Biomedical subjects

G Engelhardt

Publications and source records attributed to G Engelhardt.

At least 19 recordsLinked to original sources

PubMed2000

Effects of caffeine and paracetamol alone or in combination with acetylsalicylic acid on prostaglandin E(2) synthesis in rat microglial cells.

Paracetamol has mild analgesic and antipyretic properties and is, along with acetylsalicylic acid, one of the most popular "over the counter" analgesic agents. However, the mechanism underlying its clinical effects is unknown. Another drug whose mechanism of action is unknown is caffeine, which is often used in combination with other analgesics, augmenting their effect. We investigated the inhibitory effect of paracetamol and caffeine on lipopolysaccharide (LPS)-induced cyclooxygenase (COX)- and prostaglandin (PG)E(2)-synthesis in primary rat microglial cells and compared it with the effect of acetylsalicylic acid, salicylic acid, and dipyrone. Furthermore, combinations of these drugs were used to investigate a possible synergistic inhibitory effect on PGE(2)-synthesis. Both paracetamol (IC(50)=7.45 microM) and caffeine (IC(50)=42.5 microM) dose-dependently inhibited microglial PGE(2) synthesis. In combination with acetylsalicylic acid (IC(50)=3.12 microM), both substances augmented the inhibitory effect of acetylsalicylic acid on LPS-induced PGE(2)-synthesis. Whereas paracetamol inhibited only COX enzyme activity, caffeine also inhibited COX-2 protein synthesis. These results are compatible with the view that the clinical activity of paracetamol and caffeine is due to inhibition of COX. Furthermore, these results may help explain the clinical experience of an adjuvant analgesic effect of caffeine and paracetamol when combined with acetylsalicylic acid.

Acetaminophen↗

PubMed2000

In vitro micronucleus assay with Chinese hamster V79 cells - results of a collaborative study with in situ exposure to 26 chemical substances.

A collaborative study with 10 participating laboratories was conducted to evaluate a test protocol for the performance of the in vitro micronucleus (MN) test using the V79 cell line with one treatment and one sampling time only. A total of 26 coded substances were tested in this study for MN-inducing properties. Three substances were tested by all 10 laboratories and 23 substances were tested by three or four laboratories in parallel. Six aneugenic, 7 clastogenic and 6 non-genotoxic chemicals were uniformly recognised as such by all laboratories. Three chemicals were tested uniformly negative by three laboratories although also clastogenic properties have been reported for these substances. Another set of three clastogenic substances showed inconsistent results and one non-clastogenic substance was found to be positive by one out of three laboratories. Within the study, the applicability of the determination of a proliferation index (PI) as an internal cytotoxicity parameter in comparison with the determination of the mitotic index (MI) was also evaluated. Both parameters were found to be useful for the interpretation of the MN test result with regard to the control of cell cycle kinetics and the mode of action for MN induction. The MN test in vitro was found to be easy to perform and its results were mainly in accordance with results from chromosomal aberration tests in vitro.

Animals↗

PubMed1999

Strategies for extracting NMR parameters from 23Na MAS, DOR and MQMAS spectra. A case study for Na4P2O7.

The 23Na magic-angle spinning (MAS), double rotation (DOR) and multiple-quantum magic-angle spinning (MQMAS) NMR spectra of anhydrous sodium pyrophosphate, Na4P2O7, measured at five different Larmor frequencies (nuL) ranging from 105.8 MHz (corresponding to 400 MHz 1H frequency) to 211.6 MHz (800 MHz) are analysed and the complete set of NMR parameters (C(qcc), etaQ and delta(iso)) of the four crystallographically inequivalent sodium sites were determined with high accuracy. Different approaches of spectra evaluation are discussed and their results are compared. The most reliable results are obtained from a combined evaluation of five DOR and three MQMAS spectra but also from two DOR and one MAS spectra or even from a single MQMAS spectrum all data can be derived. It is shown that Na4P2O7 may serve as a useful reference material for experimental set-up and reliability tests of the various NMR experiments.

Crystallography↗

PubMed1998

Genotoxic bifunctional aldehydes produce specific images in the comet assay.

Seven genotoxic aldehydes (acrolein, chloroacetaldehyde, crotonaldehyde, formaldehyde, glutardialdehyde, glyoxal, and methylacrolein) have been studied in vitro using the alkaline version of the comet assay (or single cell microgel electrophoresis assay) in freshly isolated rat hepatocytes. Chloroacetaldehyde, glyoxal and methylacrolein treatment resulted in an elevated tail moment (TM), used as indicator for an DNA damaging activity and formation of comet like structures. In addition, this treatment also caused characteristic DNA spot images with small, highly condensed areas within the otherwise circular DNA spots. These were not seen in solvent and N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG)-treated control cells. Treatment of hepatocytes with acrolein, crotonaldehyde, formaldehyde and glutardialdehyde resulted in an TM which did not differ from those of control values although 86-95% of the cells showed characteristic changes of their DNA spot images. The condensed areas are probably the consequence of the known DNA and protein crosslinking activities of these bifunctional aldehydes. It is suggested that using the alkaline comet assay both TM (or overall comet length) as well as changes in the DNA spot image should be evaluated.

Aldehydes↗

PubMed1998

Differential inhibition of cyclooxygenases-1 and -2 by meloxicam and its 4'-isomer.

OBJECTIVE AND DESIGN: Two structurally related compounds, meloxicam (Mel) and its structural 4'-isomer (4'-Mel), were compared to examine the role of a slightly different chemical structure on cyclooxygenase (COX) selectivity in in vitro and in vivo experimental models. MATERIAL OR SUBJECTS: In vitro studies were performed using human whole blood obtained from healthy volunteers, in vivo studies were performed in rats. TREATMENT: A concentration-response curve was obtained in the whole blood assay for Mel, 4'-Mel, indomethacin, piroxicam and diclofenac. These were used to calculate the respective IC50 values of either prostaglandin E2 (PGE2) or thromboxane B2 (TxB2). Similarly, a dose-response curve was obtained for Mel, 4'-Mel and piroxicam when measuring in vivo prostaglandin production, anti-inflammatory activity and gastric tolerance to determine the dose resulting in a 50% reduction of the each parameter. METHODS: COX selectivity was investigated in vitro using a human whole blood assay. PGE2 synthesis in vivo was measured in inflammatory exudate, in the stomach and kidneys of rats. Anti-inflammatory effects were measured in an adjuvant arthritis model and gastric tolerance was tested in an ulcerogenicity model in vivo in rats. RESULTS: In the human whole blood assay, the ratio of IC50 values for COX-1 vs. COX-2 inhibition was 13 for Mel and 1.8 for 4'-Mel. In inflammatory exudate in rats, Mel and 4'-Mel inhibited PGE2 synthesis to a similar extent, ID50 values approximately 0.3 mg/kg. In contrast, Mel was a weaker inhibitor of PG synthesis than 4'-Mel in the rat stomach and in the rat kidney. Paw swelling was reduced by 50% with 0.1 and 0.2 mg/kg for Mel and 4'-Mel, respectively, in the rat adjuvant arthritis model. Gastric tolerance (UD50) was 2.4 mg/kg for Mel and 0.4 mg/kg for 4'-Mel. CONCLUSIONS: These data demonstrate that the in vitro and in vivo pharmacological profile of meloxicam is structurally dependent and that minor structural changes can lead to significant differences in the selectivity for COX-1 and COX-2 in vitro and to different profiles in vivo suggesting different therapeutic potential.

Animals↗

PubMed1997

Ambroxol improves the broncho-spasmolytic activity of clenbuterol in the guinea-pig.

The effects of ambroxol on the spasmolytic action of clenbuterol were investigated on acetylcholine-induced bronchospasm in guinea-pigs. Ambroxol (50 mg kg-1 day-1) or vehicle was administered orally for 14 days. Approximately 45 min after the final dose on day 14, the animals were anaesthetized and the spasmolytic effects of clenbuterol (3, 6 or 12 micrograms kg-1 injected intravenously) were determined by use of acetylcholine (40 micrograms kg-1, i.v.)-induced bronchoconstriction. For both vehicle- and ambroxol-treated animals, a positive linear relationship was observed between the log-dose of clenbuterol and the percent inhibition of bronchospasm. The calculated ED25 of clenbuterol (i.e., the dose producing 25% inhibition of the acetylcholine-induced bronchospasm) was 3.98 micrograms kg-1 (3.29 to 4.82 micrograms kg-1, 95% confidence interval) in the presence of ambroxol and 5.81 micrograms kg-1 (4.98 to 6.79 micrograms kg-1) in the absence of ambroxol. The linear regressions with or without ambroxol differed from each other (P < 0.001) but ran parallel (covariance analysis), enabling us to calculate a relative potency, the value of which was 1.46 (1.16 to 1.84). These results demonstrate that the spasmolytic activity of clenbuterol is significantly improved in animals pretreated with ambroxol.

Ambroxol↗

PubMed1997

Role of caffeine in combined analgesic drugs from the point of view of experimental pharmacology.

The interactions of caffeine (CAS 58-08-2) with acetylsalicylic acid (CAS 50-78-2, ASA) and paracetamol (CAS 103-90-2) were investigated with regard to the analgesic, antiphlogistic, antipyretic and other properties. The inhibitory effect of paracetamol and ASA on the prostaglandin biosynthesis in a cyclooxygenase preparation from bovine brain in vitro was not affected by the addition of caffeine. Caffeine additively increases the antinociceptive effect of paracetamol with regard to the heat-induced pain in the mouse, as does aminophenazone. The antinociceptive effect of aminophenazone on the mechanically induced pain in the mouse is also additively increased by caffeine. In contrast to the effect of aminophenazone on the inflammatory pain in the rat, the effect of ASA is not increased by caffeine and that of paracetamol only negligibly. The antipyretic effect of paracetamol is additively increased by caffeine in the normothermic rat. The antipyretic effect of ASA and paracetamol on the yeast-induced pyrexia of the rat is not affected by caffeine. Caffeine additively increases the acute antiexudative effect of ASA and aminophenazone on the carageenin-induced oedema of the hind paw of the rat. The increase in locomotor activity caused by caffeine in mouse and rat is neutralised or diminished when the caffeine is given in combination with paracetamol. This effect is maintained even if the rats are pretreated with the combination of active ingredients for 3 weeks. The ulcerogenic effect of ASA in the stomach of the rat is not increased by caffeine. The protective effect of ASA against the hepatotoxic effect of paracetamol in the mouse is not influenced by the addition of caffeine. The plasma levels after the oral administration of 20 mg/caffeine/ kg and 80 mg paracetamol/kg in the rat are not significantly changed when the substances are given in combination. The toxicological advantages resulting from combining ASA and paracetamol with caffeine are discussed.

Acetaminophen↗

PubMed1996

Meloxicam: influence on arachidonic acid metabolism. Part II. In vivo findings.

Meloxicam is a new nonsteroidal anti-inflammatory drug (NSAID) derived from enolic acid. Preclinical studies have indicated that meloxicam has potent anti-inflammatory activity, together with a good gastrointestinal and renal tolerability profile. This report summarizes studies undertaken to compare meloxicam to other NSAIDs in the inhibition of the inducible cyclooxygenase (COX-2) in inflamed areas (pleurisy of the rat, peritonitis of mice) and their influence on the activity of the constitutive cyclooxygenase (COX-1) in stomach, kidney, brain, and blood. In pleurisy of the rat, meloxicam was twice as potent as tenoxicam, 3 times as potent as flurbiprofen, 8 times as potent as diclofenac, and 20 times as potent as tenidap at inhibiting prostaglandin E2 (PGE2) biosynthesis. In the peritonitis model in mice, meloxicam was approximately twice as active as piroxicam, and more than 10 times as active as diclofenac in the suppression of PGE biosynthesis. Doses of meloxicam sufficient to inhibit PGE2 biosynthesis in the pleural exudate and peritoneal exudate had no influence on leukotriene-B4 (LTB4) or leukotriene-C4 (LTC4) content. The effect of meloxicam on the PGE2 content of rat gastric juice and rat urine was weaker than that of piroxicam or diclofenac. Meloxicam was a weaker inhibitor of the increased PGE2 concentration in brain of rats and mice (induced by convulsant doses of pentetrazole) than piroxicam, diclofenac, or indomethacin. Meloxicam had a weaker effect on serum thromboxane-B2 (TXB2) concentration in rats than piroxicam or tenoxicam. The in vivo findings confirm the results of in vitro tests, conducted separately, showing that meloxicam preferentially inhibits COX-2 over COX-1. COX-2 is the inducible isoenzyme implicated in the inflammatory response, whereas COX-1 has cytoprotective effects in the gastric mucosa. Therefore, a preferential selectivity for one isoenzyme over another, as displayed by meloxicam, may have implications in the clinical setting in terms of a more favorable risk: benefit profile.

Administration, Oral↗

PubMed1996

Meloxicam: influence on arachidonic acid metabolism. Part 1. In vitro findings.

Meloxicam is a new nonsteroidal anti-inflammatory drug (NSAID) derived from enolic acid. Meloxicam has shown potent anti-inflammatory activity in animal models together with low gastrointestinal and renal toxicity. Studies were undertaken to compare meloxicam to other NSAIDS in their ability to inhibit either constitutive cyclooxygenase (COX-1) or inducible cyclooxygenase (COX-2). COX-1 was isolated as a cell-free enzyme from bovine seminal vesicles or bovine brain or was present in nonstimulated macrophages derived from the guinea-pig peritoneum. COX-2 was induced in peritoneal macrophages stimulated by lipopolysaccharide (LPS) or isolated as a cell-free enzyme from sheep placenta. Of all NSAIDs tested, meloxicam was the most selective inhibitor of COX-2 in intact cells. In cell-free enzyme preparations, however, meloxicam showed the same activity against COX-1 and COX-2. All other NSAIDs tested were more potent inhibitors of COX-1 than of COX-2. The inducible cyclooxygenase COX-2 has been implicated in the mediation of the inflammatory reaction, whereas the products of the constitutive cyclooxygenase COX-1 have cytoprotective effects in the gastric mucosa, support microcirculation in the kidney, and are antithrombogenic. Therefore, differential inhibitory effects of NSAIDs on COX-1 and COX-2 may have a bearing on the risk-benefit profile displayed in clinical practice. Meloxicam shows a preferential inhibitory effect on COX-2 over COX-1, which may be directly related to the favorable tolerability profile with potent anti-inflammatory effects observed in animal studies.

Animals↗

PubMed1996

Transformation of the mycotoxin ochratoxin A in plants: 1. Isolation and identification of metabolites formed in cell suspension cultures of wheat and maize.

The metabolism of the mycotoxin ochratoxin A in plant cells was investigated using cell suspension cultures of wheat and maize. A number of metabolites were detected by HPLC-chromatography with fluorescence detection. The main metabolites were ochratoxin alpha, ochratoxin A methyl ester, two isomers of hydroxyochratoxin A, and the glucosides and methyl esters of both hydroxyochratoxin A isomers. The compounds were isolated by TLC and preparative HPLC and identified by mass spectrometry and specific enzymic reactions.

Biotransformation↗

PubMed1996

Transformation of the mycotoxin ochratoxin A in plants. 2. Time course and rates of degradation and metabolite production in cell-suspension cultures of different crop plants.

Ochratoxin A, one of the most toxic mycotoxins, can be metabolized nearly completely by suspension cultures of various plant cells. The transformation products identified in this study were almost the same in the cell-suspension cultures of maize, carrot, tomato, potato, soybean, wheat and barley, but the quantitative distribution differed strongly depending on incubation time and species of plant-cell culture. The compounds were extracted with ethyl acetate and detected by reversed-phase HPLC with gradient elution. From the result it is supposed that besides ochratoxin A also ochratoxin derivatives may occur in food and feedstuff of plant origin.

Biotransformation↗

PubMed1996

General pharmacology of meloxicam--Part I: Effects on CNS, gastric emptying, intestinal transport, water, electrolyte and creatinine excretion.

The general pharmacodynamic properties of meloxicam, a new nonsteroidal anti-inflammatory drug (NSAID), were examined. Characteristics that distinguish meloxicam from conventional NSAIDs were investigated. No central-nervous-system effects were observed in the mouse at oral doses up to 100 mg/kg. In vitro studies showed meloxicam had no antagonistic properties against mediators such as histamine, PGE2 and angiotensin II. The rate of gastric emptying or intestinal transport in the rat was not influenced by therapeutic doses of meloxicam and, of all the NSAIDs investigated, meloxicam showed the mildest effect on gastric acidity. In doses well above those required for anti-inflammatory action, meloxicam had no influence on water, electrolyte or creatinine excretion.

Animals↗

PubMed1996

General pharmacology of meloxicam--Part II: Effects on blood pressure, blood flow, heart rate, ECG, respiratory minute volume and interactions with paracetamol, pirenzepine, chlorthalidone, phenprocoumon and tolbutamide.

The pharmacodynamic properties of meloxicam, a new nonsteroidal antiinflammatory drug (NSAID), that go beyond those typical of an NSAID were examined. The extent to which meloxican shows NSAID-like interactions with paracetamol, pirenzepine, chlorthalidone, phenprocoumon and tolbutamide was also investigated. In the dose range studied, meloxicam had no influence on the blood pressure of the unanaesthetized rat, blood flow, heart rate, ECG and respiratory minute volume of the anaesthetized cat or on the blood pressure, heart rate and respiratory minute volume of the anaesthetized dog. The acute toxicity level of meloxicam after oral and parenteral administration to the rat and mouse proved considerably lower than that of indomethacin. Meloxicam showed excellent tissue tolerability following parenteral administration. The effects against inflammatory pain and acute antiexudative effects of meloxicam were enhanced by simultaneous low doses of paracetamol. Pirenzepine showed an antagonistic effect on the ulcerogenicity of meloxicam in the rat stomach. The diuretic effect of chlorthalidone in the rat was not influenced by high doses of meloxicam. The effect of phenprocoumon in the rat was enhanced by high doses of meloxicam. However, the hypoglycaemic effect of tolbutamide in the rabbit was not influenced by meloxicam.

Acetaminophen↗

PubMed1996

Characterisation of sodium cations in dehydrated zeolite NaX by 23Na NMR spectroscopy.

23Na MAS, 2D nutation MAS, and DOR NMR spectroscopy has been applied to characterise the location of sodium cations in dehydrated zeolite NaX (Si/Al = 1.23). The 23Na MAS NMR spectra recorded at three different magnetic field strengths were decomposed by computer simulation into five lines, which were attributed to five crystallographically distinct cation sites known from X-ray diffraction studies. The assignments of the lines follow from electric field gradient calculations at the 23Na nuclei applying a simple point charge model based on crystal structure data. A weak Gaussian line at low field (delta iso = -6 ppm) is assigned to sodium cations at site I, two broad quadrupole patterns at the high-field side of the spectra are attributed to site I' (delta iso = -19 ppm, QCC = 5.2 MHz, eta = 0) and site II cations (delta iso = -15 ppm, QCC = 4.6 MHz, eta = 0), and two quadrupolar lines dominating the central region of the spectra originate from Na+ at two different III' sites (delta iso = -13 and -29 ppm, QCC = 2.6 and 1.6 MHz, eta = 0.7 and 0.9, respectively). Na+ ions located on a second I' site could be identified from the DOR NMR spectra. The line assignment is further corroborated by the reasonable agreement of the site occupancies estimated from the line intensities with those determined by X-ray diffraction. In addition, sodium site populations of five dehydrated zeolites NaX and NaY with Si/Al ratios between 1.09 and 4.0 were derived from the 23Na MAS NMR spectra.

Cations↗

PubMed1996

Pharmacology of meloxicam, a new non-steroidal anti-inflammatory drug with an improved safety profile through preferential inhibition of COX-2.

This review focuses on the key pharmacological findings with a new NSAID, meloxicam. Unlike established NSAIDs, it preferentially inhibits inducible COX-2 in guinea-pigs peritoneal macrophages and human COX-2 in COS cells. Compared with other NSAIDs, meloxicam is the most potent inhibitor of prostaglandin biosynthesis in pleural and peritoneal exudate, but only a weak inhibitor in the gastric tract and kidney. Ulcerogenicity in the rat stomach is weak in relation to anti-inflammatory potency, resulting in a high therapeutic index. Meloxicam's high anti-inflammatory potency combined with good tolerability can be explained by its preferential inhibition of COX-2. In adjuvant arthritis rats, meloxicam inhibits not only paw swelling, but also bone and cartilage destruction and systemic signs of disease. It inhibits leucocyte migration, but has no effect on leucotriene B4 or C4. Meloxicam shows a long-lasting anti-inflammatory and analgesic effect on inflammatory pain and reduces pyrogen-induced fever, but has no central nervous system effects. The pharmacokinetic profile of meloxicam in the rat is similar to that in man. Metabolites are inactive.

Analgesics↗

PubMed1996

Distinct isoforms (COX-1 and COX-2) of cyclooxygenase: possible physiological and therapeutic implications.

The discovery of an inducible isoform of cyclooxygenase (COX-2) requires a refinement of the theory that inhibition of cyclooxygenase activity explains both therapeutic and side effects of non-steroidal anti-inflammatory drugs (NSAIDs). Indeed, new pharmacological results suggest that COX-2 inhibition provides the therapeutic (ie, anti-inflammatory) activity of NSAIDs, whereas inhibition of constitutive COX-1 is responsible for their gastric and renal side effects as well as for their antithrombotic activity. However, a role of COX-1 in inflammation cannot be excluded. Furthermore, the functional relevance of COX-2 expression and induction in various tissues warrants further investigation. These studies should help in predicting potential adverse effects as well as new indications for selective COX-2 inhibitors.

Animals↗

PubMed1996

Effect of acetylsalicylic acid, paracetamol, caffeine and a combination of these substances on the renal prostaglandin E2, 6-keto-prostaglandin F1 alpha, water, creatinine and electrolyte excretion of the rat.

The aim of the study was to investigate the effect of acetylsalicylic acid (CAS 50-78-2, ASA), paracetamol (CAS 103-90-2) and caffeine (CAS 58-08-2) and a combination of these substances on the renal prostaglandin excretion of rats loaded with water. In addition to the effects on the renal excretion of prostaglandin E2 (PGE2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), the effect on the electrolyte, creatinine and water excretion was measured. Even in low doses ASA led to a dose-dependent reduction in the renal PGE2 and 6-keto-PGF1 alpha excretion. In oral doses up to 200 mg/kg paracetamol did not have any effect on the renal prostanoid excretion. In the combination it did not change the effect of ASA on the prostaglandin excretion. Caffeine caused a marked dose-dependent increase in the PGE2 excretion. The effect of caffeine on the renal 6-keto-PGF1 alpha excretion was less marked. In combination with ASA, with and without the addition of paracetamol, caffeine reduced the inhibitory effect of ASA on the excretion of arachidonic acid metabolites. The values for the renal prostaglandin excretion did not show any clear correlation with the other parameters of diuresis.

6-Ketoprostaglandin F1 alpha↗

PubMed1996

Effects of acetylsalicylic acid, paracetamol and caffeine and a combination of these substances on kidney glutathione levels.

Following preliminary tests in which rats proved to be fairly insensitive to the depletory effect of paracetamol (CAS 103-90-2) on kidney glutathione levels, old male mice from a strain exhibiting particular susceptibility to paracetamol were investigated in respect of the comparative effects of paracetamol, acetylsalicylic acid (CAS 50-78-2, ASA) and caffeine (CAS 58-08-2), and a combination of these substances, on kidney glutathione levels. Additionally, the effects of paracetamol and ASA on hepatic glutathione in mice were also measured. When administered separately at oral doses of 150-600 mg/kg both paracetamol and ASA produced dose- and time-dependent depletion of kidney glutathione concentrations in the mice. The effect of ASA at a given dose was weaker than that of paracetamol. Caffeine showed only a very weak and transient depletory effect up to an oral dose of 60 mg/kg. The effects of the combined administration of paracetamol and ASA on kidney glutathione levels were only additive in nature. The administration of caffeine did not increase the reduction in kidney glutathione levels produced by the combination of paracetamol and ASA. The reduction in hepatic glutathione induced in the mice by paracetamol was considerably more pronounced than that observed in the kidneys. ASA, on the other hand, did not affect glutathione in the mouse liver at those doses which had led to a reduction in kidney glutathione levels.

Acetaminophen↗