Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

A controlled study was performed to determine the potential toxic effects of the new nonsteroidal anti-inflammatory drug, eltenac (4-[(2,6-dichlorophenyl) amino]-3-thiopheneacetic acid), in horses. Four treatment groups were formed, each composed of 6 horses. The drug was injected intravenously, once daily, at a dose rate of 0.5 mg/kg, 1.5mg/kg or 2.5 mg/kg for 15 days. A control group was injected with sterile saline solution. Parameters assessed were hay and water consumption, daily clinical observations (evaluation of attitude, mentation, pulse and respiratory rate, fecal consistency, skin condition, and color and hydration of mucous membranes), physical examinations, complete hemogram, coagulation profiles, serum biochemical profiles, urinalysis, gastroscopic examinations and gross post-mortem and histopathological examinations on all organ systems. All examiners were blinded to group assignment and dosage levels until the completion of the study. A few glandular gastric ulcers, mild in severity, developed in seven animals during the treatment period. This occurred more often in horses treated with high doses of eltenac (P=.02). A dose dependent change of WBC count and neutrophil count were noted. Total protein, albumin and globulin levels had dose dependent decreases. One horse in the high dose group (2.5mg/kg) developed ventral edema as well as hypoproteinemia. N one of the horses in any of the dosage groups exhibited depression or anorexia. Gross post-mortem and histologic examination did not reveal any signs of drug related gastrointestinal, renal or hepatic abnormalities. Minimal toxic effects of eltenac given intravenously were greatest in horses treated with 2.5 mg/kg of the compound for 15 days. / Master of Science

Activation of spinal N-methyl-D-aspartate (NMDA) receptors stimulates cyclooxygenase and nitric oxide pathways. Compounds that block the activity of these NMDA receptor systems reduce pain hypersensitivity. However, their usefulness is limited by the side effects they produce. One way of reducing side effects is by combining drugs that produce the same overt effect by different mechanisms, which hopefully increase the net effect. In these series of studies, drugs that interact with NMDA receptor systems and their combinations were screened in vitro to identify spinal antinociceptive synergistic combinations that could be assessed in vivo. Based on developmental changes in thresholds, conduction velocities and blocking actions of the local anaesthetic lignocaine in neonatal rat L4/L5 dorsal root potentials, it was decided to use spinal cord in vitro preparation from 5- to 7-day-old rat pups. In single drug studies, the NMDA receptor channel blocker ketamine (1-50 µM) and the non-steroidal anti-inflammatory drug (NSAID) ketoprofen (200-600 µM), but not the NSAID salicylate (1000 µM) and the nitric oxide synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME; 1-100 µM), reduced spinal NMDA receptor-mediated transmission. Ketamine also depressed non-NMDA receptor-mediated transmission. Using isobolographic and composite additive line analyses, fixed-ratio combinations of ketamine and ketoprofen, ketamine and L-NAME, and ketopofen and L-NAME synergistically depressed NMDA receptor-mediated transmission. The two former combinations had a subadditive effect on non-NMDA receptor-mediated transmission, and the latter had no significant effect. These studies identified that all combinations synergistically reduced both nociceptive transmission and potential side effects. In free-moving sheep implanted with indwelling cervical intrathecal catheters, 100 µ1 subdural administration of ketamine (25-400 µM) and ketoprofen (200-3200 µM) alone and in a fixed-ratio combination (873.95-3350.78 µM, 0.045:0.955) did not raise nociceptive thresholds as assessed by mechanical stimulation of one foreleg. Subdural administration of NMDA (2 mM) decreased mechanical nociceptive thresholds, and this was prevented by the highest concentrations of ketamine and ketoprofen alone and in combination. These findings demonstrated that NMDA receptor channel blockers and NSAIDs alone or in combination had no direct hypoalgesic effects when given onto the spinal cord of sheep, but they prevented NMDA-induced pain hypersensitivity. Simultaneous blockade of NMDA receptor systems could have important clinical implications.