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Biomedical subjects

F J Frey

Publications and source records attributed to F J Frey.

At least 73 records · Page 4Linked to original sources
PubMed1997

Illustration of a method for selecting research grant applications.

BACKGROUND: The method used by granting agencies to select applications they wish to support should be explicit, consistent, and fair, especially when the applications are diverse and controversial in nature, or when funds are limited, which is often the case. This study demonstrates the use of a method to satisfy such standards. METHODS: An expert committee appointed by the Swiss National Research Foundation planned and advertised a program for the evaluation of alternative therapies. The selection of applications to be supported was assisted by the use of Judgement Analysis. In the first phase, appropriate standards such as relevance to the program objectives and methodological adequacy were established. In the second phase, the relative weights attached to these standards by individual members were obtained by multiple linear regression analysis. In the third phase, a single common policy based on the standards that had been made explicit was applied to the choice of projects to be supported. RESULTS: 219 grant applications that proposed a variety of alternative treatments for various indications were reviewed; 17 were funded. CONCLUSIONS: The method of Judgment Analysis was acceptable to the experts, who were drawn from several disciplines and had diverse points of view. The method proved understandable and easy to use.

Complementary Therapies↗
PubMed1996

Interaction of plant lipids with 14 kDa phospholipase A2 enzymes.

Several structurally related plant lipids were isolated and their effect was assessed on the enzyme activity of group I (pancreatic and Naja mocambique venom) and group II (Crotalus atrox venom) phospholipase A2 (PLA2) enzymes, with labelled Escherichia coli as an enzyme substrate. The neutral monogalactosyldiacylglycerol (MGDG) and negatively charged diacylglyceryl alpha-D-glucuronide (DGGA) did not influence the enzyme activity of either group. Digalactosyldiacylglycerol (DGDG), another uncharged glycolipid, inhibited PLA2 activity in a dose-dependent manner to 60-70% of the control. Sulphoquinovosyldiacylglycerol (SQDG), which is also anionic, activated both groups of PLA2 enzyme. A similar activation was observed with the zwitterionic diacylglyceryl-O-(N,N,N-trimethylhomoserine) (DGTS) and diacylglyceryl-O-(hydroxymethyl)(N,N, N-trimethyl)-beta-alanine (DGTA). DGDG, SQDG and DGTS are dispersed homogeneously with low critical micelle concentrations (CMCs). The hydrodynamic radius of neutral DGDG is an order of magnitude larger than the charged lipids SQDG and DGTS. The inhibition of pig pancreatic PLA2 by DGDG was dependent on substrate concentration. The intrinsic fluorescence spectra of the enzyme was not changed in the presence of native or hydrogenated DGDG. Thus the inhibition is most probably due to a non-specific interaction of plant lipids with the substrate. Different lengths and saturations of the fatty acyl chains of DGDG did not alter the inhibition of PLA2, whereas deacylation abrogated the inhibitory effect. Both SQDG and DGTS activated pig pancreatic PLA2 in a dose-dependent manner. Saturation of the double bonds of these lipids decreased the activating effect. The fluorescence of pig pancreatic PLA2 incubated with SQDG and DGTS was enhanced by 2-fold and 3-fold respectively, suggesting the formation of a complex between enzyme and lipids. In conclusion, the effect of different plant lipids on PLA2 activity depends on different structural elements of the polar head group and their charge as well as the degree of unsaturation of the fatty acyl chains.

Animals↗
PubMed1996

Liver cirrhosis induces renal and liver phospholipase A2 activity in rats.

Maintenance of renal function in liver cirrhosis requires increased synthesis of arachidonic acid derived prostaglandin metabolites. Arachidonate metabolites have been reported to be involved in modulation of liver damage. The purpose of the present study was to establish whether the first enzyme of the prostaglandin cascade synthesis, the phospholipase A2(PLA2) is altered in liver cirrhosis induced by bile duct excision. The mRNA of PLA2(group I and II) and annexin-I a presumptive inhibitor of PLA2 enzyme was measured by PCR using glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as an internal standard. The mean mRNA ratio of group II PLA2/GAPDH was increased in liver tissue by 126% (P < 0.001) and in kidney tissue by 263% (P < 0.006) following induction of liver cirrhosis. The increase in group II PLA2 mRNA in cirrhotic animals was reflected by an increase in PLA2 protein and enzyme activity in both liver and kidney tissues. Since the mRNA of group I PLA2 was not detectable and Group IV PLA2 activity measured in liver and kidney tissue samples was very low and not changed following induction of cirrhosis, it is likely that the major PLA2 activity measured in liver and kidney corresponds to group II PLA2 enzyme. The mean mRNA ratio of annexin-I/GAPDH was increased in liver tissue by 115% (P < 0.05) but unchanged in kidney tissue following induction of cirrhosis. The protein content of annexin-I and -V were not affected by bile duct excision in liver and kidney tissue indicating that upregulation of group II PLA2 activity was not due to downregulation of annexin-I or -V. Group II PLA2 activity of glomerular mesangial cells stimulated by interleukin-1 beta was enhanced by bile juice and various bile salts. In conclusion, activity of group II PLA2 is upregulated partly due to enhanced transcription and translation in cirrhosis and is furthermore augmented by elevated levels of bile salts.

Animals↗
PubMed1996

Differences in phospholipase A2 activity between males and females and Asian Indians and Caucasians.

There is epidemiological evidence that chronic inflammatory diseases occur more frequently in female than in male subjects and prevail differently in various ethnic populations. Phospholipase A2 (PLA2) (group II) plays a key role in many inflammatory reactions by releasing free arachidonic acid, which is a prerequisite for the production of proinflammatory lipid mediators. We therefore, measured PLA2 activity in plasma, serum, leucocytes and lymphocytes in 20 female and 20 male subjects, 10 of each group being of Asian Indian and of Caucasian origin respectively. When PLA2 activity was measured in crude plasma and serum no dependency from gender and ethnicity was observed. Following acid extraction and heating, PLA2 activity in plasma was higher in Caucasians (27.8 +/- 2.2 nmol L-1 mg-1 protein 60 min-1) than in Asian Indians (17.9 +/- 2.5 nmol L-1 mg-1 protein 60 min-1) (P < 0.005) and higher in females (28.5 +/- 2.6 nmol L-1 mg-1 protein 60 min-1) than in males (17.3 +/- 2.0 nmol L-1 mg-1 protein 60 min-1) (P < 0.001). Similar differences were observed when only Asian Indian or Caucasian females were compared with their corresponding males. Contrary to plasma, in which the specific activity of PLA2 increased following acid extraction and heating, the activity was completely abrogated in serum after extraction and heating. Lymphocytes exhibited lower activities of PLA2 than neutrophils in all four groups of subjects investigated. Females had a tendency towards higher PLA2 activity in both lymphocytes and neutrophils than males. In conclusion the present investigation revealed an ethnic and sex-dependent basal activity of PLA2, a key enzyme in the pathogenesis of chronic inflammatory diseases.

Adult↗
PubMed1996

Pharmacokinetics of fleroxacin after multiple oral dosing in patients receiving regular hemodialysis.

The pharmacokinetic profile of fleroxacin was studied in eight noninfected patients receiving regular hemodialysis (four women and four men; mean age, 63 years; age range, 48 to 73 years). Dialysis clearances (mean +/- standard deviation) calculated from the amount of drug recovered in the dialysate exceeded those calculated from rates of extraction from plasma for fleroxacin (126 +/- 29 versus 73 +/- 11 ml/min) and its metabolite N-demethylfleroxacin (103 +/- 31 versus 72 +/- 15 ml/min) but not that for the metabolite fleroxacin N-oxide (100 +/- 25 versus 100 +/- 12 ml/min). Data were fitted to a two-compartment model over the total observation period of 8 days (six oral daily doses of 200 mg of fleroxacin on days 1 to 6 and hemodialysis treatments on day 1,3, and 6) by nonlinear mixed-effects modeling. The random variability of plasma fleroxacin concentrations was 13% about its prediction. The estimated metabolic clearance was 25 ml/min (coefficient of variation, 43%), and the calculated steady-state volume of distribution was 84 liters (coefficient of variation, 16%). The model was expanded for the two major metabolites by the addition of a two-compartment metabolite distribution. Formation clearances of N-demethylfleroxacin and fleroxacin N-oxide were estimated to be 54 and 33% of fleroxacin's metabolic clearance, respectively. The conclusions were as follows. Because of the slow metabolic clearance and intermittent dialysis treatment, steady-state conditions were not reached after 1 week of oral fleroxacin therapy, and there was relevant accumulation of fleroxacin as well as that of fleroxacin N-oxide in our patients with end-stage renal disease. We recommend that infected hemodialysis patients be treated with an initial oral dose of 400 mg of fleroxacin and then daily oral doses of 200 mg. One cannot recommend the treatment of this patient population with fleroxacin over prolonged time periods until more date about the levels of accumulation of fleroxacin and its metabolites in infected patients with renal disease are available.

Administration, Oral↗
PubMed1996

Effects of growth hormone and IGF-I on glucocorticoid-induced protein catabolism in humans.

The effects of similar increases in total insulin-like growth factor I (IGF-I) plasma concentrations achieved by either recombinant human (rh) growth hormone (GH) or rhIGF-I administration on whole body protein and glucose kinetics were assessed. Twenty-six healthy subjects received methylprednisolone (0.5 mg.kg-1.day-1 orally) during 6 days in combination with either placebo (saline sc), GH (0.3 mg.kg-1.day-1 sc), or IGF-I (80 micrograms.kg-1.day-1 sc) in a double-blind randomized fashion. Glucocorticoid administration resulted in protein catabolism as indicated by an increase in leucine flux and a 62 +/- 13% increase in leucine oxidation ([1-13C]leucine infusion technique); this increase was abolished by GH (-1 +/- 18%) as was statistically insignificant during IGF-I treatment (+53 +/- 25%). GH increased endogenous glucose production by 28 +/- 8%, augmented glucocorticoid-induced insulin resistance of peripheral glucose clearance (euglycemic clamp), and increased circulating lipids. IGF-I administration resulted in both increased endogenous glucose production and increased peripheral glucose clearance such that plasma glucose concentrations remained unchanged by IGF-I. IGF-I lowered circulating GH and insulin and altered IGF binding proteins, which all may have reduced bioactivity of IGF-I. The data demonstrate that, in spite of similar total IGF-I plasma concentrations during treatment, GH and IGF-I exert markedly different effects on whole body leucine, glucose, and lipid metabolism.

Adult↗
PubMed1996

Acute cyclosporine-induced nephrotoxicity in renal transplant recipients: the role of the transplanted kidney.

Cyclosporine A causes an acute reduction in GFR. The interindividual variable reduction in GFR is most likely the result of arteriolar vasoconstriction. Vasoconstriction is attributable either to a local effect of cyclosporine on renal blood vessels (intrinsic mechanism) or to a systemic effect of cyclosporine on circulating and/or neuronal factors (extrinsic mechanism). The aim of the investigation presented here was to establish whether intrinsic or extrinsic mechanisms account for the interindividual differences in the susceptibility to acute cyclosporine-induced nephrotoxicity. For that purpose, this study took advantage of the clinical transplant situation in which two (intrinsically identical) kidneys from a cadaveric donor are transplanted into two (extrinsically) different subjects. The preexisting regular daily cyclosporine doses were raised by 25% for 2 wk and by 50% for another 2 wk in 16 patients with stable renal graft function, representing eight pairs of patients, each of whom had received kidneys from the same donor. In these patients, a mean (+/- SD) maximum cyclosporine-induced increase in serum creatinine concentration of 13 +/- 11% (P < 0.001) and in serum BUN of 27 +/- 33% (P < 0.01), together with a decline in the fractional uric acid excretion of 51 +/- 89% (P < 0.02) were observed. The percentage change in serum creatinine concentrations after increased dosing of cyclosporine paralleled within the subjects receiving their kidneys from the same donor, i.e., when one recipient experienced a large percentage of change after increases of cyclosporine dosing, the corresponding recipient of a kidney from the same donor had a change of the same magnitude. Seven of eight pairs showed a consistent response with respect to a clinically significant increase in serum creatinine concentration of > 15%, with a consistent response purely by chance being < 5%. Thus, the transplanted kidney itself rather than the recipient determines the susceptibility to acute cyclosporine-induced nephrotoxicity.

Acute Kidney Injury↗
PubMed1996

Haemodialysis activates phospholipase A2 enzyme.

BACKGROUND: Clinical and experimental evidence suggest that haemodialysis (HD) procedure is an inflammatory process. For the production of proinflammatory lipid mediators in many inflammatory reactions, the release of arachidonic acid by phospholipase A2 (PLA2) enzyme is a prerequisite. Therefore, the purpose of the present investigation was to establish whether the activity of PLA2 increases during HD and whether the increase depends on the type of dialyser used. METHODS: We performed dialysis in eight chronic HD patients. Blood samples entering and leaving the dialyser were obtained before and at 15, 60, 120 and 180 min after the dialysis was started, on one occasion using a cuprophane and on another occasion a cellulose triacetate dialyser. PLA2 activity was assessed in crude plasma and in plasma extract. RESULTS: PLA2 activity in plasma extract exhibited similar biochemical properties to that of inflammatory human synovial fluid PLA2 enzyme which is of group II PLA2. PLA2 activity in crude plasma represents a type of PLA2 other than the synovial type. In HD patients, baseline PLA2 activities in a crude plasma and plasma extract were significantly increased when compared to normal subjects. An increase in PLA2 activity was observed in crude plasma with a peak appearing at 15 min when the patients were dialysed with cuprophane and cellulose triacetate membranes. This increase was observed in both arterial and venous blood samples and was more pronounced when the patients were dialysed with cuprophane than with cellulose triacetate membranes. When PLA2 was assessed in plasma extract, the activity increased only with cuprophane but not with cellulose triacetate membranes. CONCLUSION: PLA2 activity in plasma is increased in HD patients and increases during the dialysis procedure to a greater extent with a less biocompatible membrane. Continuous activation of PLA2 might be relevant for long-term deleterious consequences of HD.

Adult↗
PubMed1996

Does continuous renal replacement therapy favourably influence the outcome of the patients?

Continuous haemodialysis and continuous haemofiltration are efficient and safe techniques for the treatment of acute renal failure. Theoretical advantages are improved haemodynamic stability and easier fluid removal. All 15 available studies comparing intermittent (522 patients) with continuous (651 patients) renal replacement therapy have been reviewed. From these studies it cannot be established, whether the use of a continuous instead of an intermittent treatment modality improves the outcome in patients with acute renal failure. Reviewing all 67 published studies dealing with continuous renal replacement therapy revealed a trend to a decreasing mortality rate (P<0.08) over the last 11 years, whereas the mean age and the severity of illness of the patients, measured by the APACHE II score, did not change, In order to establish whether the quality of treatment has improved as a function of time, two quality factors (QF) were created, i.e. QF for age (mean age/mean mortality rate of the patients treated) and QF for severity of diseases (mean APACHE II/mean mortality rate). Both QF improved from 1984 until 1994, when analyzed for continuous (P<0.001) or intermittent (P<0.001) treatment modality. Thus the quality of treatment of patients with acute renal failure improved during the last decade. However, there is no evidence with respect to survival rate that a continuous renal replacement therapy is superior to an intermittent one.

Acute Kidney Injury↗
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↗
PubMed1995

[Erythropoietin, a milestone in the history of nephrology].

Erythropoietin, a glycoprotein, is synthesized mainly in the kidney. With the destruction of renal tissue, erythropoietin production decreases; this is a major factor in the development of anemia in patients with renal failure. For about ten years now, recombinant human erythropoietin has been available for the treatment of renal anemia. All patients with renal insufficiency, independent of their plan for future renal replacement therapy, may benefit from erythropoietin. At what extent of anemia erythropoietin therapy should be started is still discussed and is certainly dependent on the degree of the patient's impairment by his anemia. Before beginning a therapy with erythropoietin, other forms of anemia observed in patients with renal failure, i.e. mainly iron deficiency, have to be excluded. A strict monitoring of hematocrit during treatment with erythropoietin is mandatory. Hypertension, seizures and cardiovascular complications have been observed with overdosing of erythropoietin. Special emphasis of this review is therefore put on the discussion of the dynamics of the erythropoietin-red cell system.

Anemia, Hypochromic↗
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

Measurement of lactate in acutely ischemic rat kidneys using magnetic resonance spectroscopy.

RATIONALE AND OBJECTIVES: Quantification of lactate in the kidney by 1H magnetic resonance spectroscopy (MRS) is a difficult task because of the presence of large amounts of peri-renal fat. When an editing scheme is used to detect lactate that filters out all resonances except lactate, there is no suitable metabolite to serve as an internal standard. In this study, the authors evaluate the potential of MRS to measure the absolute lactate concentration in rat kidneys during acute ischemia using MRS. MATERIALS AND METHODS: The authors propose a method based on a double resonance lactate editing scheme used in combination with the fully relaxed water peak as an internal standard. Experiments were performed on the left kidney rendered ischemic in eight rats. RESULTS: Renal lactate concentrations measured by MRS were compared with values derived from chemical analysis. The mean (+/- standard deviation) renal lactate concentrations measured by MRS and determined chemically were 12 +/- 1.2 umol/g, and 12.94 +/- 1.07 umol/g wet weight, respectively. The coefficient of variation for paired observations was 2.96%, indicating excellent agreement between the two methods used for measuring lactate. DISCUSSION: The study results demonstrate that it is possible to assess the lactate concentration in a rat model of ischemic kidney with MRS and suggest that the total lactate pool is detectable by this method under these experimental conditions.

Animals↗
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↗