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In a double-blind cross-over study on 22 healthy subjects the analgesic efficacies of the antipyretic analgesic drugs ibuprofen, dipyrone and paracetamol were tested against placebo using a model of experimentally induced pain. To this purpose interdigital webs were pinched repeatedly for 2 min periods. The painfulness of these stimuli was assessed by the subjects on an electronically controlled visual analogue scale at 10 sec intervals. In addition to the subjective pain rating the stimulus induced reflex diminution of the blood flow in the stimulated hand was measured with photoplethysmography and laser Doppler flow analysis. The flare response around the stimulated area was assessed with infrared thermography. In this assay system ibuprofen and dipyrone, but not paracetamol, showed statistically significant analgesic effects by preventing hyperalgesia which is normally induced by the repeated stimulation of a skin site. This hypoalgesic effect was not related to the subjective impression of the subjects of the analgesic potency of the respective drug. Sympathetic reflex vasoconstriction was not quantitatively related to the drug induced hypoalgesia. Ibuprofen and, to a minor extent, the other antipyretic analgesic drugs also diminished the stimulus induced flare reaction around the stimulated skin sites. [ABSTRACT FROM AUTHOR]

Achieving objective and quantitative measurement of experimental pain in human volunteers and establishing the impact of drugs remains a difficult task. This problem may be overcome by employing a method which allows the simultaneous measurement of pain ratings elicited by standardized stimulation of the nasal mucosa by carbon dioxide, together with pain-related chemo-somatosensory evoked potentials (CSSEP) and vigilance. We assessed the effect of pentazocine and acetylsalicylic acid on these parameters in 14 human volunteers and related the effects to the pharmacokinetic parameters of the drugs measured at the same time. Pentazocine was found to reduce the pain ratings as well as the amplitudes of the pain-related evoked potentials and to increase their latencies. Vigilance (measured by EEG power spectra and performance of a tracking task) was also significantly reduced. These effects were observed during the distribution phase and the first period of the terminal elimination phase of the drug. Acetylsalicylic acid had no significant effects on pain ratings, but reduced the amplitudes of the event-related potentials when compared to placebo controls. At the same time a slight, but significant, effect on vigilance (reduced performance of the tracking task) was observed. These effects could not be related to the presence of unmetabolized acetylsalicylic acid in the plasma. They appeared at later times when only salicylic acid was left. It is concluded that chemical stimuli of sufficient intensity produce pain which may be suppressed by opioid analgesics such as pentazocine. The effect of acetylsalicylic acid on this experimental pain did not reach significance for all measured parameters under the experimental conditions chosen. The changes in vigilance and in the amplitudes of pain-related chemo-somatosensory evoked potentials indicated as yet unknown CNS-effects of this non-steroidal anti-inflammatory drug. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The distribution of three radioactively labelled salicylate derivatives with low ulcerogenic activity was compared with that of acetylsalicylic acid (ASA) and salicylic acid using whole body autoradiography and liquid scintillation counting techniques in rats. The methyl ester of ASA (AME) was distributed in vivo very similarly to that observed with ASA and salicylic acid. AME is rapidly demethylated following absorption from the stomach and is subsequently converted to ASA and salicylate. Salicylate is the main metabolite produced from both AME and ASA, which specifically accumulates in inflamed tissues. The 3-methyl-and 6-methyl-substituted salicylic acids are not as rapidly absorbed as either ASA or salicylic acid and do not pass readily into the brain or bone marrow. These results show that the methyl (ester) group of AME (which adequately protects the gastric mucosa from damage caused by ASA itself) does not impair the quantity of pharmacologically active form of drug (salicylate and ASA) generated in vivo. However, insertion of the methyl group at the 3- and 6-position of salicylic acid markedly affects both absorption, distribution and pharmaco-activity of these acids. [ABSTRACT FROM AUTHOR]

It is the intention of this communication to present a simple and reliable in vitro system for the evaluation of anti-inflammatory drugs. The system described appears to combine the advantages of two established procedures, i.e. measurement of the inhibition of prostaglandin (PG) synthesis in vitro using microsomal enzyme preparations and the measurement of the inhibitory effects of drugs on PG synthesis in vivo avoiding major limitations. We propose to measure the effect of drugs on the PG release from mouse peritoneal macrophages in vitro. The influence of culture conditions, phagocytosis and drugs on the PG release from these cells is described. We found that antibody-coated erythrocytes are especially suitable triggers of PG release, and that the release can be inhibited by steroidal and nonsteroidal anti-inflammatory drugs in concentrations resembling their effective doses in vivo. [ABSTRACT FROM AUTHOR]

A variety of acidic and non-acidic compounds are potent inhibitors of prostaglandin (PG) synthesis in vitro. However, only a few, namely the acidic nonsteroid anti-inflammatory drugs (NSAID) are useful anti-inflammatory analgesics in the clinic. Since inhibition of PG-synthesis is believed to be the main target of NSAID in inflammation this superiority of acidic compounds remains unexplained. We have considered that one explanation could be that only acidic NSAID appear in high concentrations in inflamed tissue to inhibit PG-synthesis sufficiently. To test this hypothesis the following experiments were carried out: From these observations it is concluded that a specific pharmacokinetic behaviour of acidic NSAID leading to high concentrations in inflamed tissue is a decisive aspect of their anti-inflammatory action. [ABSTRACT FROM AUTHOR]

Ibuprofen (IBU) is a non-steroidal anti-inflammatory drug exhibiting optical isomerism. Only the racemate is in clincal use. In in vitro studies it has been demonstrated that only the S(+)-enantiomer inhibits the PG synthetase system. Nevertheless, it is widely believed that the sole use of the active isomer does not comprise any advantages since the inactive isomer is converted within the human body. In a triple cross-over study (300 mg S(+), 300 mg R(−), 600 mg racemic IBU; n=8), we could show that the converted R(−)-IBU after racemate administration provides for only one third of the AUC of S(+)-IBU obtained after S(+)-application. Highest S(+)-peak plasma levels were reached after S(+)-IBU, lower ones after racemate. We, therefore, studied 4 patients with classical rheumatoid arthritis treated with 2-3 doses of 500 mg of S(+)-IBU/day over a two week period. Significant clinical recovery (Ritchie-index p<0.01; analogue scale pain p<0.05, motion p<0.01) was reached after one week. The results indicate that a reduction of dose and of metabolic load is possible if the S(+)-enantiomer is administrated. [ABSTRACT FROM AUTHOR]

Graft-versus-Host reactions in irradiated mice induced by the intradermal or intravenous injection of immunologically competent rat lymphoid cells are specifically inhibited by anti-rat lymphocyte serum. Anti-mouse lymphocyte serum increases the reactions. The opportunity to use lymphocytes and antilymphocyte sera of any heterologous origin may provide an assay for anti-human antilymphocyte sera. [ABSTRACT FROM AUTHOR]

Ab Initio, molecular orbital methods are being used to analyze and interpret structure-activity relationships in anti-inflammatory phenols, benzoates and salicylates. The results show a correlation between the potency of the active compounds as inhibitors of prostaglandin production in cell cultures and the orbital energy of the highest occupied molecular orbital with a correlation coefficient of r ∼ 0.8. The mode(s) of action and structural requirements of anti-inflammatory, non-narcotic analgesics continues to defy rationalization. Even the most plausible proposed molecular mechanism of their anti-inflammatory action, i.e., inhibition of prostaglandin biosynthesis [1], is still subject to controversy [2, 3]. Therefore other approaches may be fruitful for relating the NSAID's biological activity to molecular structure and properties. One such approach is to relate the biological activity to structural indices obtained from molecular orbital theory. From the results of such quantum chemical calculations it is hoped that deeper insight can be obtained into the NSAID's mode(s) of action by evaluating their dependance on the electronic structure of the biologically active species. A complicating factor in the present studies is that the existence of a specific receptor has not yet been firmly established. For the present work biological activity is defined as the potency of the given compound to inhibit the 12- O-tetradecanoylphorbol-13-acetate (TPA) induced PGE release from macrophages isolated from the peritoneum of young male NMRI mice. For methodological details see Ref. [4]. From about 80 compounds which have been assayed a sample of 30 molecules was selected for quantum chemical study. The sample comprises phenol, benzoic acid, and salicylic acid and their hydroxy, fluoro- and chloro congenrs. All calculations were carried out using ab initio molecular orbital methods with programs developed in this laboratory. The σ and π orbital energies of the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) were analyzed for correlation with the potency of 18 (or 17) active molecules. As the correlation coefficients in Table 1 show, the π-HOMO orbital energies exhibit a significant correlation with the pIC's, whereas the σ-HOMO and the LUMO orbital energies do not. The observed correlation shows that potency increases with increasing π-HOMO orbital energy, i.e., weaker binding of the π-HOMO electrons, which enhances the potential for interaction with specific or non-specific interaction sites. Examination of the correlations reported in Table 1 suggests that the first and second row substituents correlate similarly with the π-HOMO orbital energy, but that the second row group is displaced from the first row group. Separate analysis of the two groups is also given in Table 1. These latter correlation coefficients are about 10% higher than for the whole sample. It is noteworthy that for the other orbital energies the single group correlation coefficients can also be quite high, but that the combined correlation is small to completely random. Three models have been proposed for the cyclooxygenase receptor where the NSAID's carry out their purported inhibitory function [5-7]. Although these models differ considerably in their details, all three include a π-electron interaction (acceptor) region. The present results support the need for such a region and suggest that enhanced ability to donate π-electrons helps increase potency in inhibiting the release of PGE in macrophages. A detailed report of this work will be given elsewhere. [ABSTRACT FROM AUTHOR]