[Pain therapy with non-prescription analgesics].
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Analgesics↗
Biomedical subjects
K Brune
Publications and source records attributed to K Brune.
Stereoselective high-performance liquid chromatographic determination of the enantiomers of ketamine and norketamine in plasma.
An enantioselective high-performance liquid chromatographic assay for the quantitation of the enantiomers of ketamine and its major metabolite norketamine in human plasma is described (assay I). The procedure involved extraction of the compounds from alkalized plasma into cyclohexane. Stereoselective separation was achieved with a prepacked alpha 1-acid glycoprotein column without any derivatization procedure. A second assay using a conventional reversed-phase column to determine total (racemic) ketamine and norketamine is also described. Because of interfering plasma peaks (assay II) the cyclohexane solution was reextracted into 1 M hydrochloric acid. The detection wavelength was 215 nm for all substances. The limit of quantification of the method was ca. 40 ng/ml in plasma. The assays were sensitive and reproducible. The method was demonstrated to be sensitive for stereoselective pharmacokinetic studies of ketamine after clinical doses.
Chromatography, High Pressure Liquid↗
Aspirin-like drugs may block pain independently of prostaglandin synthesis inhibition.
Using flurbiprofen, a chiral anti-inflammatory and analgesic 2-arylpropionic acid derivative, the enantiomers of which are not converted to each other (less than 5%) in rats or man, we obtained evidence that prostaglandin synthesis inhibition is primarily mediating the anti-inflammatory activity but prostaglandin synthesis independent mechanisms contribute to the analgesic effects. Thus, the S-form inhibited prostaglandin synthesis, inflammation and nociception in rats. The R-form had much less effect on prostaglandin synthesis and did not affect inflammation. It did, however, block nociception in rats almost as potently as the S-form. S-flurbiprofen, in contrast to the R-form, was clearly ulcerogenic in the gastrointestinal mucosa. These results indicate additional molecular mechanisms of analgesia and suggest the use of R-arylpropionic acids as analgesics.
Animals↗
A monoclonal antibody against the sulfidopeptide leukotrienes LTC4, LTD4 and LTE4.
A monoclonal antibody (1A-LDR1) against sulfidopeptide leukotrienes (LT) is described. The mAb shows a nearly identical detection limit of about 0.04 ng for LTC4, LTD4, LTE4 and NacLTE4 in standard fluid phase RIA. Steric modifications, however, diminish the sensitivity, as determined for the examples 5-epi-LTC4, 6-epi-LTC4, 5,6-epi-LTC4 and 11-trans-LTC4. No crossreactivity could be observed for LTB4. Crossreactions with components of the LT peptide chain such as L-cysteine or glutathione, as well as with arachidonic acid, were not detectable. In assessing the accuracy of the LT-RIA, recovery experiments with supernatants of mouse peritoneal macrophages and incubates of gastric mucosa showed a good correlation of r = 0.993 and 0.990, respectively. Results of an inhibition experiment with mouse peritoneal macrophages, incubated with several concentrations of indomethacin and nordihydroguaiaretic acid (NDGA), support the reliability of RIA and ELISA. The new LT-mAB allows an almost complete detection of peptide leukotrienes in one assay.
Animals↗
Pharmacokinetics of ibuprofen enantiomers in dogs.
Inversion of inactive (R)-ibuprofen to active (S)-ibuprofen has been suggested to occur presystemically only. In order to investigate the site of inversion in dogs we administered both enantiomers either intravenously or intraduodenally (10 mg/kg) to adult, male beagle dogs (n = 3) in a crossover design. Plasma, urine, and bile were collected for up to 6 h and analyzed stereospecifically by HPLC, according to a previously published method. Pharmacokinetic parameters were calculated using a linear computer program. Absorption after intraduodenal administration occurred rapidly, resulting in maximum plasma concentrations 0.2 h after giving the enantiomer. Approximately 70% of the (R)-enantiomer (according to AUC) was inverted to the S-enantiomer independent of route of administration. No R-ibuprofen could be detected in plasma after (S)-ibuprofen administration. Mean residence time was found to be 2 to 3 times longer for (S)- than for (R)-ibuprofen. Total systemic clearance from plasma was twice as high for (R)- than for (S)-ibuprofen. There were no differences between plasma clearances after intravenous and intraduodenal administration. Between 8 and 17% of dose was recovered in bile [especially as free and conjugated (S)-ibuprofen] and 3-12% in urine [as (S)-ibuprofen, hydroxy- and carboxyibuprofen, free and conjugated forms]. Small amounts of (R)-ibuprofen were detected in bile after intraduodenal administration of (R)-ibuprofen only (1.8% of dose). In short, the unidirectional inversion of R-ibuprofen appears to occur systemically rather than presystemically in dogs.
Animals↗
Towards safer nonsteroidal anti-inflammatory drugs.
More than one hundred years ago salicylic acid and its salts were introduced into the therapy of rheumatic diseases. Ninety years ago aspirin was discovered, and within the last forty years phenylbutazone, indomethacin, ibuprofen, the oxicams and many others were discovered. All of these drugs are acidic. They inhibit the prostaglandin synthetase, combine analgesic and anti-inflammatory activity and show side-effects mainly in the GI-tract, liver, bone-marrow, and kidney. Within the last twenty years, however, distinct relationships between effects and side-effects could be shown: 1. Rapid absorption beginning in the stomach goes along with intensive gastric-duodenal irritation and ulceration. 2. A high degree of enterohepatic circulation appears to be associated with ileal and jejunal ulcerations and perforations. 3. Intensive hepatic metabolisation may be related to enhanced hepatic damage. 4. Intensive intrarenal circulation of the active moiety may be related to kidney damage. These observations indicate that certain pharmacokinetic characteristics of distinct nonsteroidal anti-inflammatory drugs (NSAIDs) are responsible, at least in part, for well-known side-effects. It is obvious that modifying the pharmacokinetics of the active principle may reduce specific types of side-effects. The clinical success of these attempts are limited but altogether promising.
Animals↗
S-ibuprofen versus ibuprofen-racemate. A randomized double-blind study in patients with rheumatoid arthritis.
Ibuprofen (ibu) is a racemic 2-arylpropionic acid non-steroidal anti-inflammatory drug whose activity is due mainly to the S-enantiomer. So far only the racemic compound is in clinical use. A double-blind randomized trial was carried out for a 2-week period in 50 patients with classical rheumatoid arthritis (RA) (Steinbrocker II-III) to compare the effectiveness and tolerance of S-ibu (400 mg T.I.D.) with that of the racemic compound (600 mg T.I.D.). Ritchie-index, limitation of movement, joint pain on pressure and pain at night decreased significantly in both groups. Due to lack of effectiveness, the dose had to be increased in 3 patients from the S-ibu group as well as in 6 patients from the racemic group resulting in mean daily doses of 1220 mg S-ibuprofen and 1870 mg racemic ibu. No statistically significant difference could be found between both groups concerning efficacy and unwanted effects. Therefore, S-ibu given alone may be advantageous because the metabolic load to the human body is reduced and patients are more likely to comply with drug doses of 1.2 g/day as compared to 1.8 g/day.
Adult↗
Effects of pure enantiomers of flurbiprofen in comparison to racemic flurbiprofen on eicosanoid release from various rat organs ex vivo.
The effects of oral treatment of rats with pure enantiomers of flurbiprofen in comparison to racemic flurbiprofen on ex vivo release of eicosanoids from gastric mucosa, jejunum, lung, brain and clotting whole blood were investigated. With the S(+) enantiomer and the racemate dose-dependent inhibition of release of cyclooxygenase products of arachidonate metabolism in all tissues tested was observed, while release of leukotriene (LT) C4 was inhibited in gastric mucosa, but not in jejunum and lung. On the other hand, the R(-) enantiomer inhibited cyclooxygenase in the various tissues less potently and to a variable degree with no significant effect in the jejunum. The R(-) enantiomer had no effect on LTC4 release from any of the tissues investigated. Furthermore, the effect of a high dose of 25 mg/kg of the S(+) enantiomer on release of cyclooxygenase products from the various tissues was much longer lasting than that of an identical dose of the R(-) enantiomer. Stereoselective pharmacokinetics of the flurbiprofen enantiomers and/or organ specific cyclooxygenase activities could underly these results. The more potent cyclooxygenase inhibition by the S(+) enantiomer correlates with its higher anti-inflammatory activity and gastrointestinal toxicity. On the other hand, both enantiomers have been shown previously to be almost equally effective analgesics. Inhibition of brain cyclooxygenase might contribute to this effect.
Animals↗
Pharmacokinetics of diflunisal in patients.
There are few pharmacokinetic data available on the disposition of diflunisal in patients; this study, therefore, looked at the oral absorption, distribution and elimination of this drug. Ten pharmacokinetic profiles obtained from 8 patients showed a maximum plasma diflunisal concentration of 62.0 +/- 26.5 mg/L after 2.76 +/- 1.87 hours, and an area under the plasma concentration-time curve (AUC) of 678.3 +/- 362.3 mg/L.h. Significant intra- and intersubject variability was observed in this group of patients. Analysis of biliary secretion of diflunisal in 4 patients suggested a biliary elimination and subsequent enterohepatic circulation ranging between 2.4 and 15.1%. The AUC for diflunisal in synovial fluid collected from 66 patients was about 70% of that for plasma. In none of 28 patients studied could any trace of diflunisal be observed in cerebrospinal fluid, even though the sensitivity of the assay allowed detection of concentrations as low as 0.01 mg/L.
Adult↗
Dissociation between the antinociceptive and anti-inflammatory effects of the nonsteroidal anti-inflammatory drugs. A survey of their analgesic efficacy.
The authors challenge the general view that the analgesic effect of the nonsteroidal anti-inflammatory drugs (NSAIDs) can be universally attributed to their inhibitory effects on the synthesis of peripherally formed prostaglandins. Analgesic activity by some of these compounds in the reduction of physiological pain elicited by a single noxious stimulus, or the treatment of acute pain which results from sudden trauma to otherwise healthy tissue, is better described as an antinociceptive effect. Single-dose studies in the dental pain model that have been conducted in double-blind conditions and included a placebo control group have been reviewed; those NSAIDs which are significantly superior to the reference compound aspirin 650mg and those which could represent real alternatives to the use of narcotics in certain situations for the management of acute pain have been identified. Azapropazone, diflunisal, naproxen, oxaprozin and tolmetin are all weak inhibitors of prostaglandin synthesis, yet they have been shown to be more effective than aspirin. In a model of joint pain, azapropazone 600mg has been shown to be as effective as pethidine (meperidine) 100mg despite being the weakest inhibitor of prostaglandin synthesis. Whether the antinociceptive effect of azapropazone acts at a peripheral or a central level, or both, is not clear; evidence for the effects of NSAIDs on the central nervous system (CNS) is discussed. Historically, the antinociceptive character of some NSAIDs is apparent in several studies in both animals and humans. More recently, experimental algesimetry models designed to distinguish the antinociceptive effects of NSAIDs include the use in humans of photoplethysmography and computer-supported infrared thermographic imaging.
Administration, Oral↗
[Cholera infection with acute renal failure].
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Acute Kidney Injury↗
Stereoselective high-performance liquid chromatographic determination of ketoprofen, ibuprofen and fenoprofen in plasma using a chiral alpha 1-acid glycoprotein column.
The effect of mobile phase composition, pH and temperature on the chiral resolution and retention of some 2-arylpropionic acids using the chiral alpha 1-acid glycoprotein column EnantioPac is described. Furthermore, a direct stereoselective high-performance liquid chromatographic assay to determine the enantiomers of ketoprofen, ibuprofen and fenoprofen in plasma is presented. Detection was at 260, 220 and 220 nm for ketoprofen, ibuprofen and fenoprofen, respectively. The limit of detection was 0.1 micrograms/ml for the enantiomers of ketoprofen and ibuprofen, and 0.25 micrograms/ml for the enantiomers of fenoprofen. The method was demonstrated to be applicable for stereoselective pharmacokinetic studies of ketoprofen, ibuprofen and fenoprofen after administration under clinical conditions.
1-Propanol↗
High-performance liquid chromatographic determination of pentazocine in plasma.
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Chromatography, High Pressure Liquid↗
[Homeopathy: science or healing doctrine. A current trend to become involved with homeopathy].
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Clinical Trials as Topic↗
Humoral autoimmunity to cartilage in rheumatoid arthritis?
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Adult↗
Effects of pentazocine and acetylsalicylic acid on pain-rating, pain-related evoked potentials and vigilance in relationship to pharmacokinetic parameters.
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.
Adult↗
The amphiprotic character of azapropazone and its relevance to the gastric mucosa.
Since most non-steroidal anti-inflammatory drugs (NSAIDs) contain only one obvious ionisable group at physiological pH levels then they may be easily identified as having either acidic or basic character. Basic NSAIDs are simply non-acidic NSAIDs capable of accepting a proton within the physiological pH range. Within this range, however, a few NSAIDs contain two obvious ionisable groups, one acidic and the other basic. Such compounds should be described as amphiprotic, and include NSAIDs such as 4- and 5-amino substituted salicylic acids, niflumic acid, amfenac, WY 18251, and azapropazone. The aqueous ionisation equilibrium of such compounds is complex and is described by two macroscopic ionisation constants. Evidence has accumulated during the last decade to support the view that the pharmacokinetic behaviour of NSAIDs contributes not only decisively to their therapeutic effects but also to the type and incidence of their side-effects. A priori, using a physicochemical argument, certain amphiprotic NSAIDs should be better tolerated by the gastric mucosa than the classical acidic compound. Of those NSAIDs commercially available in the United Kingdom azapropazone remains the only one for which amphiprotic behaviour has been described. Following our examination of available data for azapropazone we conclude that the use of amphiprotic compounds represents a logical approach towards solving the problem of NSAID-induced gastric mucosal damage.
Animals↗
Gastrointestinal ulcerations induced by anti-inflammatory drugs in rats. Physicochemical and biochemical factors involved.
Aspirin, diclofenac, diflunisal, ibuprofen and indomethacin were given orally or intravenously to fasted or fed rats. The resulting gastric and intestinal damage was assessed using standard methods. The same drugs were administered to rats with biliary fistulas, and the fraction of drug excreted in bile was quantified using HPLC methods. We found that gastric damage occurred only in the fasted animals and was found to be dose-dependent and related to the amount (r = 0.871) and solubility (r = 0.909) of the individual drug. As far as acute gastric toxicity is concerned, neither the potency of a drug as an inhibitor of cyclo-oxygenase nor the fraction of unchanged or conjugated agent excreted in bile appeared to be relevant. Secondly, ulcerations of the small intestine occurred in fed animals only. The degree of damage was related to the amount of unchanged or conjugated drug excreted in bile and cyclo-oxygenase inhibitory potency (r = 0.873). The administered dose (within the range investigated) and drug solubility appeared not to contribute to intestinal toxicity. It is concluded that, in the rat, acute gastric and intestinal toxicity of non-steroidal anti-inflammatory drugs are due to different mechanisms. Whereas gastric toxicity is strongly influenced by the amount of drug dissolved under the pH conditions in the stomach, intestinal toxicity appears to depend on biliary excretion and enterohepatic circulation of a drug as well as on its potency as an inhibitor of prostaglandin synthesis.
Administration, Oral↗