The opioid analgesic tramadol is a racemate and consists of 50% (+)- and 50% (-)-enantiomer. This study investigated analgesic efficacy and safety of both enantiomers after intravenous (i.v.) injection in comparison with the racemate. Ninety-eight patients recovering from major gynaecological surgery under opioid-free halothane anaesthesia were treated in a randomised, double-blind study with (+)-tramadol, (-)-tramadol or the racemate. Following an individualised i.v. loading dose up to a maximum of 200 mg, patient-controlled analgesia with demand doses of 20 mg was made available for 24 h. The primary criterion was of efficacy was the decrease of pain intensity on a 5-point verbal rating scale from severe or maximum pain to mild or no pain intensity on a 5-point verbal rating scale from severe or maximum pain to mild or no pain within the first hour after the loading dose. The secondary criterion was patient satisfaction with pain relief during the 24-h observation period stated in the final interview. Patients who terminated the study prematurely were evaluated as non-responders. Of patients treated with (+)-tramadol, tramadol racemate, and (-)-tramadol, 12%, 15%, and 53% of treated patients, respectively, terminated the study prematurely because of inefficacy. Of patients treated with (+)-tramadol, racemate or (-)-tramadol 67%, 48% and 38%, respectively, were considered responders regarding the primary criterion of efficacy (P = 0.061), and 82%, 76%, or 41% with respect to the secondary criterion (P = 0.001). Assessment of laboratory screening, adverse events, vital signs and blood gas monitoring showed no serious drug-related events. Nausea and vomiting were the most frequently reported non-serious side effects and were most often seen with (+)-tramadol. Taking into account both efficacy and safety aspects, the racemate seems to be superior to either enantiomer alone.

In the quality assurance of medical products, tests for sterility are essential. For parenteral pharmaceuticals, avoiding the presence of pyrogens is crucial. These fever-inducing substances (endotoxins and non-endotoxins) are not eliminated by standard sterilisation processes, and are biologically active once in the bloodstream, causing risks to human health, ranging from mild reactions (e.g. fever) to septic shock and death. Therefore, for injectable formulations, pyrogen testing is mandatory. Over the years, various pyrogen testing methods have been introduced, namely: in the 1940s, the rabbit pyrogen test, which is an in vivo test that measures the fever reaction as an endpoint; in the 1970s, the Limulus Amoebocyte Lysate (LAL) test, which is an in vitro test (with the haemolymph of the horseshoe crab) that specifically detects endotoxin; and in 2010, the Monocyte-Activation Test (MAT), which is a non-animal based in vitro pyrogen test that represents a full replacement of the rabbit test. Due to the ubiquity and biological significance of pyrogens, we are currently further developing the MAT so that it can be used for other applications. More specifically, our focus is on the detection of pyrogenic contamination on medical devices, as well as on the measurement of air quality. In addition, further improvements to permit the use of cryopreserved blood in the MAT, to overcome the limitations in the availability of freshly-drawn blood from human donors, are ongoing.

Cotton-based surgical invasive devices with their desired hemostyptic properties have been used for decades in the surgical field. However, in cardiac surgery using the heartlung machine with direct retransfusion of suction blood, activated blood may re-enter the circulation without filtration and may trigger a cascade reaction leading to systemic inflammation and thrombosis. We therefore set out to evaluate the inflammatory potential of untreated and pyrogen-impregnated cotton-based surgical invasive medical devices. After incubation of the swabs with whole blood or PBMC, the cell-free supernatant was investigated for IL1β and IL6. While the reaction of human whole blood toward cotton swabs could not be influenced by any sterilization technique, dry heat and gammairradiation were able to diminish the inflammatory reaction of PBMC toward the material and the used pyrogens. In conclusion, using PBMC in direct contact to cotton we are the first to establish a suitable test method for quantification of the pyrogenic/inflammatory activity of this material. The unaltered reaction of whole blood, however, suggests a crosstalk of cells and plasma proteins in the inflammation activation that is not prevented by sterilization of the swabs. This new in vitro testing methodology may help to better display the clinical situation during development of new materials.

The MAT-based in vitro pyrogen test should be GLP-accredited for use in medical device testing

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