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Biomedical subjects

F Brunner

Publications and source records attributed to F Brunner.

At least 55 records · Page 3Linked to original sources
PubMed1985

Prazosin binding to human alpha 1-acid glycoprotein (orosomucoid), human serum albumin, and human serum. Further characterization of the 'single drug binding site' of orosomucoid.

The plasma protein binding of the alpha 1-adrenergic blocking agent prazosin was investigated by means of circular dichroism (CD) and equilibrium dialysis (ED) measurements. The interaction of prazosin with human alpha 1-acid glycoprotein (alpha 1-AGP) results in pronounced negative extrinsic Cotton effects at 255 nm and a smaller negative band at 285 nm which are associated with the binding of prazosin to only one site of the protein. Various basic drugs, and warfarin also, at 50 microM displace prazosin 10 microM from its binding site on alpha 1-AGP and reduce the CD-spectra at 255 nm by 26% (disopyramide), 52% (mepivacaine), about 70% (verapamil, biperiden), and 90-100% (trihexyphenidyl, warfarin). (+/-)-Propranolol reduces the CD-spectra by 76%, its (-)-isomer by 89%, and the (+)-isomer by 65%. ED experiments indicated that the binding of prazosin to alpha 1-AGP is saturable with an association constant of 48 000 M-1 and 0.85 binding sites per protein molecule. Displacement of prazosin from alpha 1-AGP by the same drug as used for the CD experiments at displacer/prazosin ratios of 5 resulted in comparable reductions of the fraction bound as obtained by the CD experiments. Prazosin was also highly bound to human serum albumin (600 microM) with about 80-85% bound at prazosin concentrations from 1-100 microM. Since prazosin binding to human serum is only slightly higher (80-90%) it is concluded that prazosin binding in serum is largely mediated by the albumin fraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding Sites↗
PubMed1984

The underlying bases of pharmacological results in agreement or disagreement with the law of initial value.

Dose-response studies in vitro and in vivo revealed four types of alterations of dose-response curves along with changes in the baseline, two of them in accordance and two in disagreement with Wilder's law of initial value (LIV). The following conclusions have been drawn: The magnitude of drug-induced changes is in agreement with the LIV under conditions where the ED50 of a compound studied is not affected by changes in the baseline. Disagreement with the LIV is due to factors which potentiate the action of a compound at higher initial values. Not the initial value or activity by itself determines the response to drugs or stimuli; the response is dependent on the factor(s) changing the initial value.

Animals↗
PubMed1984

Assessment of adrenergic beta-blockade in the anesthetized rat at different baseline values.

The influence of different baseline values (blood pressure, heart rate) on ED50- and Emax-values of isoprenaline dose-response curves (DRC) in the presence and absence of beta-blocking drugs was assessed in urethane-anesthetized rats. The results show that Urethane is a suitable anesthetic in this animal model. Different baselines have no influence in ED50-values. Assessment of potency of competitive antagonists (pA2) from complete DRC appears unaffected by differences in baseline or in Emax. Pharmacologic effects (heart rate, blood pressure) are better depicted as absolute effect values than delta-values.

Adrenergic beta-Antagonists↗
PubMed1984

Plasma protein binding of metbufen, a new non-steroid anti-inflammatory drug, in humans.

The binding of 14C-metbufen to human serum albumin and to plasma of cirrhotic patients was measured by equilibrium dialysis at 37 degrees C, pH = 7.4. Between 0.37-373 microM, binding of metbufen to human serum is linear and 99% complete. HSA is the only binding protein with two classes of saturable binding sites. The binding parameters are n1 = 3-5; K1 = 40000 M-1; n2 = 5-8; K2 = 2000 M-1 and n1 = 2; K1 = 148000 M-1, n2 = 7.5; K2 = 2800 M-1 to serum (600 microM HSA) and HSA (600 microM), respectively. The higher affinity constants of pure commercial HSA than found in serum and the lower number of binding sites are thought to be due to albumin polymerization in commercial HSA. In plasma from cirrhotic patients (total bilirubin: 232 microM; HSA = 450 microM), at 7.5 and 30 microM, metbufen-free fractions increased from 1.4 to 2.4% and 1.3 to 3.6%, respectively. At 2 or 8 micrograms/ml, metbufen is not displaced by salicylic acid (300 micrograms/ml), CPIB (200 micrograms/ml), furosemide (2 micrograms/ml), itanoxone (20 micrograms/ml), tolbutamide (100 micrograms/ml), warfarin (3 micrograms/ml), or diazepam (0.75 micrograms/ml). Finally, metbufen interacts with both the diazepam and warfarin binding sites of HSA to some degree.

Anti-Inflammatory Agents↗
PubMed1984

Cyclosporine alone or in combination with prednisone in cadaveric renal transplantation.

One hundred recipients of first cadaveric kidney transplants were treated with three different immunosuppressive regimens: (1) conventional immunosuppression, (2) CsA alone, and (3) low-dose CsA in combination with low-dose prednisone, with rapid adjustment to give CsA whole blood trough levels of 300 to 800 ng/mL. One-year graft survival in the aza + pred group was 76%, and in the CsA alone group 75%. Graft survival at two and six months in the CsA-pred group was 94%. The dose of CsA in the CsA-pred group in the first two months posttransplant was only about half that given to the CsA-alone group. Surprisingly, the reduction in the CsA dose also reduced the number of methylprednisolone pulses given for treating rejection by greater than 50%. The incidence of nephrotoxicity and extrarenal side effects also fell considerably. Withdrawal of prednisone in the CsA-pred group after five months led to reversible rejection in two cases. In conclusion, (1) the rapid reduction in the CsA dosage is beneficial and has no drawbacks, and (2) our guidelines for withdrawing prednisone (timing of withdrawal, rate of reduction in dosage) still need further refinement.

Adult↗
PubMed1983

Cyclosporin A used alone or in combination with low-dose steroids in cadaveric renal transplantation.

The actual survival rate of 25 primary cadaveric kidney grafts in recipients treated initially with cyclosporin A (CyA) alone was 84%. The survival rate in 37 patients under conventional immunosuppression was 76%. The mean number of dialyses required in the first 4 weeks after transplantation was 1.2 per patient in both groups. At 15-28 months posttransplant, mean serum creatinine levels have remained stable at 175 mumol/l in the CyA group. The mean daily dose of steroids (including methylprednisolone i.v.) in the first two months was 2.07 mg/kg/d in patients under conventional immunosuppression and 0.76 mg/kg/d in the patients receiving CyA (p less than 0.001). The combination of CyA with low-dose steroids enabled the dose of CyA to be rapidly tapered off in once-weekly steps. CyA levels were monitored by determination of whole blood trough concentrations (target level: 300-800 ng/ml). At 60 days posttransplant the average dose of CyA was 6.0 +/- 0.5 mg/kg/d compared with an average daily dose of 11.4 +/- 0.9 as recommended for CyA alone in the protocol for the European multicentre study. This more rapid reduction in the CyA dose reduced nephrotoxicity (serum creatinine levels 174 +/- 14 as compared with 289 +/- 31 mumol/l) (p less than 0.05) and almost halved the number of methylprednisolone pulses given up to the end of the second month. We conclude from these results (1) that previously the dosage of CyA administered at this centre was probably too high, and (2) early adjustment of dose levels on the basis of blood concentrations and with low-dose prednisone cover appears to be safe and effective, but requires further verification.

Azathioprine↗
PubMed1983

Intravenous cyclosporine kinetics in renal failure.

Kinetics of the novel immunosuppressive cyclosporine were determined in four patients with terminal renal failure. After a short intravenous infusion (2.05 to 3.5 mg/kg in 4 hr), blood and plasma concentrations were measured (HPLC and radioimmunoassay [RIA] up to 36 hr. After infusion, concentration curves of the drug were characterized by a rapid initial fall (t 1/2 alpha 0.10 +/- 0.03 hr), followed by a biphasic elimination phase with corresponding t 1/2s of 1.08 +/- 0.25 hr (t 1/2 beta) and 15.8 +/- 8.4 hr (t 1/2 gamma). The volumes of distribution, calculated from whole blood concentrations (HPLC), were 0.140 +/- 0.48 l/kg (volume of the central compartment) and 3.49 +/- 2.65 l/kg (volume of distribution at steady state), whereas systemic clearances were 0.369 +/- 0.08 l/hr/kg. Blood levels measured by RIA exceeded the HPLC values after the fourth hour by up to 100%, indicating the production of cross-reacting cyclosporine metabolites. Plasma concentrations were considerably lower than in whole blood. Elimination of unchanged cyclosporine in patients with renal failure appears to be of the same order as in those with normal kidney function. Modification of the initial dosage regimens is therefore probably not required.

Chromatography, High Pressure Liquid↗
PubMed1983

The plasmid pattern as an epidemiologic tool for Salmonella typhimurium epidemics: comparison with the lysotype.

In the study of a limited epidemic of Salmonella typhimurium infections, the plasmid content (pattern) of bacteria was used as an epidemiologic tool outside the hospital environment. Comparisons were made with lysotyping, resistance pattern determination (14 antibiotics), and biotyping. Plasmid pattern determination was found to be as useful and accurate as lysotyping, whereas resistance pattern determination was of more limited interest. However, in this report biotyping was of no use.

Bacteriophage Typing↗
PubMed1983

The effects of chronic renal insufficiency on the pharmacokinetics of doxycycline in man.

The pharmacokinetics as well as erythrocyte and plasma protein binding of doxycycline were studied in fifteen patients with various renal function impairments after oral doxycycline polyphosphate single administration. Plasma half-life (t 1/2), area under the plasma concentration-time curve (AUC), urinary excretion, renal clearance, erythrocyte and plasma protein binding (%) were regressed vs creatinine clearance. No significant correlations were observed between t 1/2 or AUC and renal function nor plasma protein binding and plasma albumin concentrations. Significant correlations were obtained between urinary excretion, renal clearance, erythrocyte binding, plasma protein binding and creatinine clearance. Significant correlation was obtained between haematocrit and erythrocyte binding. Constancy of overall elimination parameters in renal failure is due to parallel increase in plasma free fraction of doxycycline.

Adult↗