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Biomedical subjects

K Brune

Publications and source records attributed to K Brune.

At least 199 records · Page 11Linked to original sources
PubMed1988

The pharmacological profile of non-opioid (OTC) analgesics: aspirin, paracetamol (acetaminophen), ibuprofen, and phenazones.

All non-opioid analgesics are believed to act via inhibition of cyclo-oxygenase. With respect to their inhibitory potency towards the enzyme, these drugs differ not only from most non-steroidal anti-inflammatory drugs but also among themselves. The differences appear to be of some therapeutic relevance. They explain why many non-steroidal anti-inflammatory drugs are unsuitable for over-the-counter (OTC) use and why the OTC drugs have different profiles of effects and side effects. In addition, the suitability of non-opioid analgesics in everyday practice is widely determined by their pharmacokinetic parameters. These parameters are here compiled for aspirin, paracetamol (acetaminophen), ibuprofen, and metamizol (dipyrone), then compared, and finally evaluated as to their therapeutic implications.

Acetaminophen↗
PubMed1988

Serum antibodies against chondrocyte cell surface proteins in osteoarthritis and rheumatoid arthritis.

Serum autoantibodies to cartilage cell surface proteins have been detected in the blood from patients with osteoarthritis (OA) and rheumatoid arthritis (RA). As tested by ELISA using plasma membrane vesicles as a substrate, patients with RA exhibited significantly elevated antibody titers, whereas titers were somewhat lower in OA, and only marginal in controls. The antibodies did not crossreact with plasma membranes from fibroblasts or epithelial cells, but showed interspecies crossreactivity towards chicken and rat cartilage cell surface proteins. A group of at least 9 distinct immunoreactive polypeptides could be characterized by Western blot analysis. These peptides had molecular weights of Mr28, 30, 38, 42, 66, 76, 78, 116, and 155 kD. The patients each expressed an individual pattern of reactive antibodies against these proteins. Autoantibody reactivity to cell surface associated collagen type II was also observed.

Adult↗
PubMed1987

Classical absorption theory and the development of gastric mucosal damage associated with the non-steroidal anti-inflammatory drugs.

Evidence has accumulated during the last decade to support the view that the pharmacokinetic behaviour of non-steroidal anti-inflammatory drugs (NSAIDs) contributes not only decisively to their therapeutic effects but also to the type and incidence of their side effects. It has been shown that NSAIDs reach particularly high concentrations in those compartments in which they cause effects and side effects. Specifically, the data reviewed herein indicate that the accumulation of NSAID within gastric mucosal cells a priori is a principal factor associated with the intervention of intracellular biochemical events and resultant gastric mucosal damage. To a large extent this behaviour is according to the precepts of classical absorption theory; in this respect the limitations of such theory are examined. Our survey further indicates that the failure of certain NSAIDs to significantly reduce gastric mucosal levels of prostaglandins (PG) in vivo may reflect pharmacokinetic differences between NSAIDs rather than tissue-specific differences in their potency as inhibitors of cyclo-oxygenase.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1987

Recent insight into the mechanism of gastrointestinal tract ulceration.

Non-steroidal anti-inflammatory drugs (NSAIDs) are well known for their gastrotoxic and duodenotoxic effects. A few years ago the introduction of a sustained-release form of indomethacin led to an apparently high incidence of jejunal and ileal perforations. Recently, Langman in England was able to demonstrate that the intake of some NSAIDs is related to an enhanced incidence of ileal and jejunal perforations in rats and dogs, even after parenteral or rectal administration. We have been able to show that: (i) There is a correlation between biliary excretion of NSAIDs or ester conjugates of these drugs and ileal perforations in rats. (ii) In contrast to dogs there is no (ibuprofen) or little enterohepatic circulation (diclofenac and diflunisal) in man. This agrees with the low incidence of ileal and jejunal ulcers reported with these drugs in contrast to indomethacin or piroxicam. (iii) Reduction of enterohepatic circulation of indomethacin in rats by dietary means reduces the degree of small intestinal erosions and ulcerations in parallel with the reduced biliary excretion of the drug. It may be safely assumed that the enterohepatic circulation of some NSAIDs, particularly indomethacin and piroxicam, may contribute to the reported incidence of ileal and jejunal damage caused by these drugs. These drugs may, on the other hand, have clearcut advantages as well.

Animals↗
PubMed1987

Pharmacology of centrally acting analgesics: an introduction.

Aspirin-like drugs, paracetamol and amidopyrine exert their analgesic action predominantly at the site of origin of pain, e.g. in inflamed or functionally altered tissues. Opioids are thought to inhibit processing of pain-related neuronal inputs in the CNS including the spinal cord. This hypothesis has been extended by the discovery of opioid receptors, enkephalins and endorphins and interactions of these mediators with others including substance P, serotonin and other aminergic neurotransmitters. A review of the present situation is presented focussing on possible new sites of action of centrally acting analgesics.

Analgesics↗
PubMed1987

Recent insight into the mechanism of gastrointestinal tract ulceration.

Non-steroidal anti-inflammatory drugs (NSAIDs) are well known for their gastrotoxic and duodenotoxic effects. A few years ago the introduction of a sustained release form of indomethacin led to an apparently high incidence of jejunal and ileal perforations. Recently, Langman in England was able to demonstrate that the intake of some NSAIDs is related to an enhanced incidence of ileal and jejunal perforations in rats and dogs, even after parenteral or rectal administration. We have been able to show that: 1. There is a correlation between biliary excretion of NSAIDs or ester conjugates of these drugs and ileal perforations in rats. 2. In contrast to dogs there is no (ibuprofen) or little enterohepatic circulation (diclofenac and diflunisal) in man. This agrees with the low incidence of ileal and jejunal ulcers reported with these drugs in contrast to indomethacin or piroxicam. 3. Reduction of enterohepatic circulation of indomethacin in rats by dietary means reduces the degree of small intestinal erosions and ulcerations in parallel with the reduced biliary excretion of the drug. It may be safely assumed that the enterohepatic circulation of some NSAIDs, particularly indomethacin and piroxicam, may contribute to the reported incidence of ileal and jejunal damage caused by these drugs. These drugs may, on the other hand, have clear-cut advantages as well.

Animals↗
PubMed1987

Clinical relevance of nonsteroidal anti-inflammatory drug pharmacokinetics.

Only recently have the pharmacokinetic characteristics of nonsteroidal anti-inflammatory drugs (NSAIDs) been recognized as decisive factors in understanding the effects and side effects of these drugs. The accumulation of NSAIDs in inflamed tissue is central to the anti-inflammatory action, whereas high drug concentrations in the gastrointestinal tract wall, kidneys, blood, and liver may be major contributing factors to the incidence and severity of side effects. Also, variations in pharmacokinetic handling of NSAIDs by different patients may contribute considerably to differences in therapeutic response. An evaluation of the response-related pharmacokinetics of the three most widely used NSAIDs, diclofenac, indomethacin, and piroxicam, shows some obvious reasons for these differences: The onset of absorption and the bioavailability of diclofenac can vary considerably, and relevant inter-patient differences are found in the terminal plasma half-life of indomethacin and piroxicam. The variability in these parameters may contribute significantly to the observed variations in clinical response and to the incidence of unwanted drug effects.

Absorption↗
PubMed1986

Antipyretic analgesics inhibit prostaglandin release from astrocytes and macrophages similarly.

The effect of acid and non-acid antipyretic analgesics on prostaglandin (PG) release from cultured mouse astrocytes and peritoneal macrophages was investigated in order to test the hypothesis that the non-acid compounds are more potent inhibitors of PG formation in brain than in peripheral tissues. Stimulation of the cells by the divalent cation ionophore A 23187 (10(-6) mol/l) induced PG release from astrocytes and macrophages (mainly PGD2 and PGE2, respectively). This PG release was inhibited by acetylsalicylic acid (10(-5) - 10(-6) mol/l) and indomethacin (10(-6) - 10(-9) mol/l) but also by high concentrations (10(-3) - 10(-5) mol/l) of the non-acid compounds 4-methyl-aminophenazone, the main active metabolite of dipyrone (metamizol), and acetaminophen (paracetamol). No difference was found in the inhibitory potency of the drugs in astrocytes and macrophages, suggesting that a specific sensitivity of brain cells toward non-acid antipyretic analgesics does not contribute to their analgesic effect.

Animals↗
PubMed1986

Opioid activity and distribution of fentanyl metabolites.

Fentanyl, a short-term analgesic frequently used in neuroleptanalgesia, has in a number of cases been reported to cause unexpected, severe postanesthetic respiratory depression which can successfully be treated with naloxone. Several explanations for this rebound effect produced by fentanyl (in combination with other drugs) have been proposed, though so far none has proved completely satisfactory. The possibility that this effect may be due to a secondary accumulation of fentanyl or fentanyl metabolites with opioid activity in the brain has led us to investigate the relative opioid potency of several known or proposed metabolites by measuring their inhibitory action on the contraction of guinea-pig ileum in comparison with that of morphine, pethidine, and fentanyl itself. Two proposed metabolites containing the phenethyl sidechain were found to possess an opioid activity lying between that of morphine and pethidine, whereas metabolites without the side-chain were generally less active than pethidine. Using thin-layer chromatography, it was possible to detect one of these proposed active metabolites in vivo in rats. This result may have some relevance for the understanding of the fentanyl rebound. However, the possibility that multiple doses of fentanyl, such as may be given during neuroleptanalgesia, or interactions with other drugs, e.g. tranquilizers and general anesthetics, may be the cause of fentanyl rebound, remains open.

Animals↗
PubMed1986

Possible role of sulfhydryls in mucosal protection induced by aluminum hydroxide.

The involvement of sulfhydryl-containing compounds was investigated in the cytoprotective effect of certain antacids against ethanol-induced gastric mucosal damage in the rat. Not only the protective effect of a sulfhydryl containing compound, N-acetylcysteine, was abolished after pretreatment with N-ethylmaleimide, but also the adaptive cytoprotection induced by 20% ethanol. Pretreatment of the animals with the cyclooxygenase inhibitor indomethacin or with the thiol reagent N-ethylmaleimide significantly diminished the cytoprotection evoked by aluminum hydroxide. However, the protective effect of aluminium hydroxide could only be totally abolished by pretreatment with the combination of indomethacin and N-ethylmaleimide. The present results suggest the additional role of sulfhydryl-containing compounds localized in the gastric mucosa in the cytoprotection induced by a mild irritant or by aluminium hydroxide and aluminium hydroxide-containing antacids as well.

Acetylcysteine↗
PubMed1986

Tissue culture methods for the investigation of anti-inflammatory drugs.

Tissue culture methods are used increasingly in the investigation of anti-inflammatory drugs. Compared to in vivo experiments they offer the advantages of a) relative reproducibility, b) reduced cost, and c) simplified interpretation of results. Moreover, tissue culture methods can be applied without major ethical concern. The disadvantage of cell culture techniques is the need to re-check in vivo the medical relevance of all data obtained. A few applications of cell culture methods are exemplified by results obtained in our laboratory from experiments using macrophages, endothelial cells and chondrocytes.

Anti-Inflammatory Agents↗
PubMed1986

The effects of acidic and nonacidic pyrazoles on arachidonic acid metabolism in mouse peritoneal macrophages.

The effects of acidic and nonacidic pyrazole derivatives and their metabolites on arachidonic acid metabolism have been investigated in mouse peritoneal macrophages stimulated with the calcium ionophore A 23 187 (10(-6) Mol/l). In the group of the acidic compounds with anti-inflammatory properties, phenylbutazone and butyl malonic acid mono (1-phenylhydrazide), the hydrolysis product of mofebutazone, inhibited prostaglandin production in a dose-dependent manner (10(-4)-10(-6) Mol/l). In contrast, mofebutazone itself and its hydroxylation product, 4-OH-mofebutazone, failed to show any activity. Similarly, in the case of bumadizone, an anti-inflammatory drug structurally related to phenylbutazone, no inhibitory effect on prostaglandin release was found either. The nonacidic pyrazole derivatives with antipyretic and anti-inflammatory activity, antipyrine, isopropylaminophenazone, as well as metamizol and its active metabolites 4-methylaminophenazone and 4-aminophenazone, also inhibited prostaglandin release dose-dependently. This was found to be paralleled by an increased leukotriene C4 production. Neither of the main excretory metabolites of metamizol, acetyl- and formylaminophenazone, showed any effect. The concentration levels at which the nonacidic compounds affected arachidonic acid metabolism (approx. 10(-4) Mol/l) were high enough to elicit anti-inflammatory effects. They were far higher, though, than the plasma levels producing antipyretic and analgesic effects that are reached after therapeutic doses.

Aminopyrine↗
PubMed1986

Effect of anti-inflammatory and analgesic pyrazoles on arachidonic acid metabolism in isolated heart and gastric mucosa preparations.

The effects of acidic and nonacidic pyrazoles on the release of arachidonic acid-derived mediators from isolated perfused anaphylactic guinea pig hearts as well as rat and human gastric mucosa were investigated. High concentrations of the acidic drugs phenylbutazone and oxyphenbutazone as well as of the nonacidic metabolites of metamizol, i.e. 4-methylaminoantipyrine and 4-aminoantipyrine, inhibited the release of the cyclo-oxygenase products of arachidonic acid metabolism, TXB2 and 6-keto-PGF1 alpha, and simultaneously increased the release of LTC4-like immunoreactivity in hearts. By contrast, comparatively high concentrations of the metamizol metabolites 4-formylaminoantipyrine and 4-acetylaminoantipyrine were without effect. The comparable effects of acidic and nonacidic pyrazoles on eicosanoid release from anaphylactic hearts support the concept that hypersensitivity reactions to NSAIDs are related to their effect on arachidonic acid metabolism. The anti-inflammatory effects of phenylbutazone and oxyphenbutazone and of high concentrations of metamizol seem to be correlated with the inhibition of cyclo-oxygenase. On the other hand, lower concentrations of metamizol, which have analgesic and anti-pyretic effects, only marginally inhibit cardiac cyclo-oxygenase. It remains to be investigated whether the partial inhibition of the synthesis of PGI2, a major hyperalgesiccyclo-oxygenase product of arachidonic acid metabolism, at lower concentrations of the active metamizol metabolites contributes to the analgesic effect of metamizol. The acidic NSAID mofebutazone and its metabolite butyl malonic acid mono (1-phenylhydrazide) had no effect on the cardiac release of arachidonic acid-derived cyclo-oxygenase and lipoxygenase products. The anti-inflammatory effect of these compounds requires further investigation. In isolated gastric mucosa, the active metabolite of metamizol 4-methylaminoantipyrine was found to inhibit fatty acid cyclo-oxygenase dose-dependently. Pharmacokinetic differences due to the nonacidic structure of metamizol and its metabolites as compared to acidic NSAIDs may be responsible for the fact that metamizol is better tolerated than e.g. indomethacin. In rat experiments, phenylbutazone was found to inhibit gastric mucosal cyclo-oxygenase like indomethacin. On the other hand, mofebutazone and its metabolite butyl malonic acid mono (1-phenylhydrazide) did not affect gastric mucosal synthesis of 6-keto-PGF1 alpha. This lack of effect on gastric mucosal cyclo-oxygenase seems to be correlated with the considerably lower gastric toxicity of mofebutazone as compared to phenylbutazone.

6-Ketoprostaglandin F1 alpha↗