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Biomedical subjects

P Rohdewald

Publications and source records attributed to P Rohdewald.

At least 37 records · Page 2Linked to original sources
PubMed1998

Biochemical characterization of a glucocorticoid-induced membrane protein (RM3/1) in human monocytes and its application as model system for ranking glucocorticoid potency.

PURPOSE: Upon glucocorticoid stimulation, human mononuclear leucocytes express an antigen, RM3/1, which characterizes a subpopulation of human monocytes and macrophages evolving in late phase of inflammation. We investigated biochemical properties of the RM3/1 antigen and correlations between antigen expression and glucocorticoid potency. METHODS: Biochemical properties were analyzed after solubilization by immunoaffinity methods and SDS-PAGE. RESULTS: Induction of the RM3/1 antigen is a glucocorticoid receptor mediated process, in contrast, inflammatory mediators such as LPS or TPA were not able to upregulate RM3/1 expression. After SDS-PAGE, the antigen appeared as a 130 kDa (nonreduced)/150 kDa (reduced) glycoprotein with a 25 kDa N-linked glycoportion. The interdependence between antigen density and glucocorticoid efficacy was assessed by calculation of relative antigen expression induced by dexamethasone, fluticasone propionate, budesonide, triamcinolone acetonide, flunisolide, beclomethasone, prednisolone and triamcinolone. Relative antigen expression was significantly correlated with the relative receptor affinity of the glucocorticoid. CONCLUSIONS: We described biochemical properties of the glucocorticoid-induced protein RM3/1. Though the precise role of the RM3/1 antigen in the antiinflammatory process is not fully understood yet, an useful application of the induced expression could already be demonstrated for pre-clinical screening of glucocorticoid potency.

Antigens, CD↗
PubMed1998

Endothelium-dependent vascular effects of Pycnogenol.

Pycnogenol (P) is purported to exhibit effects that could be beneficial in terms of prevention of chronic age-related diseases such as atherosclerosis. The most studied of these effects is its antioxidant/free radical-scavenging activity. In this study, we investigated the possibility that this supplement might produce vascular effects by stimulation of nitric oxide (NO) production by vascular endothelial cells. In the in vitro experiments, P (1-10 microg/ml) relaxed epinephrine (E)-, norepinephrine (NE)-, and phenylephrine (PE)-contracted intact rat aortic ring preparations in a concentration-dependent manner. However, when the endothelial lining of the aortic ring was removed, P had no effect, indicating an endothelium-dependent relaxing (EDR) effect. This EDR response was caused by enhanced NO levels, because the NO synthase (NOS) inhibitor N-methyl-L-arginine (NMA) reversed (or prevented) the relaxation, and this response, in turn, was reversed by addition of L-arginine, the normal substrate for NOS. Pycnogenol-induced EDR persisted after exposure of intact rings to high levels of superoxide dismutase (SOD), suggesting that the mechanism of EDR did not involve scavenging of superoxide anion. In addition to causing relaxation, preincubation of aortic rings with P (1-10 microg/ml) inhibited subsequent E- and NE-induced contractions in a concentration-dependent manner. Fractionation of P by Sephadex LH-20 chromatography resulted in three fractions, one of which (fraction 3, oligomeric procyanidins) exhibited potent EDR activity. These results indicate that P, in addition to its antioxidant activity, stimulates constitutive endothelial NOS (eNOS) activity to increase NO levels, which could counteract the vasoconstrictor effects of E and NE. Furthermore, additional protective effects could result from the well-established properties of NO to decrease platelet aggregation and adhesion, as well as to inhibit low-density lipoprotein (LDL) cholesterol oxidation, all of which could protect against atherogenesis and thrombus formation.

Animals↗
PubMed1997

Distribution of inhaled fluticasone propionate between human lung tissue and serum in vivo.

High retention of inhaled glucocorticoids in the airways means prolonged anti-inflammatory action and low delivery into the serum. The objective of this study was to investigate the retention in and distribution of inhaled fluticasone propionate (FP) between central and peripheral human lung tissue and serum in vivo. In 17 patients undergoing lung resection surgery, a single 1.0 mg dose of FP was inhaled at varying time-points (range 2.8-21.7 h) preoperatively. Peripheral and central lung tissue was obtained, and blood was drawn simultaneously. FP concentrations in central lung tissue were approximately three to four times higher than peripheral lung tissue concentrations, which in turn, exceeded those found in serum by 10 times. FP was detectable up to 21 and 16 h, respectively, after inhalation, with drug levels falling almost in parallel in peripheral lung tissue and in serum. The results of this study demonstrate that fluticasone propionate is retained in lung tissue for a long time. Serum concentrations after a single inhaled dose are low. Retention of high concentrations of fluticasone propionate in the airways may promote high topical anti-inflammatory activity.

Administration, Inhalation↗
PubMed1997

Antiinflammatory activities of procyanidin-containing extracts from Pinus pinaster Ait. after oral and cutaneous application.

Orally in liquid diet administered procyanidin-containing extracts from Pinus pinaster Ait. decreased the croton oil-induced ear edema in mice or the compound 48/80-induced hind paw edema in rats to a statistically significant extent. Most effective were the extracts containing mainly oligomeric procyanidins with chain lengths greater then 4 units (extracts A or B). Further, the different extracts incorporated in various concentrations (1.0, 3.0 or 0.1%) in 5% hydroxyethylcellulose gel and applied topically on the shaved back of rats, inhibited significantly the ultraviolet radiation-induced increased capillary permeability. In these experiments, normalisation of capillary permeability was not correlated with the content of the extracts on higher oligomeric procyanidins.

Administration, Oral↗
PubMed1994

Binding kinetics of fluticasone propionate to the human glucocorticoid receptor.

Receptor-ligand interactions of fluticasone propionate (FP), a glucocorticoid used for inhalation therapy, were determined and compared with dexamethasone, budesonide, and beclomethasone-17-monopropionate, the active metabolite of beclomethasone dipropionate. Two approaches, evaluation of binding kinetics and competition assays, were applied to obtain relative receptor affinities (RRAs) with dexamethasone as reference. A higher association rate constant and a distinctly lower dissociation rate constant for FP compared with the other glucocorticoids resulted in an equilibrium dissociation constant (Kd) of 0.49 nmol/l. Kd dexamethasone was 9.36 nmol/l; derived RRA of FP was 1910. The calculated half-time of the FP-receptor complex was 10 h, thus exceeding the half-times of all other glucocorticoids as well as their RRAs. Competition assays clearly confirmed the rank order of the tested glucocorticoids, although RRAs were generally lower than those found in kinetic assays and strongly dependent on the assay conditions. The high receptor affinity of FP is reflected by clinical trials demonstrating its superiority to other glucocorticoids. For therapeutic application, the long half-time of the FP-receptor complex should support the practicality of longer dose-intervals.

Administration, Topical↗
PubMed1993

Pharmacokinetics of bromfenac in healthy subjects after single oral administration of three different doses.

The pharmacokinetic profile of bromfenac (2-amino-3-(4-bromobenzoyl) benzeneacetic acid, CAS91714-93-1) has been investigated in 12 healthy subjects (6 male and 6 female) after single oral doses of 25, 50 and 75 mg. Plasma concentrations were determined by a sensitive HPLC method with spectrophotometric detection. Sampling was performed up to 300 min after drug ingestion. Linear pharmacokinetics could be verified for this dose-range; there was a clear, positive dose-plasma concentration relationship. Bromfenac exhibits a cmax of 3.49 +/- 1.65-8.81 +/- 3.45 micrograms/ml at tmax 52 +/- 27-42 +/- 15 min. The elimination half-life was 39.8 +/- 7.3-34.2 +/- 8.0 min with a clearance (Cl/f) of 120.6 +/- 51.6-135.3 +/- 34.6 ml/min and a volume of distribution (Vd/f) 6.82 +/- 2.88-6.64 +/- 2.29 l. The results obtained show a fast absorption and rapid elimination of bromfenac when administered orally. The short plasma half-life of bromfenac apparently presents no direct relationship to its clinical effectiveness.

Administration, Oral↗
PubMed1990

Activation of beclomethasone dipropionate by hydrolysis to beclomethasone-17-monopropionate.

The relative affinity of beclomethasone (B), beclomethasone-17-monopropionate (17-BMP), beclomethasone-21-monopropionate (21-BMP), and beclomethasone dipropionate (BDP) has been determined. BDP binds to the glucocorticoid receptor with about half the affinity of the potent glucocorticoid dexamethasone (Dexa), B was found to be 0.75 times less active than Dexa. The 21-BMP has no binding affinity whereas the 17-BMP is about 13 times as potent as Dexa. The affinity data indicate that metabolism of BDP to 17-BMP is an important activation step. To evaluate the relationship between local and systemic activity incubation studies with BDP in human lung, simulated gastric and intestinal fluid and plasma were performed. In cytosol from human lung cells BDP is hydrolysed rapidly to the more stable 17-BMP. During gastric passage BDP is stable but is immediately hydrolysed to 17-BMP in intestinal fluid. In human plasma BDP is hydrolysed to 17-BMP and an interesterification of 17-BMP to the inactive 21-BMP was also found.

Beclomethasone↗
PubMed1989

Determination of the alkyl lysophospholipid derivative ET-18-OCH3, a new antineoplastic drug, in plasma.

We describe a sensitive method for measuring the concentration of the new antineoplastic drug ET-18-OCH3 in plasma. After plasma lipids are extracted, ET-18-OCH3 is separated from the excess of endogenous lipids by thin-layer chromatography and specific enzymatic hydrolysis of sphingomyelin by the action of sphingomyelinase. Analytical recovery after the complete isolation was 73.5% (CV = 9.8%, n = 15). [3H]-ET-18-OCH3 is used as internal standard. A densitometric method in which 8-anilino-1-naphthalenesulfonate, Mg salt, is used as fluorescent agent (excitation at 367 nm and emission greater than 390 nm) allows the sensitive determination of ET-18-OCH3 down to 0.1 mg/L (CV greater than 30%). The day-to-day CV is 25% for concentrations of 0.15 to 0.625 mg/L, 12% for 1.5 to 5.0 mg/L. Preliminary pharmacokinetic data reveal gastrointestinal absorption of ET-18-OCH3 after multiple oral administration.

Administration, Oral↗
PubMed1988

Comparative pharmacokinetics of methylprednisolone phosphate and hemisuccinate in high doses.

The pharmacokinetics of methylprednisolone and two methylprednisolone esters, the phosphate and the hemisuccinate, were investigated after intravenous administration of the esters to 12 healthy male subjects in two different doses (250 and 1000 mg). Methylprednisolone was formed more rapidly from phosphate than from hemisuccinate. During the first 30 min methylprednisolone levels were three to four times higher after phosphate administration than after hemisuccinate. The mean residence time of the hemisuccinate was significantly longer and the total-body clearance lower than those of the phosphate. Whereas very little of the phosphate (mean, 1.7%) was eliminated unchanged into the urine, there were significant amounts of hemisuccinate (mean, 14.7%) excreted renally and therefore not bioavailable. Methylprednisolone saliva levels paralleled plasma levels; the average saliva/plasma ratio was 0.22. Neither phosphate nor hemisuccinate could be detected in saliva. An average of 7.2% of the administered dose was eliminated in the form of methylprednisolone in urine. Renal clearance was 24 ml/min and not dose or prodrug dependent. For both doses endogenous hydrocortisone levels were lowered after 24 hr. For the 1000-mg dose the depression was still significant after 48 hr. The results indicate that methylprednisolone phosphate results in a faster and more efficient conversion to its active form, methylprednisolone, than methylprednisolone hemisuccinate.

Adolescent↗
PubMed1988

Glucocorticoid receptors in human synovial tissue and relative receptor affinities of glucocorticoid-21-esters.

A dexamethasone binding protein was detected in cytosol of 11 human synovial tissues from patients with chronic polyarthritis. The apparent dissociation constant (KD) ranged from 3.3 to 17.1 (mean, 7.0 +/- 4.3) nmol/liter, and the receptor concentration (Ro) from 17 to 65 (mean, 42 + 15) fmol/mg protein. Results of competition assays with an excess of unlabeled aldosterone, estradiol, pregnenolone, and testosterone confirmed that the binding protein had characteristics of a glucocorticoid receptor. With the use of diisopropylfluorophosphate (DFP) for esterase inhibition, and considering the purity of the starting material and the hydrolysis products, we could determine the relative receptor affinities of glucocorticoid-21-esters. In contrast to the high affinity of the glucocorticoid-17-ester examined, esterification in position 21 abolishes binding affinities. Glucocorticoid-21-esters are true prodrugs for which the glucocorticoid action is caused only by the corresponding glucocorticoid alcohol.

Chromatography, High Pressure Liquid↗
PubMed1988

Comparison of the analgesic efficacy of metamizole and tramadol in experimental pain.

The analgesic efficacy of 50 and 100 mg tramadol and 500 and 1,000 mg metamizole was compared using a randomized double-blind design on 10 volunteers; drugs were given orally as solutions. Constant painful stimuli were applied by controlled electrical stimulation of tooth pulp. Analgesia was monitored by verbal pain rating, by measurement of the current necessary to evoke sensation in a tooth and with the aid of the amplitude of somatosensory evoked potential. All 3 algesimetric methods showed in complete agreement higher analgesia by the 100-mg dose of tramadol compared to all other medications; 50 mg tramadol and 1,000 mg metamizole were equipotent analgesic doses. The mean relative potencies of metamizole and tramadol were found to be 1:23 in agreement with clinical studies. Pain relief was limited to 3-4 h for 100 mg tramadol; 500 and 1,000 mg metamizole and 50 mg tramadol had a shorter period of analgesia.

Administration, Oral↗
PubMed1988

[Pharmacokinetics of triamcinolone following oral administration].

Plasma levels of triamcinolone were measured by RIA (radioimmunoassay) on 10 patients following oral application of 16 mg triamcinolone (Delphicort), the pharmacokinetic parameters were calculated. The terminal half-life of 2.7 +/- 1.3 h and tmax of 1.9 +/- 0.5 h are in agreement with corresponding data of other glucocorticoids, whereas the normalized plasma concentration and the volume of distribution are different. The normalized volume of distribution for triamcinolone is twice the value of prednisolone or methylprednisolone, cmax is about 2/3 of the values of these two other glucocorticoids.

Administration, Oral↗
PubMed1988

[Dose-dependence of the analgesic action of metamizol].

Whereas dipyrone is used in many countries in clinical practice at doses up to 2.5 g, the dose-response relationship of the analgesic effect has not been investigated in humans. In the present study, doses of 0.5, 1.0, 1.5, 2.0, and 2.5 g dipyrone (Novalgin) were applied orally as film-coated tablets to 18 volunteers in a randomized, placebo-controlled, double-blind design. Pain attenuation was quantified following constant and painful electrical stimulation of tooth pulp at different time intervals up to 7 h after drug administration. Tooth pulp stimulation was performed by bipolar stimulation using individually formed impressions of the teeth with controlled current. Verbal pain ratings by the volunteers, measurement of the threshold of sensation on the tooth, and measurement of somatosensory evoked potential by an averaging technique were used as parameters for the quantification of the analgesic effect, intraindividually comparing the effects of the different doses. All doses of dipyrone had a significantly higher analgesic effect than placebo. Covering the dose range from 0.5-2.5 g dipyrone, the dose-response relationship was highly significant (Figs. 1-3). Maximal analgesia was observed 1 h after administration of the tablets, independent of the dose. An increase in analgesic effect related to dose was observed at this time, the increase being less pronounced with doses exceeding 1.5 g. Generally, analgesia persisted longer with increasing dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

[Nasal concentrations of fusafungin following administration of a dosage aerosol (Locabiosol)].

Following investigations on content uniformity and of the drug content delivered per each dose from a pressurised aerosol (Locabiosol) the concentration of the locally acting antibiotic fusafungin was determined in nasal secretions of volunteers. Quantitative HPLC-assay of fusafungin was performed following the extraction of cotton swabs used to collect nasal secretions. The volume of the nasal secretions results from the mass difference of the swabs before and after application. The concentrations of fusafungin measured on 41 volunteers over a period of 3 hrs were evidently higher than the minimum inhibitory concentrations reported in literature. The results of controlled clinical studies of other authors are in agreement with these results.

Adult↗