is well established in the field of organ transplantation. More recently, prospective controlled trials were performed in patients with other diseases. The efficacy of cyclosporine for the following clinical entities was proven by the trials: endogenous uveitis, rheumatoid arthritis, Sjögren's syndrome, myasthenia gravis, psoriasis and Crohn's disease. Furthermore, there is evidence from a controlled trial of some benefit for patients with aplastic anemia. The proteinuria of patients with glomerulonephritis was reduced by cyclosporine, though no improvement in glomerular filtration rate was observed. Large controlled trials in patients with multiple sclerosis or amyotrophic lateral sclerosis revealed a beneficial effect on some clinical parameters. Nevertheless, cyclosporine cannot be recommended for these patients at the present time, since the ratio between the (slight) beneficial effects and the side effects was unfavourable. In patients with primary biliary cirrhosis, cholestasis slightly diminished after the administration of cyclosporine. Whether this improvement in laboratory parameters predicts an improved outcome in patients with primary biliary cirrhosis has yet to be demonstrated. Some patients with recently diagnosed insulin dependent diabetes needed no further insulin therapy as long as cyclosporine was administered. This is an observation of tremendous potential practical relevance for the future, when methodology may be available for diagnosing autoimmune destruction of beta-cells before clinically overt diabetes is present. Cyclosporine combined with prednisone was slightly more efficacious in patients with Graves' ophthalmopathy than prednisone alone. For all other autoimmune diseases, no controlled studies with cyclosporine are available at the present time. The most important side effects of cyclosporine are renal dysfunction, hypertension, gout, tremor, gingival hyperplasia and hypertrichosis. These side effects are manageable by appropriate dosage of cyclosporine and prophylactic measures. Side effects caused interruption of cyclosporine therapy in less than 5% of the patients. Thus, cyclosporine appears to be an efficacious new agent for treatment of some groups of patient with immune diseases.

Amyotrophic Lateral Sclerosis↗