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Biomedical subjects

K Brune

Publications and source records attributed to K Brune.

At least 217 records · Page 12Linked to original sources
PubMed1986

Comparative pharmacology of 'non-opioid' analgesics.

Pain is the most prominent symptom of disease in man and analgesics are the most widely used drugs. More than 90% of the analgesics used belong to the so-called peripherally acting, non-opioid (non-narcotic) or mild analgesics. They all derive from 3 types of compounds: aspirin and other acidic non-steroidal anti-inflammatory drugs (NSAIDs), aniline derivatives such as paracetamol (acetaminophen) and non-acidic pyrazole drugs like propyphenazone and dipyrone (metamizole). These compounds and all of their derivatives differ in their analgesic activity and their typical profile of side effects. While NSAIDs are particularly useful in the treatment of pain related to inflammation these compounds are well known to cause gastrointestinal, haematological and kidney side effects. Aniline derivatives such as paracetamol are not very effective analgesics, but reasonably good antipyretics. These compounds, unlike aspirin-like drugs, do not interfere with inflammatory pain. Their main side effects are allergic but, particularly at overdose, they cause liver and kidney damage. Rarely, they have also been associated with kidney damage and malignomas of the urinary system after long term administration. Non-acidic pyrazole drugs are supposedly particularly active in pain originating from spasms of smooth muscles. They are not very effective anti-inflammatory drugs but are good antipyretics. Their major side effects consist of mild allergic reactions. They have also rarely been associated with agranulocytosis and shock. In addition to these differences in therapeutic application and side effect profile the major representatives of the groups of analgesics mentioned differ in their pharmacokinetic behaviour in the human body. Aspirin shows non-linear pharmacokinetics not seen with ibuprofen, a more modern NSAID.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗
PubMed1985

Monoclonal antibodies against E- and F-type prostaglandins. High specificity and sensitivity in conventional radioimmunoassays.

Polyclonal antisera against prostaglandins (PGs) are widely used for the assessment of the biological role of these mediators, but even the most specific contain antibodies against the major metabolites and degradation products of the haptens employed. To overcome this inherent problem we produced monoclonal antibodies (mAs) against PGE2, PGF2 alpha and 6-keto-PGF1 alpha using the somatic cell hybridization technique. The mAs against 6-keto-PGF1 alpha and PGF2 alpha proved to be highly specific, but allowed only for moderate detection limits (1-2 ng) in conventional fluid phase radioimmunoassays (RIAs). One of the mAs against PGE2 permitted a 100-fold improvement in the detection limit while being almost devoid of cross-reactivity with metabolites and other structurally related PGs. These results show that highly specific mAs against PGs can be produced to improve the available RIA technique for PG quantification.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Pharmacokinetic factors as causes of variability in response to non-steroidal anti-inflammatory drugs.

Even the most widely used non-steroidal anti-inflammatory drugs (NSAID's) show considerable variations in their pharmacokinetic behaviour in volunteers and moreso in patients. An evaluation of the response-related pharmacokinetic parameters of the three presently most widely used NSAID's, namely diclofenac, indomethacin and piroxicam shows some obvious reasons: While the onset of absorption and the bioavailability of diclofenac varies considerably, we find relevant differences in the terminal plasma half-life of indomethacin and particularly piroxicam. Inter-patient variability in these parameters may contribute significantly to the observed variations in clinical response.

Anti-Inflammatory Agents↗
PubMed1985

Distribution of fentanyl in rats: an autoradiographic study.

Unexpected respiratory depression reported to have occurred up to 2 h after neurolept analgesia with fentanyl has been proposed to be a redistribution phenomenon due to a gastro-entero systemic recirculation of fentanyl sequestered in the stomach. In the study presented here, this redistribution hypothesis was tested by employing whole-body autoradiography (WBAR) in two series of time-course experiments, designated to further elucidate the distribution of intravenously administered fentanyl which was radiolabelled in different parts of the molecule respectively. However, there was no evidence of a secondary accumulation of radioactivity in the brain. The possibility that fentanyl trapped in the stomach may be reabsorbed as it passes through the small intestines was investigated by intragastric administration of the drug. Its oral bioavailability was found to be only 1.5%. Also, evidence of a strong metabolic effect was obtained by analysis employing high performance thin-layer chromatography (HPTLC). In conclusion, the results obtained from this work do not support the hypothesis that the fentanyl rebound effect is due to a secondary rise in brain levels of the parent drug and its major metabolites, an event which could be brought about by reabsorption of fentanyl sequestered in the stomach.

Administration, Oral↗
PubMed1985

Modulation by drugs of leukotriene and prostaglandin production from mouse peritoneal macrophages.

Leukotriene and prostaglandin production by mouse peritoneal macrophages was investigated. It could be shown that the tumour promoter 12-O-tetradecanoylphorbol-13-acetate, despite initiating the release of prostaglandin E2, had little effect on the release of leukotriene C4-like immunoreactivity. The divalent cation ionophore A 23187 at concentrations between 10(-6) and 10(-8) mol/l initiated prostaglandin as well as leukotriene release. This prostaglandin and leukotriene release could be modulated by drugs. Non-steroidal anti-inflammatory drugs inhibited prostaglandin release but enhanced leukotriene production. The experimental compound BW 755C inhibited prostaglandin and leukotriene production, whereas the antithrombotic compound nafazatrom inhibited the production of leukotriene C4-like immunoreactivity but enhanced the prostaglandin E2 production. Nordihydroguaiaretic acid inhibited prostaglandin and leukotriene production. The results show that the metabolism of arachidonic acid in macrophages via the cyclooxygenase or the lipoxygenase pathway is dependent on the stimulus applied. Both pathways can be inhibited conjointly or selectively by drugs. The experimental system described may be used for assessing the potency of drugs to inhibit the lipoxygenase and the cyclooxygenase pathway of arachidonic acid metabolism.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1984

Pharmacological control of leukotriene and prostaglandin production from mouse peritoneal macrophages.

Leukotriene and prostaglandin production by mouse peritoneal macrophages was investigated. It could be shown that the tumour promoter 12-O-tetradecanoylphorbol-13-acetate initiated the release of prostaglandin E2 but had little effect on the release of leukotriene C4-like immunoreactivity. The divalent cation ionophore A 23187 at concentrations between 10(-6) and 10(-8) mol/l initiated prostaglandin as well as leukotriene release. This prostaglandin and leukotriene release could be modulated by drugs. Non-steroidal anti-inflammatory drugs including benoxaprofen inhibited prostaglandin release but simultaneously enhanced leukotriene production. The analgesics paracetamol and 4-methylaminoantipyrine had similar effects at high concentrations. The experimental compound BW 755 c inhibited prostaglandin and leukotriene production while the antithrombotic compound nafazatrom inhibited the production of leukotriene C4-like immunoreactivity but enhanced prostaglandin E2 production. Nordihydroguaiaretic acid inhibited prostaglandin and leukotriene production. The results show that the metabolism of arachidonic acid in macrophages via the cyclooxygenase or the lipoxygenase pathway is dependent on the stimulus applied. Both pathways can be inhibited conjointly or selectively by drugs. Our results do not provide evidence that differences in anti-inflammatory activity claimed for some of the drugs tested can be explained by differential inhibition of either pathway. The experimental system described may be used for assessing the potency of drugs to inhibit the lipoxygenase and the cyclooxygenase pathway of arachidonic acid metabolism.

Analgesics↗
PubMed1984

Mode of action of peripheral analgesics.

Peripheral analgesics amount to more than 95% of the analgesic market. The most important drugs of this group, salicylates, p-aminophenol derivatives, and nonacidic pyrazoles, have been used in therapy for about 100 years, their mode of action remaining unclear until today. This brief review gives a survey on the current knowledge of the therapeutic mechanisms and the molecular causes of the effects and the most important side effects of peripheral analgesics. At present, two theories cannot be rejected on the basis of current knowledge. The first and very popular concept postulates that peripheral analgesics act by inhibiting the formation of arachidonic acid metabolites. The alternative hypothesis relates the effects of the salicylates and related drugs to inhibition of various cell functions by unspecific, concentration-dependent incorporation of drug molecules in the cellular membrane. These two concepts are discussed, and the importance of the physiochemical characteristics and the pharmacokinetic behaviour of peripheral analgesics for the understanding of their effects and side effects is pointed out.

Analgesics↗
PubMed1983

Prostaglandins and the mode of action of antipyretic analgesic drugs.

Antipyretic analgesics account for more than 95 percent of the analgesic market. The most important agents of this group--salicylates, aniline derivatives such as acetaminophen, and nonacidic pyrazolones--have been used for almost 100 years. Nevertheless, their therapeutic mechanisms and the molecular causes of the most important side effects remain unclear. Several common theories are discussed and challenged.

Animals↗
PubMed1983

An in vitro system for measuring endothelial permeability under hydrostatic pressure.

A system was developed, using early passage porcine aortic endothelial cells cultured on a microporous substratum mounted in a two-compartment chamber. It allows the application of a transendothelial pressure gradient and quantitative measurement of the resulting flow rate of fluid. Initial application of a hydrostatic pressure gradient of 20 mmHg resulted in a continuous decrease in the flow rate which reached a steady state after a period of 1-3 h. Further variations in the pressure resulted in pressure-dependent increase or decrease in the flow rate. The physiological relevance of this response is supported by the fact that decrease in permeability occurred only in the presence of Ca2+ ions. Removal of Ca2+ from a monolayer by EGTA led to an immediate increase in the flow rate, whereas readdition of Ca2+ in concentrations between 0.5 and 20 mM was observed to cause a concentration-dependent decrease in flow rate. Initial application of pressure with Ca2+-free medium failed to produce permeability changes of the cultured endothelium. These findings indicate that the permeability of a cultured endothelium to water and solutes is pressure- and Ca2+-dependent.

Animals↗
PubMed1983

Distribution of the acetyl compared with the salicyl moiety of acetylsalicylic acid. Acetylation of macromolecules in organs wherein side-effects are manifest.

The distribution in rats of the acetyl group of aspirin has been compared with that of the salicyl moiety with the objective of establishing if: (1) there are differences in their biodisposition which might be important in the development of side- or therapeutic effects of aspirin, and (2) the range of organs and biomolecules therein which are acetylated by aspirin. Using whole-body autoradiography and liquid scintillation counting techniques it was found that the acetyl group of 3H- or 14C-acetyl-labelled aspirin became bound to a wide variety of proteins, glycoproteins and lipids of the glandular and non-glandular region of the stomach, kidney, liver and to a lesser extent bone marrow, i.e. organs in which side-effects are frequently encountered. It is suggested that: (1) the acetylation of biomolecules may be a major factor in the development of side-effects in these organs, and (2) in addition to acetylation of prostaglandin synthetase, the acetylation of enzymes and other biomolecules may have a much wider bearing on the biochemical changes underlying the development of these side-effects. Acetylation of the protein/macromolecular components was especially pronounced in inflamed (c.f. control) hindpaws of carrageenan-injected rats. This could be a result of acetylation of the drug-carrier protein, albumin, and other proteins carried into inflamed tissues and this acetylation could have marked consequences for the functions of these proteins.

Acetates↗
PubMed1983

Non-acidic pyrazoles: inhibition of prostaglandin production, carrageenan oedema and yeast fever.

Prostaglandin production from mouse peritoneal macrophages was elicited by the tumour promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA). The inhibitory potency (IC50) of metamizole and its major metabolites as well as other non-acidic pyrazoles was defined in this system. A reliable IC50-value could not be assigned to metamizole. Isopropylaminophenazone was as active as acetylsalicylic acid while aminophenazone and methylaminophenazone, the major metabolites of metamizole, were about 10 times and phenazone 100 times less potent than acetylsalicylic acid. The major excretion products of metamizole, 4-formyl- and 4-acetyl-aminophenazone were inactive. The IC50-values obtained agree with those necessary for manifestation of anti-inflammatory effects in rats but are up to 10 times higher than those measurable in human plasma after administration of analgesic-antipyretic doses.

Animals↗
PubMed1983

Inhibition of prostaglandin E2 release by salicylates, benzoates and phenols: a quantitative structure-activity study.

Concentrations inhibiting 50% of the prostaglandin E2 release from phorbol ester-stimulated mouse peritoneal macrophages in-vitro were determined for 59 monosubstituted congeners of salicylic acid, benzoic acid and phenol. Twenty-seven further compounds, mainly benzoic acids, were found to be inactive. An attempt was made to establish a quantitative structure-activity relationship (QSAR) form our experimental data using literature or calculated values for the logarithmic n-octanol/water partition coefficients of the compounds, molar refractivity and sigma values of substituents as well as structural indicator variables. The equations found have moderate predictive power and must be considered as a first step in the investigation of factors determining the biological activity of salicylates, benzoates and phenols.

Animals↗
PubMed1982

Quantum chemical analysis of structure-activity relationships in nonsteroidal anti-inflammatory drugs.

Ab initio, quantum chemical methods are being used to analyze and interpret structure-activity relationships in nonsteroidal anti-inflammatory drugs. The biological data for this study derive from full dose-response curves of the inhibitory potency of phenols, salicylates, and benzoates on prostaglandin production in mouse macrophages. To date, about 80 compounds have been assayed and from this group a sample of 30 has been selected for calculation. The results show a correlation between the potency of the active compounds and the orbital energy of the highest occupied molecular orbital (HOMO) with a correlation coefficient of r approximately 0.8. These results indicate that potency increases with decreasing binding strength of the pi-HOMO electrons, suggesting that charge transfer may be important for interaction with specific or nonspecific binding sites.

Anti-Inflammatory Agents↗