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The scope of the present work is to experimentally investigate the effect of pre-bond contamination with de-icing (DI) fluid and the combined effect of DI fluid and hygrothermal ageing on the fracture toughness of carbon fibre reinforced plastic bonded joints. These scenarios could occur in the implementation of an adhesively bonded patch repair in a composite aircraft structural part. To this end, mode I and mode II fracture toughness tests were conducted on contaminated specimens and mode II fracture toughness tests on contaminated/aged specimens. Three levels of contamination with a de-icer were considered. The hygrothermal ageing conditions applied until saturation are 70°C/85% relative humidity. The experimental results reveal a detrimental effect of DI fluid on both mode I and mode II fracture toughness of the bonded joints. With increasing the contamination level, the mode I and mode II critical energy release rates decrease. Under mode I loading, the specimens failed mainly in light-fibre-tear mode, while under mode II loading, in adhesive failure mode. Hygrothermal ageing decreased further the mode II fracture toughness of the specimens and increased the adhesive failure mode. The present study reveals that the pre-bond DI contamination and after-bond ageing could critically degrade the strength of adhesively bonded patch repairs. [ABSTRACT FROM AUTHOR]

Acetaminophen/paracetamol is the most widely used drug of the world. At the same time, it is probably one of the most dangerous compounds in medical use, causing hundreds of deaths in all industrialized countries due to acute liver failure (ALF). Publications of the last 130 years found in the usual databases were analyzed. Personal contacts existed to renowned researchers having contributed to the medical use of paracetamol and its precursors as H.U. Zollinger, S. Moeschlin, U. Dubach, J. Axelrod and others. Further information is found in earlier reviews by Eichengrün, Rodnan and Benedek, Sneader, Brune; comp. references. The history of the discovery of paracetamol starts with an error (active against worms), continues with a false assumption (paracetamol is safer than phenacetin), describes the first side ‐ effect ‘epidemy’ (phenacetin nephropathy, drug ‐ induced interstitial nephritis) and ends with the discovery of second ‐ generation problems due to the unavoidable production of a highly toxic metabolite of paracetamol N ‐ acetyl ‐ p ‐ benzoquinone imine (NAPQI) that may cause not only ALF and kidney damage but also impaired development of the fetus and the newborn child. It appears timely to reassess the risk/benefit ratio of this compound. [ABSTRACT FROM AUTHOR]

Objective Administering cyclooxygenase-2 inhibitors preoperatively appears attractive since these drugs reduce post-operative pain, but do not increase the risk of post-operative bleeds, asthmatic attacks and stress-related gastrointestinal ulcers. In a former investigation, we could show that post-operative administration of etoricoxib reduces prostaglandin production in wound fluid, but the onset of action is variable due to delayed post-operative absorption. Methods In this study, we investigated the preoperative administration of etoricoxib in patients undergoing hip replacement. They received 120 mg etoricoxib or placebo 2 h before surgery and 1 day after in a double-blinded, randomized, parallel group design. Results A total of 11 patients were randomized (placebo n = 5; verum n = 6). We found high and constant levels of the drug in blood, central nervous system and wound fluid already at the end of surgery (tmax < 2 h). This was accompanied by inhibition of prostaglandin production in the wound tissue (treatment p < 0.05), suppression of interleukin 6 increase in plasma (treatment p < 0.01), and - despite existing standard pain relief procedures - higher satisfaction with analgesics (time vs. treatment p < 0.05) and less demand for opioids (treatment p < 0.01) and intrathecal bupivacaine (treatment p = 0.05) administration. Conclusion Administration of etoricoxib 2 h before surgery allows for an effective drug concentration in critical tissues, a reduction of the production of pro-inflammatory mediators and for better pain relief. [ABSTRACT FROM AUTHOR]

Dormann H, Neubert A, Criegee-Rieck M, Egger T, Radespiel-Tröger M, Azaz-Livshits T, Levy M, Brune K, Hahn EG (University of Erlangen-Nuremberg, Germany; and Hadassah-Hebrew University Medical Center, Jerusalem, Israel) Readmissions and adverse drug reactions in internal medicine: the economic impact. J Intern Med 2004; 255: 653–663. Recent studies show that nearly half of the hospitalized patients are readmitted within 6 months from discharge. No data exist about the relationship between adverse drug reactions (ADRs) and readmittance to a department of internal medicine. The primary aims of the study were to determine if ADRs could be used as predictors for recurrent hospitalizations in internal medicine and to evaluate the economic impact of ADRs on hospitalization costs. A cohort-based, prospective, 18-month pharmacoepidemiological survey was conducted in the Department I of Internal Medicine at the University Hospital of Erlangen. All patients were intensively monitored for ADRs by a pharmacoepidemiological team. ADRs were evaluated for their offending drugs, probability, severity, preventability and classified by WHO-ART. During a 6-month period ADR-positive patients were matched to non-ADR patients applying diagnosis-related group categorization in order to measure the impact of ADRs on the duration and frequency of hospitalization. Of 1000 admissions 424 patients had single admissions and 206 patients had recurrent readmissions (min 1, max 9). The prevalence of readmissions was 37% ( n = 370). In 145 (23%) of 630 patients, 305 ADRs were observed. The ADR incidence was similar in first admissions and readmissions. ADRs were not found to predict further readmissions and lack of ADRs did not preclude readmissions. ADRs caused hospitalizations in 6.2% of first admissions and in 4.2% of readmissions. According to the Schumock algorithm 135 (44.3%) ADRs were found to be preventable. The occurrence and numbers of ADRs per admission were found to prolong hospitalization period significantly ( r = 0.48 and 0.51, P < 0.001, n = 135). Of 9107 treatment days 20% were caused by in-house (1130 days) and community-acquired ADRs (669 days). In admissions and readmissions 11% (>973 days) of all treatment days were judged to be preventable. Intensified drug monitoring supported by information technology in internal medicine is essential for early detecting and prevention of ADRs and saving hospital resources. [ABSTRACT FROM AUTHOR]

: To investigate the effectiveness of a computer monitoring system that detects adverse drug reactions (ADRs) by laboratory signals in gastroenterology. : A prospective, 6-month, pharmacoepidemiological survey was carried out on a gastroenterological ward at the University Hospital Erlangen-Nuremberg. Two methods were used to identify ADRs. (i) All charts were reviewed daily by physicians and clinical pharmacists. (ii) A computer monitoring system generated a daily list of automatic laboratory signals and alerts of ADRs, including patient data and dates of events. : One hundred and nine ADRs were detected in 474 admissions (377 patients). The computer monitoring system generated 4454 automatic laboratory signals from 39 819 laboratory parameters tested, and issued 2328 alerts, 914 (39%) of which were associated with ADRs; 574 (25%) were associated with ADR-positive admissions. Of all the alerts generated, signals of hepatotoxicity (1255), followed by coagulation disorders (407) and haematological toxicity (207), were prevalent. Correspondingly, the prevailing ADRs were concerned with the metabolic and hepato-gastrointestinal system (61). The sensitivity was 91%: 69 of 76 ADR-positive patients were indicated by an alert. The specificity of alerts was increased from 23% to 76% after implementation of an automatic laboratory signal trend monitoring algorithm. : This study shows that a computer monitoring system is a useful tool for the systematic and automated detection of ADRs in gastroenterological patients. [ABSTRACT FROM AUTHOR]

Background: It has been claimed that the risk of adverse drug reactions increases with age. However, only limited data exist for disease-group specific risks and none for patients with liver and gastrointestinal diseases. Aims: To determine the incidence and characteristics of adverse drug reactions and the physicians’ awareness of adverse drug reactions. Methods: During a 7-month period, a prospective survey of 532 male patients (158 aged 65 years or older; 30%) was conducted on a hepatogastroenterological ward of a tertiary-care university hospital, using intensive bedside and computer-assisted drug surveillance methods. Results: No difference was found in the overall rate of adverse drug reactions between older and younger patients (25.9% vs. 24.2%) during 6213 treatment days. However, a significantly higher risk for developing adverse drug reactions could be shown for the elderly with biliary tract diseases (P < 0.01). Independently of age, patients suffering from gastric ulcers, acute episodes of pancreatitis, cholangitis or inflammatory bowel diseases were at high risk of adverse drug reactions. Adverse drug reaction-associated mortality was encountered in four elderly and none of the younger patients. Secondary pharmacological effects and drug toxicity were the main types of adverse drug reactions for both age groups. Although 75.3% of the adverse drug reactions were predictable, only 37.5% of all adverse drug reactions were recognized by the staff physicians. Conclusion: In hepatogastroenterological patients, advancing age was not associated with an overall increased risk of adverse drug reactions except for patients with biliary tract diseases. In the elderly, adverse drug reactions were more severe and carried higher mortality. Guidelines and educational programs should be developed to increase the awareness of adverse drug reactions and their prevention, especially in high risk patients and, thus, to improve patient outcomes. [ABSTRACT FROM AUTHOR]

Aims To investigate the pharmacokinetics of the enantiomers of flurbiprofen and inhibition of prostanoid production in blister fluid and serum. Methods Eleven healthy volunteers received 75 mg R-, 75 mg S-flurbiprofen or no medication in a randomized 3-way cross-over study. Flurbiprofen concentrations were determined by h.p.l.c. TXB2 and PGE2 were determined by enzyme immunoassay and chemiluminescence immunoassay respectively. Results S-flurbiprofen produced almost complete (>99% vs baseline) inhibition of thromboxane B2 (TXB2 ) in serum in all volunteers and significant inhibition of prostaglandin E2 (PGE2 ) generation in blister fluid, but there was a considerable inter-individual variation in the response ranging from −78 to +190% change from control PGE2 AUC. After administration of R-flurbiprofen, there was a mean maximum TXB2 inhibition of 65.2±15.0% in serum but no significant changes of PGE2 levels in blister fluid were observed. The pharmacokinetic parameters in serum and blister fluid were not significantly different between enantiomers. R- to S-inversion did not occur to a clinically relevant extent. For R-flurbiprofen, the complex rate constant of transfer into blister fluid was greater at the u.v.-exposed site (0.110±0.050) than at the control site (0.079±0.026, P<0.05) which corresponded to a higher AUC and Cmax of R-flurbiprofen in u.v.-exposed blister as compared with control. For inhibition of TXB2 generation after administration of S-flurbiprofen, a sigmoidal log-linear concentration-response relationship was established in all subjects (E C50: 0.123±0.092 μg ml−1 ). In contrast, inhibition of PGE2 production in blister showed no clear concentration-response relationship when correlated with concentrations of S-flurbiprofen in either serum or blister fluid. After administration of R-flurbiprofen, no concentration-effect relationship could be established. Conclusions It is concluded that the blister model may have value for studying the pharmacokinetics and pharmacodynamics of antiinflammatory drugs in humans. Interestingly, inter-individual variation in the pharmacokinetics of flurbiprofen enantiomers could not account for the variability in response observed in the blister model. [ABSTRACT FROM AUTHOR]

We report the isolation and characterization of a 65,000 MW chondrocyte autoantigen (CH65) which may be involved in rheumatoid arthritis. This chondrocyte-specific antigen reacted with sera from patients with rheumatoid arthritis (RA). CH65 did not cross-react with a polyclonal antibody raised against microbial heat-shock protein (hsp) 65, anti-human hsp 65 monoclonal antibodies (mAb) (LK1 and LK2), anti-microbial hsp 65 mAb (IA10, IIC8 and WTB-78H1) and anti-cytokeratin 8, 18, 19 mAb (NCL5D3MAb). CH65 could be purified from chicken chondrocyte membranes by ammonium sulphate precipitation and a novel electro-gelfiltration method. The amino acid analysis yielded an unusually high degree of glycine, serine and asparagin residues. The internal amino acid sequence obtained by tryptic digestion revealed homologies with the cytokeratin family. Despite these homologies, CH65 lacked immunological cross-reactivity with commercial anti-cytokeratin antibodies. Mice mAb generated against the purified CH65 (C6) were used to identify the protein as a tissue-specific constitutive protein membrane from chondrocytes. Sera from patients with RA crossreacted with purified CH65. The stress or heat-shock protein (hsp 65), implicated in the development of experimental and clinical arthritis, showed no immunological cross-reactivity with CH65 in Western blots. These findings suggest that CH65 may represent an interesting cartilage-specific new antigen in RA. The availability of this antigen in purified form and specific mAb may offer useful tools in arthritis research. [ABSTRACT FROM AUTHOR]

The antiparasitic effects of cylosporin A were examined in leishmanial infection by analysing the role of CsA-binding proteins (cyclophilins) in the host-parasite interaction. We hypothesized that the leishmanicidal effects of CsA on Leishmania major infected macrophages might be mediated through a cyclophilin of either the parasite or the host cell. Two cyclophilins (20 and 22 kDa) were purified from L. major parasites and N-terminally sequenced. Although enzyme activity of these cyclophilins was inhibited by CsA, pretreatment of L. major parasites with CsA did not result in reduction of a subsequent macrophage infection, arguing against a role of L. major cyclophilins as infectivity potentiators. However, host-cell cyclophilin A (CypA) was found to be critically involved in the intracellular replication of L. major parasites in murine macrophages. An antisense oligonucleotide to murine CypA was constructed and added to cultures of peritoneal macrophages prior to infection with L. major parasites. This treatment strongly reduced the expression of CypA in macrophages and resulted in the inhibition of the intracellular replication of L. major amastigotes. These data indicate that interaction of amastigotes with host-cell cyclophilin is an important part of the intracellular replication machinery of L. major and define, for the first time, a direct involvement of a cyclophilin in the survival strategies of an intracellular parasite. [ABSTRACT FROM AUTHOR]

In view of evidence in animals that enterohepatic recirculation of non- steroidal anti-inflammatory drugs contributes to small intestinal mucosal damage we have investigated the extent of biliary elimination of three nonsteroidals. Ibuprofen (n = 3), diclofenac (n = 2) and indomethacin (n = 3) were given to six patients with a percutaneous transhepatic cholangiodrainage placed in the bile duct system. One patient received all three drugs. The mean biliary elimination of ibuprofen was 0.82% of the given dose compared with 50.41% urinary excretion. When diclofenac or indomethacin was administered 4.62% and 6.40% of the dose were found in bile, whereas 34.73% and 32.22% (means) were recovered from urine, respectively. The mean percentage eliminated in bile as unchanged drug and active phase II metabolites was 0.15% for ibuprofen, 1.09% for diclofenac and 5.02% for indomethacin. [ABSTRACT FROM AUTHOR]

1 Macro-autoradiographic methods were used to assess the biodistribution of [3H]-, or [14C]-acidic (aspirin, indomethacin, phenylbutazone) and non-acidic (antipyrine, aminopyrine, paracetamol) mild analgesics in rats with carrageenan-induced inflammation. 2 At anti-inflammatory doses all the acidic drugs (and/or their metabolites) were found to reach high concentrations in the stomach wall, liver, blood and bone marrow, kidney cortex and the inflamed tissue, that is, the tissues in which these drugs exert their therapeutic or side- effects. 3 In contrast, at analgesic doses, the non-acidic mild analgesics (and/or their metabolites) are equally distributed throughout the body with the exception of the gastro-intestinal lumen and the liver. This distribution pattern correlates well with the lack of acute side-effects and anti-inflammatory action of these drugs at therapeutic doses. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article related to the use of cyclooxygenase (COX) and COX-2 inhibitors by E.L. Fosbøl published in a previous issue of the journal.

Aims: Computer-assisted signal generation is an important issue for the prevention of adverse drug reactions (ADRs). However, due to poor standardization of patients' medical data and a lack of computable medical drug knowledge the specificity of computerized decision support systems for early ADR detection is too low and thus those systems are not yet implemented in daily clinical practice. We report on a method to formalize knowledge about ADRs based on the Summary of Product Characteristics (SmPCs) and linking them with structured patient data to generate safety signals automatically and with high sensitivity and specificity., Methods: A computable ADR knowledge base (ADR-KB) that inherently contains standardized concepts for ADRs (WHO-ART), drugs (ATC) and laboratory test results (LOINC) was built. The system was evaluated in study populations of paediatric and internal medicine inpatients., Results: A total of 262 different ADR concepts related to laboratory findings were linked to 212 LOINC terms. The ADR knowledge base was retrospectively applied to a study population of 970 admissions (474 internal and 496 paediatric patients), who underwent intensive ADR surveillance. The specificity increased from 7% without ADR-KB up to 73% in internal patients and from 19.6% up to 91% in paediatric inpatients, respectively., Conclusions: This study shows that contextual linkage of patients' medication data with laboratory test results is a useful and reasonable instrument for computer-assisted ADR detection and a valuable step towards a systematic drug safety process. The system enables automated detection of ADRs during clinical practice with a quality close to intensive chart review., (© 2013 The Authors. British Journal of Clinical Pharmacology © 2013 The British Pharmacological Society.)

Objective: Recent findings suggest that permanent blockade of cyclooxygenase 2 (COX-2) is one factor contributing to the cardiovascular side effects of selective COX-2 inhibitors (coxibs) and nonsteroidal antiinflammatory drugs (NSAIDs). The present study compared the extent and time course of COX-2 inhibition and the effects on cardiovascular parameters (changes in blood pressure and heart rate) between various antirheumatic doses of diclofenac, celecoxib, and rofecoxib in healthy elderly volunteers., Methods: A randomized, parallel-group study was conducted in volunteers receiving 75 mg diclofenac twice daily, 200 mg celecoxib twice daily, or 25 mg rofecoxib once daily for 8 days. Blood samples were obtained predose and at specified time points postdose, on days 1 and 8, for assay of drug plasma concentrations and COX-2 inhibition. Lipopolysaccharide-induced prostaglandin E(2) synthesis was measured ex vivo as an index of COX-2 activity in human whole blood., Results: COX-2 inhibition was significantly less pronounced after treatment with celecoxib and rofecoxib than with diclofenac. Maximal inhibitions after a single dose and at steady state, respectively, were as follows: 99% and 99% with diclofenac, 70% and 81% with celecoxib, and 56% and 72% with rofecoxib. At steady state, only diclofenac caused virtually complete COX-2 inhibition over the whole dose interval, and this corresponded to the highest increase in systolic blood pressure and greatest reduction in heart rate., Conclusion: Diclofenac elicited the most pronounced COX-2 inhibition, blood pressure elevation, and suppression of heart rate. It is assumed that the extent and time course of intravascular COX-2 inhibition may determine the differential profile of cardiovascular side effects associated with NSAIDs and coxibs, but this has to be proven in future studies.

Aim: Diclofenac-K has been recently launched at low oral doses in different countries for over-the-counter use. However, given the considerable first-pass metabolism of diclofenac, the degree of absorption of diclofenac-K at low doses remained to be determined. The aim of this study was to determine the bioavailability of low-dose diclofenac-K., Methods: A randomized, three-way, cross-over study was performed in 10 subjects. Each received diclofenac-K, 22.5 mg via short-term i.v. infusion and orally at single doses of 12.5 mg and 25 mg., Results: Mean (+/- SD) times to maximal plasma concentration (t(max)) of diclofenac were 0.48 +/- 0.28 h (12.5 mg) and 0.93 +/- 0.96 h (25 mg). The absolute bioavailability of diclofenac-K after oral administration did not differ significantly in the 12.5-mg and 25-mg dose group (63.1 +/- 12.6%vs. 65.1 +/- 19.4%, respectively). The 90% confidence intervals for the AUC(infinity) and AUC(t) ratios for the two oral regimes were 82.6, 103.4% (point estimate 92.4%) and 86.2, 112.9% (point estimate 98.6%), respectively. These values were within the acceptance criteria for bioequivalence (80-125%)., Conclusions: Our data indicate that diclofenac-K is rapidly and well absorbed at low dose, and are consistent with a rapid onset of action of the drug. Abbreviations AUC, area under plasma concentration-time curve; C(max), peak plasma concentration; CI, confidence interval; COX, cyclooxygenase; D, dose; F, absolute bioavailability; t(max), time to reach C(max).

Nociceptin/orphanin FQ (N/OFQ) is the endogenous agonist of the N/OFQ peptide receptor (NOP receptor). It is released from a larger precursor polypeptide, called prepro-nociceptin (ppN/OFQ) from which, in addition to N/OFQ, other biologically active neuropeptides may be derived. Increasing evidence indicates that exogenous application of N/OFQ to the central nervous system of mice and rats induces pro- and antinociceptive effects depending on the dose and site of administration. Much less is known about a potential contribution of endogenous N/OFQ to pain control. Here, we have used a genetic approach to address this topic. Mice deficient in either the NOP receptor (NOP-R-/- mice) or the N/OFQ precursor polypeptide (ppN/OFQ-/- mice) or both (double knockout mice) were compared with wild-type littermates in animal models of acute and tonic pain. Nociceptive responses to acute noxious heat of all three types of mutant mice were indistinguishable from those of wild-type mice. Accordingly, nociceptive behaviour was very similar in the early phase of the formalin test. However, NOP-R-/-, ppN/OFQ-/- and double knockout mice showed markedly stronger nociceptive responses during prolonged nociceptive stimulation in the second phase of the formalin test and significantly lower thermal pain thresholds in inflamed tissue after zymosan A injection. These results indicate that N/OFQ contributes significantly to endogenous pain control during prolonged nociceptive stimulation but does not affect acute pain sensitivity. Among the three types of mutant mice nociceptive behaviour was nearly identical, indicating that the lack of other potential ppN/OFQ products in the ppN/OFQ-/- mice was apparently without effect on the nociceptive phenotype.

Aims: To assess the pharmacokinetic equivalence of two different formulations of ibuprofen lysinate with special focus on the expected effects., Methods: Sixteen healthy volunteers received cross-over ibuprofen lysinate as either one tablet of 400 mg ('test') or two tablets of 200 mg ('reference'). Ibuprofen plasma concentrations were followed up for 10 h. Bioequivalence was assessed by standard noncompartmental methods. Ibuprofen plasma concentrations were fitted with a model that took bioinversion of R- to S-ibuprofen into account., Results: Peak plasma concentrations of R- and S-ibuprofen were 18.1 and 20 microg ml(-1) (test), and 18.2 and 20 microg ml(-1) (reference). Areas under the plasma concentration vs. time curves were 39.7 and 67.5 microg ml(-1) h (test), and 41.1 and 68.2 microg ml(-1) h (reference). Clearance of R-ibuprofen was 5.2 (test) and 5 l h(-1) (reference). A specific plasma concentration was reached with the test formulation about 5 min later than with the reference. Parameters from compartmental modelling were (given for R-and then for S-ibuprofen): body clearance: 4.9 and 4.64 l h(-1), central volume of distribution: 2.8 and 4.1 l, intercompartment clearance: 5.1 and 5.45 l h(-1), peripheral volume of distribution: 4.1 and 5.2 l. The absorption rate constant was 1.52 h(-1), and the test but not the reference formulation had a lag time of 0.1 h. Simulations showed similarity between formulations of the expected effects except for a calculated delay of 6 min with the test formulation., Conclusions: Ibuprofen formulations were bioequivalent. The pharmacokinetic model may serve as a basis for future pharmacokinetic/pharmacodynamic calculations after administration of racemic ibuprofen.

Aims: To estimate the frequency of adverse drug reactions (ADRs) identified through the use of automatic signals generated from laboratory data (ALS) in hospitalised patients. To determine the frequency of spontaneous recognition of these ADRs by the attending physicians and to assess the potential value of ALS for detection of ADRs., Methods: Laboratory results of patients hospitalised in a nine bed medical ward were automatically recorded over a period of 17 months. Values exceeding defined boundaries were used as ALS. Charts of every third patient were analysed retrospectively with regard to adverse drug related reactions and causality was evaluated as well as whether the ADR had been recognised during the period of hospitalisation., Results: The charts and ALS of 98 patients were analysed. In 18 cases a drug-related adverse reaction was probable. Awareness to the reaction by the treating physicians was evident in 6 out of these 18 ADRs. Approximately 80% of the ADRs were considered predictable. Three ADRs were regarded as serious., Conclusions: Adverse drug reactions are common and often preventable. Only one third of ADRs which could have been detected through ALS were recognised by the attending physicians. An increased doctor's awareness of the frequency of drug related abnormal laboratory results by means of ALS is likely to increase the recognition rate of ADRs and might help to prevent them.

Aims: To develop and assess the use of computerized laboratory data as a detection support tool of adverse drug reactions (ADRs) in hospital., Methods: This was a retrospective observational study of 153 sequential medical admissions during a 2-month period to the 34-bed medical ward at the Hadassah University Hospital, Jerusalem, Israel. Measurements made were 1) Retrospective chart review for recognized and unrecognized adverse drug reactions (ADRs) and 2) Analysis of computerizied laboratory data according to defined automatic laboratory signals (ALS) for adverse reactions., Results: Forty ADRs have been detected in 38 out of the 153 hospital admissions (24.8%). Nine reactions were considered severe. Altogether 212 ALS were generated involving 86 admissions. In 25 (65.8%) of the ADR-positive admissions ADRs were detected through automatic signals generated from the laboratory data. ALS were detected in 56 out of the 115 (48.7%) ADR-negative admissions. Twenty-four (60%) of the ADRs were not recognized as such by the attending physicians. Two of these reactions were severe. ALS could have generated an alert for 19 (79.2%) of the unrecognized reactions., Conclusions: Application of automatic laboratory signals can increase the rate of recognition of the ADRs and thereby improve medical care. The sensitivity and specificity of the method might be increased by refinement and redefinition of the signals.

1. The dose-related effects of azapropazone on (i) event-related and spontaneous EEG-activity and (ii) the subjects' pain ratings were investigated using an experimental human pain model based on both chemo-somatosensory event-related potentials (CSSERP) and subjects' pain ratings. 2. Healthy subjects (n = 20) participated in a placebo-controlled, randomized, double-blind, four-way cross-over study. Single doses of azapropazone (300 mg, 600 mg and 1200 mg) and placebo were administered intravenously. Each experiment consisted of five sessions (before and 1, 2, 4 and 8 h after administration of the medication). Each session lasted for approximately 40 min. In the first 20 min, pain was induced by short CO2-stimuli presented to the right nostril (phasic pain; interstimulus interval 30 s) and EEG was recorded from five positions. CSSERPs were obtained in response to painful CO2-stimuli. In the following 20 min period, tonic pain was induced by a constant stream of dry air introduced in the left nostril. Subjects rated the intensity of both phasic and tonic pain by means of a visual analogue scale. Additionally, a frequency analysis of the spontaneous EEG was performed. 3. Azapropazone reduced the pain-related CSSERP-amplitudes at frontal and parietal recording positions. This topographical pattern was observed in previous studies with opioids, while NSAIDs such as flurbiprofen and ketoprofen exerted effects at frontal and central positions. In contrast to other NSAIDs, administration of azapropazone resulted in a reduction of the frequency bands alpha 1, delta and theta of the spontaneous EEG. At the subjective level, analgesic effects of azapropazone were observed in the ratings of tonic pain. 4. Analgesic properties of azapropazone were demonstrated in man. The topographical pattern of the changes in the CSSERPs and the effects on EEG background activity suggest a central component of the analgesic action of azapropazone.

1. The aim of the study was to investigate the analgesic effects of flurbiprofen enantiomers using an experimental pain model based on both chemo-somatosensory event-related potentials (CSSERP) and subjective pain ratings. 2. Healthy female volunteers (n = 16, age 23-36 years) participated in a placebo-controlled, randomised, double-blind, four-way crossover study. Single doses of (S)-flurbiprofen (50 mg), (R)-flurbiprofen (50 and 100 mg) and placebo were administered orally. Measurements were taken before and 2 h after administration of the medications. During each measurement, 32 painful stimuli of gaseous carbon dioxide (200 ms duration, interval approximately 30 s) of two concentrations (60 and 65% CO2 v/v) were applied to the right nostril. EEG was recorded from five positions and CSSERP were obtained in response to the painful CO2- stimuli. Additionally, subjects rated the perceived intensity of the painful stimuli by means of a visual analogue scale (VAS). 3. The CSSERP-amplitude P2, a measure of analgesic effect, decreased after administration of both (R)- and (S)-flurbiprofen, while it increased after placebo. This was statistically significant at recording positions C4 (P < 0.01) and Fz (P < 0.05). The analgesia-related decreases in evoked potential produced by (R)-flurbiprofen were dose-dependent. Comparing similar doses of (R)- and (S)-flurbiprofen, the decrease in CSSERP-amplitudes produced by the (S)-enantiomer was somewhat more pronounced, indicating a higher analgesic potency. 4. The present data indicate that both enantiomers of flurbiprofen produce analgesic effects. Since (R)-flurbiprofen caused only little toxicity in rats as compared with the (S)-enantiomer or the racemic compound, a reduction of the quantitatively most important side effects in the gastrointestinal tract might be achieved by employing (R)-flurbiprofen in pain therapy.

The pharmacokinetics of the enantiomers of ketoprofen after oral administration of 12.5 mg, 25 mg and 50 mg and i.v. administration of 50 mg racemic ketoprofen to 24 healthy subjects were investigated. The AUC values of R- (r2 = 0.929) and S-ketoprofen (r2 = 0.930) were proportional to dose. The absolute bioavailability of the 50 mg oral dose was 84.5 (s.d. 20.6) % and 81.4 (18.0) % for R-ketoprofen and S-ketoprofen, respectively. With the exception of AUC values no dose dependent differences in pharmacokinetic parameters were observed. However, the R-enantiomer had higher AUC, lower clearance data and higher Cmax values than the S-form after oral administration. The results suggest that stereochemical and pharmacokinetic considerations cannot explain the lack of dose response observed with ketoprofen doses below 50 mg.

Plasma concentrations of the enantiomers of flurbiprofen were measured following oral administration of (S)-flurbiprofen 50 mg and (R)-flurbiprofen 50 mg and 100 mg to sixteen healthy subjects. Chiral inversion did not occur to a measurable extent. Significantly higher values of AUC (55.2 +/- 17.0 vs 44.6 +/- 11.2 micrograms ml-1h) elimination half-life (5.6 +/- 1.4 vs 4.0 +/- 1.0 h) and mean residence time (7.5 +/- 1.6 vs 5.7 +/- 1.2 h) were observed after 50 mg (S)-flurbiprofen as compared with 50 mg (R)-flurbiprofen. With the exception of Cmax and AUC values pharmacokinetic data for the 50 mg and the 100 mg dose of (R)-flurbiprofen did not differ significantly. The data are of clinical relevance if (R)-flurbiprofen also has analgesic activity in humans and is to be developed as an analgesic.

The biosynthesis of thromboxane (TX) B2 and immunoreactive prostaglandin (PG) F2 alpha in clotting whole blood ex vivo as well as collagen-induced platelet aggregation were determined before and up to 72 h after intravenous injection of 600 mg azapropazone 2H2O and intramuscular injection of 30 mg ketorolac tromethamine in six healthy subjects. The drug doses were selected on the basis of comparable analgesic activity (maximal recommended analgesic dose). Both platelet aggregation and prostanoid biosynthesis were inhibited by racketorolac to a significantly greater extent and for a longer period of time than by azapropazone. Correlations between serum concentrations and the inhibitory effects on TXB2 biosynthesis were observed for both drugs. Using the sigmoidal Emax model the mean serum concentration of azapropazone inhibiting platelet TXB2 generation by 50% (EC50) was found to be 98.1 +/- 41.9 (s.d.) micrograms ml-1, a value 1000 times higher than that for rac-ketorolac. The moderate inhibition of platelet function by azapropazone as compared with rac-ketorolac might be an advantage with regard to its use as a post-operative analgesic.

1. Patients suffering from rheumatoid arthritis received oral doses of 600 mg racemic ibuprofen (n = 25; RAC) or 400 mg (S)-ibuprofen (n = 25; S-IBU) in a double-blind, randomized parallel-group study. 2. The pharmacokinetic parameters of (S)-ibuprofen were not statistically different between treatments (P > 0.05). Comparing (S)- and (R)-ibuprofen within the group receiving the racemate significantly higher Cmax (20.3 +/- 5.3 vs 17.7 +/- 4.4 micrograms ml-1; P < 0.02; 95% confidence interval for differences (CI): 0.5-4.6), AUC (86.2 +/- 23.5 vs 67.6 +/- 26.6 micrograms ml-1 h; P < 0.001; CI: 9.5-27.6), mean residence time (4.5 +/- 1.1 vs 4.1 +/- 1.2 h; P < 0.01; CI: 0.1-0.6) and renal clearance (0.8 +/- 0.6 vs 0.0 +/- 0.0 ml min-1; P < 0.001; CI: 0.5-1.0) values were observed for the (S)-enantiomer. 3. No difference was found (P > 0.05) between treatments in the percentage of the dose recovered in the urine as (R)- or (S)-ibuprofen plus metabolites (S-IBU: 80.2 +/- 8.47 vs RAC: 74.1 +/- 14.0%). 4. Interindividual variation in the pharmacokinetics of (S)-ibuprofen following administration of the racemate was similar to that following the administration of the single isomer suggesting that chiral inversion is not a major factor contributing to variability in the disposition of this drug.