Of the panel of NSAIDs tested, lornoxicam was found to be the most potent balanced inhibitor of human COX-1/-2. The equipotent COX-isoenzyme inhibition by lornoxicam is complemented by a marked inhibition of IL-6 production and of iNOS-derived NO formation. The in vitro activities described support the marked anti-inflammatory and analgesic activities of lornoxicam found in animal models as well as in clinical studies.

HN-56249 (3-(2,4-dichlorothiophenoxy)-4-methylsulfonylamino-benzenesu lfonamide), a highly selective cyclooxygenase (COX)-2 inhibitor, is the prototype of a novel series of COX inhibitors comprising bicyclic arylethersulfonamides; of this series HN-56249 is the most potent and selective human COX-2 inhibitor. HN-56249 inhibited platelet aggregation as a measure of COX-1 activity only moderately (IC50 26.5+/-1.7 microM). In LPS-stimulated monocytic cells the release of prostaglandin (PG) F1alpha as a measure of COX-2 was markedly inhibited (IC50 0.027+/-0.001 microM). Thus, HN-56249 showed an approximately 1000-fold selectivity for COX-2 in intact cells. In whole blood assays HN-56249 showed a potent inhibitory activity for COX-2 (IC50 0.78+/-0.37 microM) only. COX-1 was only weakly inhibited (IC50 867+/-181 microM). Hence, HN-56249 exhibited a greater than 1000-fold selectivity for whole blood COX-2. HN-56249 surpassed the COX-2 selectivities of the COX-2 selective inhibitors 3-cyclohexyloxy-4-methylsulfonylamino-nitrobenzene (NS-398) and 6-(2,4-difluorophenoxy)-5-methyl-sulfonylamino-1-indanone (flosulide) in the intact cell assays by eight- and threefold, respectively, and in the whole blood assays by approximately 40-fold. Following i.v. administration HN-56249 inhibited carrageenan-induced rat paw oedema only moderately (ID50 26.2+/-5.7 mg/kg, mean +/- SEM), approximately tenfold less potent than indomethacin (ID50 2.1+/-0.2 mg/kg, mean +/- SEM). After oral administration HN-56249 reversed thermal hyperalgesia in the carrageenan-induced rat paw oedema test, however, some 30-fold less potently than diclofenac. Comparing the inhibitory potency of HN-56249 against human COX-2 with that against murine COX-2 in intact cells revealed a 300-fold selectivity for the human enzyme. Similar effects were observed with other COX-2-selective arylethersulfonamides. In contrast, non-COX-2-selective arylethersulfonamides, including a highly selective COX-1 inhibitor, inhibited human and murine COX-2 approximately equipotently. In conclusion, HN-56249 is a novel potent and highly selective COX-2 inhibitor with a marked preference for the human COX-2 enzyme in vitro. Despite excellent bioavailability and the long plasma half-life of HN-56249, anti-inflammatory effects in rodents were only moderate. We suggest these differing in vitro-in vivo effects observed could be due to significant inflammatory prostaglandin synthesis by COX-1, or to the genetic differences between human and rodent COX-2, or to both.

Plasma cortisol was measured by a protein binding technique in 81 patients with malignant tumors of different extent and various sites and in 82 patients with benign surgical diseases. The mean value of the tumor patients (x +/- s = 165 +/- 69 micrograms cortisol/l plasma) was increased significantly compared with the benign surgical disorders (100 +/- 45 micrograms/l). Within the group of patients with benign surgical disorders there was little variation by the type of disease (cortisol mean values given in brackets): benign breast tumors (95), gall stones (107), ulcer of the stomach and duodenum (96), hernia (78), appendicitis acuta (112), and struma (90). The results are in accordance with the hypothesis that glucocorticoids are involved in the increased protein catabolism of skeletal muscles and other signs of cachectic tumor patients.

Linotroban (CAS 141443-73-4), a potent and selective thromboxane (TXA2) receptor antagonist, is known as a novel antithrombotic agent. It is suggested that pharmacological inhibition of TXA2 synthesis or action merits continued evaluation in the treatment of a variety of renal diseases. The aim of this study was the determination of efficacy of this new TXA2 receptor antagonist by assessing its effect on the reduction in inulin and para-aminohippuric acid (PAH) clearances induced by the TX/prostaglandin endoperoxide mimetic U-46619 in the conscious female rats. The following doses (3, 10, 30 mg/kg/24 h) of linotroban mixed with 720 micrograms TX-mimetic U-46619/kg/24 h were administered via osmotic pumps at a delivery rate of 10 microliters/h, implanted s.c. during 72 h. Rats of the U-46619 group were administered 720 micrograms U-46619/kg/24 h alone as described above, controls received 3.5% NaHCO3, respectively. Inulin/PAH clearances were determined at the end of the 4-h clearance period (68 h-72 h). Summarizing the data, glomerular filtration rate (GFR) and PAH clearances were reduced significantly by U-46619. When linotroban (3, 10 or 30 mg/kg/24 h) was added to U-46619 the GFR and PAH clearance were reversed to values that showed no significant differences to the controls.

The antithrombotic effect of a thromboxane A₂ receptor antagonist (HN-11501:5-[2-(4-chlorophenylsulfonylamino)-ethyl]-2-thienyloxy-acetic acid) alone and in combination with other antithrombotic agents has been studied in an experimental thrombosis model in which laser lesions are used to induce a defined thrombosis in rat mesenteric venules. The thromboxane receptor antagonist showed a significant and dose-dependent antithrombotic effect if given orally. The strongest additive thrombosis-inhibiting effect was observed after oral administration of HN-11501 at a dose of 2.5 mg/kg together with an intravenous infusion of 1 µg/kg/h of a prostacyclin analogue (cicaprost). An additive antithrombotic effect was also observed after oral application of 2.5 mg/kg of HN-11501 and intravenous injection of 0.2 mg/kg of a low molecular weight heparin (Fraxiparine®). The combination of 2.5 mg/kg of HN-11501 orally with an intravenous injection of 0.1 mg/kg molsidomine also had a significant additive effect. No significant additive effect was observed when 2.5 mg/kg of HN-11501 and 10 mg/kg of acetylsalicylic acid were orally administered simultaneously.