Differences in metabolic and mitogenic signallingof insulin glargine and AspB10 human insulin in rats [corrected].

AIMS/HYPOTHESIS: In vitro, insulin glargine (A21Gly,B31Arg,B32Arg human insulin) has an insulin receptor (IR) profile similar to that of human insulin, but a slightly higher affinity for the IGF-1 receptor (IGF1R). AspB10 human insulin (AspB10), [corrected] the only insulin analogue with proven carcinogenic activity, has a greater affinity for IGF1R and IR, and a prolonged IR occupancy time. The pharmacological and signalling profile of therapeutic and suprapharmacological doses of glargine were analysed in different tissues of rats, and compared with human insulin and AspB10. METHODS: Male Wistar rats were injected s.c. with human insulin or insulin analogue at doses of 1 to 200 U/kg, and the effects on blood glucose and the phosphorylation status of IR, IGF1R, Akt and extracellular signal-regulated protein kinase 1/2 in muscle, fat, liver and heart samples were investigated. RESULTS: Glargine, AspB10 and human insulin lowered blood glucose, with the onset of action delayed with glargine. Glargine treatment resulted in phosphorylation levels of IR and Akt that were comparable with those achieved with human insulin, although delayed in time in some tissues. AspB10 treatment resulted in at least twofold higher phosphorylation levels and significantly longer duration of IR and Akt phosphorylation in most tissues. None of the insulin treatments resulted in detectable IGF1R phosphorylation in muscle or heart tissue, whereas intravenous injection of IGF-1 increased IGF1R phosphorylation. CONCLUSIONS/INTERPRETATION: The IR signalling pattern of AspB10 in vivo is distinctly different from that of human insulin and insulin glargine, and might challenge the notion that activation of IGF1R plays a role in the observed carcinogenic effect of AspB10.

Feasibility and effectiveness of a multidimensional post-discharge disease management programme for heart failure patients in clinical practice: the HerzMobil Tirol programme.

AIMS: It remains unclear whether transitional care management outside of a clinical trial setting provides benefits for patients with acute heart failure (AHF) after hospitalization. We evaluated the feasibility and effectiveness of a multidimensional post-discharge disease management programme using a telemedical monitoring system incorporated in a comprehensive network of heart failure nurses, resident physicians, and secondary and tertiary referral centres (HerzMobil Tirol, HMT), METHODS AND RESULTS: The non-randomized study included 508 AHF patients that were managed in HMT (n = 251) or contemporaneously in usual care (UC, n = 257) after discharge from hospital from 2016 to 2019. Groups were retrospectively matched for age and sex. The primary endpoint was time to HF readmission and all-cause mortality within 6 months. Multivariable Cox proportional hazard models were used to assess the effectiveness. The primary endpoint occurred in 48 patients (19.1%) in HMT and 89 (34.6%) in UC. Compared with UC, management by HMT was associated with a 46%-reduction in the primary endpoint (adjusted HR 0.54; 95% CI 0.37-0.77; P < 0.001). Subgroup analyses revealed consistent effectiveness. The composite of recurrent HF hospitalization and death within 6 months per 100 patient-years was 64.2 in HMT and 108.2 in UC (adjusted HR 0.41; 95% CI 0.29-0.55; P < 0.001 with death considered as a competing risk). After 1 year, 25 (10%) patients died in HMT compared with 66 (25.7%) in UC (HR 0.38; 95% CI 0.23-0.61, P < 0.001). CONCLUSIONS: A multidimensional post-discharge disease management programme, comprising a telemedical monitoring system incorporated in a comprehensive network of specialized heart failure nurses and resident physicians, is feasible and effective in clinical practice.

Toll-like receptor expression and function in subsets of human gammadelta T lymphocytes.

Two subsets of human gammadelta T cells can be identified by T cell receptor (TCR) V gene usage. Vdelta2Vgamma9 T cells dominate in peripheral blood and recognize microbe- or tumour-derived phosphoantigens. Vdelta1 T cells are abundant in mucosal tissue and recognize stress-induced MHC-related molecules. Toll-like receptors (TLRs) are known to co-stimulate interferon-gamma (IFN-gamma) production in peripheral blood gammadelta T cells and in Vdelta2Vgamma9 T cell lines. By microarray analysis, we have identified a range of genes differentially regulated in freshly isolated gammadelta T cells by TCR versus TCR plus TLR3 stimulation. Furthermore, we have investigated TLR expression in freshly isolated Vdelta1 and Vdelta2 subsets and cytokine/chemokine production in response to TLR1/2/6, 3 and 5 ligands. TLR1,2,6,7 RNA was abundantly expressed in both subsets, whereas TLR3 RNA was present at low levels, and TLR5 and 8 RNA only marginally in both subsets. Despite abundant RNA expression, TLR1 was rarely detectable by flow cytometry. In contrast, TLR2 and TLR6 proteins were detected in purified Vdelta1 and Vdelta2 T cells, and TLR3 protein was detected intracellularly in both subsets. TLR1/2/6, 3 and 5 ligands co-stimulated the IFN-gamma and chemokine secretion in TCR-activated Vdelta1 and Vdelta2 subsets, although the levels of IFN-gamma secreted by Vdelta1 T cells were much lower than those produced by Vdelta2 T cells. Our results reveal comparable expression of TLRs and functional responses to TLR ligands in freshly isolated Vdelta1 and Vdelta2 T cells and underscore the intrinsically different capacity for IFN-gamma secretion of Vdelta1 versus Vdelta2 T cells.

Redistribution of glycolipid raft domain components induces insulin-mimetic signaling in rat adipocytes.

Caveolae and caveolin-containing detergent-insoluble glycolipid-enriched rafts (DIG) have been implicated to function as plasma membrane microcompartments or domains for the preassembly of signaling complexes, keeping them in the basal inactive state. So far, only limited in vivo evidence is available for the regulation of the interaction between caveolae-DIG and signaling components in response to extracellular stimuli. Here, we demonstrate that in isolated rat adipocytes, synthetic intracellular caveolin binding domain (CBD) peptide derived from caveolin-associated pp59(Lyn) (10 to 100 microM) or exogenous phosphoinositolglycan derived from glycosyl-phosphatidylinositol (GPI) membrane protein anchor (PIG; 1 to 10 microM) triggers the concentration-dependent release of caveolar components and the GPI-anchored protein Gce1, as well as the nonreceptor tyrosine kinases pp59(Lyn) and pp125(Fak), from interaction with caveolin (up to 45 to 85%). This dissociation, which parallels redistribution of the components from DIG to non-DIG areas of the adipocyte plasma membrane (up to 30 to 75%), is accompanied by tyrosine phosphorylation and activation of pp59(Lyn) and pp125(Fak) (up to 8- and 11-fold) but not of the insulin receptor. This correlates well to increased tyrosine phosphorylation of caveolin and the insulin receptor substrate protein 1 (up to 6- and 15-fold), as well as elevated phosphatidylinositol-3' kinase activity and glucose transport (to up to 7- and 13-fold). Insulin-mimetic signaling by both CBD peptide and PIG as well as redistribution induced by CBD peptide, but not by PIG, was blocked by synthetic intracellular caveolin scaffolding domain (CSD) peptide. These data suggest that in adipocytes a subset of signaling components is concentrated at caveolae-DIG via the interaction between their CBD and the CSD of caveolin. These inhibitory interactions are relieved by PIG. Thus, caveolae-DIG may operate as signalosomes for insulin-independent positive cross talk to metabolic insulin signaling downstream of the insulin receptor based on redistribution and accompanying activation of nonreceptor tyrosine kinases.

Evaluation of an Integrated Telemonitoring Surveillance System in Patients with Coronary Heart Disease.

OBJECTIVES: Cardiovascular diseases are the most frequent cause of death in industrialized countries. Non-adherence with prescribed medication and recommended lifestyle changes significantly increases the risk of major cardiovascular events. The telemonitoring programme MyCor (Myokardinfarkt und Koronarstent Programm in Tirol) is a multi-modal intervention programme to improve lifestyle and medication management of patients with coronary heart disease (CHD). It includes patient education, self-monitoring with goal-setting and feedback, and regular clinical visits. We evaluated the MyCor telemonitoring programme regarding technical feasibility, user acceptance, patient adherence, change in health status, and change in quality of life. METHODS: A 4½-month study was conducted with two telemonitoring phases and one interim phase. The study comprised patient surveys, standardized assessment of quality of life using the MacNew questionnaire at study entry and after 4 and 18 weeks, analysis of adherence to medication and physical activity during the two telemonitoring phases, and analysis of reached goals regarding health conditions during the telemonitoring phases. RESULTS: Twenty-five patients (mean age: 63 years) participated in the study. Patients showed a high acceptance of the MyCor telemonitoring programme. Patients reported feelings of self-control, motivation for lifestyle changes, and improved quality of life. Adherence to daily measurements was high with 86% and 77% in the two telemonitoring phases. Adherence to medication was also high with up to 87% and 80%. Pre-defined goals for physical activity were reached in up to 86% and 73% of days, respectively. Quality of life improved from 5.5 at study entry to 6.3 at the end (p< 0.01; MacNew questionnaire). Reductions in blood pressure and heart rate or an improvement in reaching defined goals could not be observed. CONCLUSIONS: The MyCor telemonitoring programme Tirol for CHD patients has a high rate of acceptance among included patients. Critical evaluation revealed subjective benefits regarding quality of life and health status as well as high adherence rates to medication and lifestyle changes. Achieving long-term adherence and verifying clinical outcomes, however, remains an open issue. Our findings will promote further studies, addressing different strategies for an optimal mix of patient education, telemonitoring, feedback, and clinical follow-ups.

Evaluation of chronic oral toxicity and carcinogenic potential of lornoxicam in rats.

As part of the preclinical development program for lornoxicam, a novel non-steroidal anti-inflammatory drug (NSAID), its chronic oral toxicity and carcinogenic potential was assessed in Sprague-Dawley rats. Male and female rats were administered lornoxicam by oral gavage at 0, 0.06, 0.16 or 0.40 mg/kg/day for 12 months or at 0, 0.01 or 0.06 mg/kg/day in a supplementary low-dose study of the same duration (main group: 20/sex/group; 4-wk recovery: five/sex/group; satellites for electrocardiography and toxicokinetics: five/sex/group). Drug-related toxicity mainly comprised mortality, reduced body weight gain, clinico-pathological changes indicative of anaemia resulting from blood loss, and renal damage, renal papillary necrosis and gastrointestinal mucosal lesions. The kidney-associated changes were not completely reversible during the recovery period. Toxicokinetic investigations demonstrated a dose-linear absorption of the drug. In female rats the terminal half-life was about twice that in males which led to a higher exposure of this gender to lornoxicam. A dose of 0.01 mg/kg/day was established as no-observed-effect level. In a 104-wk carcinogenicity study, lornoxicam was administered by oral gavage to male and female rats (50/sex/group) at 0 (control 1), 0 (control 2), 0.0625, 0.125 or 0.250 mg/kg/day. In females only, the high dose was reduced twice during the study due to toxicity observed (0.250 to 0.200 to 0.160 mg/kg/day). Drug-related changes were similar to those in the chronic studies and consistent with the anticipated side-effects of NSAIDs. No carcinogenic potential was revealed.

Subacute and chronic oral toxicity of lornoxicam in cynomolgus monkeys.

Lornoxicam is a novel non-steroidal anti-inflammatory compound in the same chemical class as piroxicam and tenoxicam, with potent anti-inflammatory, antipyretic and analgesic activity. As part of the preclinical safety programme, its toxicity was evaluated in a dose-range-finding and 52-wk toxicity study in cynomolgus monkeys. In the dose-range-finding study, five groups of monkeys (two per sex per group) were dosed orally by gavage for 6 wk with 0, 0.25, 0.5, 1.0 or 2.0 mg lornoxicam/kg/day. Drug-related toxicity was observed in the 1.0 and 2.0 mg/kg/day dose groups only. This included mortality, diarrhoea, prostration, decreased body weight gain and food consumption, faecal occult blood, anaemia, leucocytosis, hypoalbuminaemia, gastrointestinal erosions and ulcerations. On the basis of these results, four groups of monkeys (six per sex per group) were given the compound orally by nasogastric intubation at dose levels of 0, 0.125, 0.25 or 0.5 mg/kg/day for 52 wk. The high-dose level was increased to 0.6 mg/kg/day from wk 39 to wk 52. Treatment was followed by a 4-wk recovery period for two animals per sex per group. Histologically, drug-related changes seen were gastrointestinal erosions, ulcerations and inflammation in males and females at 0.5/0.6 mg/kg/day. Treatment-related clinicopathological findings included decreased haematocrit and hypoproteinaemia (group 0.5/0.6 mg/kg/day males), and hypoalbuminaemia (group 0.5/0.6 mg/kg/day males and females). None of these changes were present after the recovery period, thus indicating reversibility. Plasma concentration of lornoxicam measured 2 hr after dosing increased in a dose proportional manner. The estimated area under the curve (AUC) at steady state increased in a dose-proportional manner and at 0.25 mg/kg was three- to fivefold higher than the human AUC following a 16 mg dose (8 mg b.i.d.). The no-observed-effect level in the chronic toxicity study was 0.25 mg/kg/day.

Absolute bioavailability, pharmacokinetics, renal and biliary clearance of distigmine after a single oral dose in comparison to i.v. administration of 14C-distigmine-bromide in healthy volunteers.

AIM: The aim of the study was to determine the absolute bioavailability and pharmacokinetics after a single dose oral administration in comparison to i.v. administration of 14C-labelled distigmine-bromide (14C-Ubretid) in healthy male volunteers. RESULTS: After the intravenous administration, distigmine is eliminated from the body by renal excretion (85%), and for a small fraction by biliary excretion in the feces (4%). This situation is reversed after an oral administration, where 6.5% of the dose is recovered from the urine and 88% from the feces. This means that distigmine after oral administration is hardly absorbed, the calculated bioavailability is 4.65%. CONCLUSION: The mean absorption time (MAT) after oral administration was 10 h, influencing the t(1/2alpha) (1.4 vs 4.5 h) and the t(1/2beta) (60 vs 70 h) to higher values than after the i.v. administration (p < 0.05).

Syngamiasis in juvenile American robins (Turdus migratorius), with a note on the prevalence of other fecal parasites.

Of 105 juvenile American robins (Turdus migratorius L.) examined for fecal parasites, 77.1% were infected with one or more species of endoparasite. Syngamus sp. was the most commonly encountered parasite, found in 57.1% of the birds. There was a significant association between the presence of Syngamus sp. eggs in feces and signs of respiratory-tract disease. A single oral dose of fenbendazole (100 mg/kg of body weight) eliminated Syngamus sp. infection from all of 18 birds treated, yet 10 of 16 untreated controls apparently were "self-cured" over the 12-day period of observation.

Eustrongylidiasis in eastern great blue herons (Ardea herodias).

The nematode Eustrongylides ignotus was found in peritoneal lesions of several great blue herons (Ardea herodias) submitted for necropsy from a wildlife rehabilitation center in northern Delaware. Prior to death, signs of disease included ataxia, emaciation, weakness, and anemia. Blood collection was not uniformly performed, but in cases where it was performed, affected birds demonstrated abnormal clinical hematology. Postmortem findings included numerous lesions associated with verminous peritonitis. Significant histologic granulomatous response to the presence of these organisms was noted, particularly in the proventricular specimens. Other organs involved included intestine, spleen, pancreas, and liver.

The effect of concomitantly administered antacids on the bioavailability of lornoxicam, a novel highly potent NSAID.

Antacids are used in the treatment of upper gastrointestinal side-effects during therapy with nonsteroidal anti-inflammatory drugs (NSAIDs). Since pharmacokinetic interactions between antacids and NSAIDs have been reported, it was investigated whether aluminium and magnesium hydroxide (Maalox as oral suspension) or aluminium hydroxide and calcium carbonate (Solugastril as oral gel) influenced the bioavailability of Lornoxicam (rINN), a new potent NSAID from the chemical group of the oxicams. Eighteen male volunteers were given 4 mg of Lornoxicam as a film-coated tablet either alone or together with 10 ml of Maalox or 10 g of Solugastril in an open, randomized, three-way cross-over study. The levels of Lornoxicam in plasma were determined by HPLC following solid-phase extraction. It was found that none of the antacids changed significantly any of the following pharmacokinetic parameters: elimination half-life (t1/2 beta), concentration at peak time (Cmax), time to reach the peak (tmax) and area under the curve to infinity (AUCo-infinity). The results indicate that the concomitant administration of antacids did not influence the pharmacokinetic profile of Lornoxicam. Furthermore they confirm the short elimination half-life of Lornoxicam in man, which is markedly shorter than that of other oxicam-type compounds.

Pharmacokinetics and metabolism of the proton pump inhibitor pantoprazole in man.

Pantoprazole, a second-generation proton pump inhibitor, is absorbed after oral administration as enteric-coated tablet with maximum plasma concentrations within 2-3 h and a bioavailability of 77%. Food has no relevant effect on absorption. The pharmacokinetics of pantoprazole are dose linear in the therapeutic range. The parent drug is totally metabolized, mainly by the polymorphically expressed CYP2C19 and by CYP3A. The pharmacokinetic profile is practically unchanged after multiple dosing, as is expected for a drug with a short half-life of about 1 h. A lack of pharmacokinetic interactions with various drugs has been shown. No clinically relevant changes in the pharmacokinetics of pantoprazole are observed in elderly subjects and patients with severe renal insufficiency. However, clearance is decreased in poor metabolizers of (S)-mephenytoin and in patients with liver cirrhosis.

Lornoxicam, a new potent NSAID with an improved tolerability profile.

Lornoxicam is a member of the oxicam group of nonsteroidal antiinflammatory drugs (NSAIDs). Oxicams have potent antiinflammatory and analgesic effects, but their use is associated with a high risk of gastrointestinal adverse effects. Lornoxicam has been shown to be at least as effective as comparative NSAIDs and more effective than 10 mg morphine when used at doses > or = 8 mg to control pain after oral surgery. In addition, oral doses of lornoxicam of 16-24 mg daily have been more effective than tramadol 300 mg daily in pain following knee surgery. Lornoxicam combines the high therapeutic potency of oxicams with an improved gastrointestinal toxicity profile as compared to naproxen, for example. This is probably due to the short half-life of lornoxicam as compared to the other oxicams. The clinical trials published so far, mostly comparative, clearly do- cument the efficacy of lornoxicam as a potent analgesic with excellent antiinflammatory properties in a range of painful and/or inflammatory conditions, including postoperative pain and rheumatoid arthritis.

Determination of the novel non-steroidal anti-inflammatory drug lornoxicam and its main metabolite in plasma and synovial fluid.

A rapid and sensitive HPLC method for the determination of the non-steroidal anti-inflammatory drug lornoxicam in plasma samples of humans and laboratory animals is described. After addition of the internal standard (tenoxicam) the plasma sample is acidified and extracted either by dichloromethane via Extrelut columns or by solid-phase extraction using C18 columns. After evaporation of the solvent the separation is performed on a C18 column in isocratic mode with a mobile phase consisting of 0.1 M phosphate buffer (pH 6.0)-methanol and detection at 372 nm. The limit of determination was set to 10 ng/ml using 0.5 ml of sample but can be extended down to 2.0 ng/ml plasma. Using solid-phase extraction with C18 columns both lornoxicam and its main metabolite 5'-hydroxylornoxicam can be determined while extraction via Extrelut was used in studies where only lornoxicam was to be determined. This method was used successfully in several thousand samples of pharmacokinetic and bioavailability studies in animals and in humans.

Insulin-mimetic signaling by the sulfonylurea glimepiride and phosphoinositolglycans involves distinct mechanisms for redistribution of lipid raft components.

The insulin signal transduction cascade provides a number of sites downstream of the insulin receptor (IR) for cross-talk from other signaling pathways. Tyrosine phosphorylation of the IR substrates IRS-1/2 and metabolic insulin-mimetic activity in insulin-responsive cells can be provoked by soluble phosphoinositolglycans (PIG), which trigger redistribution from detergent-insoluble glycolipid-enriched raft domains (DIGs) to other areas of the plasma membrane and thereby activation of nonreceptor tyrosine kinases (NRTK) [Müller, G., Jung, C., Wied, S., Welte, S., Jordan, H., and Frick, W. (2001) Mol. Cell. Biol. 21, 4553-4567]. Here we describe that stimulation of glucose transport in isolated rat adipocytes by a different stimulus, the sulfonylurea glimepiride, is also based on IRS-1/2 tyrosine phosphorylation and downstream insulin-mimetic signaling involving activation of the NRTK, pp59(Lyn), and pp125(Fak), as well as tyrosine phosphoryation of the DIGs component caveolin. As is the case for PIG 41, glimepiride causes the concentration-dependent dissociation of pp59(Lyn) from caveolin and release of this NRTK and the glycosyl-phosphatidylinositol-anchored (GPI) proteins, Gce1 and 5'-nucleotidase, from total and anti-caveolin-immunoisolated DIGs. This results in their movement to detergent-insoluble raft domains of higher buoyant density (non-DIGs areas). IRS-1/2 tyrosine phosphorylation and glucose transport activation by both glimepiride and PIG are blocked by introduction into adipocytes of the caveolin scaffolding domain peptide which mimicks the negative effect of caveolin on pp59(Lyn) activity. Tyrosine phosphorylation of the NRTK, IRS-1/2, and caveolin as well as release of the NRTK and GPI proteins from DIGs and their redistribution into non-DIGs areas in response to PIG is also inhibited by treatment of intact adipocytes with either trypsin plus salt or N-ethylmaleimide (NEM). In contrast, the putative trypsin/salt/NEM-sensitive cell surface component (CIR) is not required for glimepiride-induced glucose transport, IRS-1/2 tyrosine phosphorylation, and redistribution of GPI proteins and NRTK. The data suggest that CIR is involved in concentrating signaling molecules at DIGs vs detergent-insoluble non-DIGs areas. These inhibitory interactions are relieved in response to putative physiological (PIG) or pharmacological (sulfonylurea) stimuli via different molecular mechanisms (dependent on or independent of CIR, respectively) thereby inducing IR-independent positive cross-talk to metabolic insulin signaling.

[The bioavailability of midodrin and alpha-2,5-dimethoxyphenyl-beta-aminoethanol hydrochloride]. / Untersuchungen zur Bioverfügbarkeit von Midodrin und alpha-2,5-Dimethoxyphenyl-beta-aminoethanol-hydrochlorid.

The pharmacokinetics of midodrin (alpha-2,5-dimethoxyphenyl-beta-glycinamidoethanol hydrochloride, ST 1085) and its main metabolite ST 1059 (alpha-2,5-dimethoxyphenyl-beta-aminoethanol hydrochloride) have been investigated in 12 male healthy volunteers. 2.5 mg midodrin hydrochloride were applied intravenously, as drinking solution or as tablet (Gutron) according to a randomized cross-over design. Plasma and urine samples collected up to 24 h after application were analyzed by high-performance liquid chromatography with fluorescence detection. The mean maximum concentration in plasma for midodrin was ca. 10 ng/ml 20-30 min after oral administration, for ST 1059 ca. 5 ng/ml after 1 h. Midodrin was eliminated with a terminal half-life of 0.5 h. The half-life of ST 1059 was determined to be 3 h. The mean area under the plasma-level vs. time curve (AUC) of ST 1059 after administration of 2.5 mg midodrin i.v. was 28.7 ng X h/ml, and as drinking solution or as tablet 25.7 and 25.6 ng X h/ml, respectively. The data of 10 volunteers could be used for the calculations of the bioavailability of ST 1059 by the AUC. Assuming an interval of equivalence of 0.75-1.25 because of the relatively small number of volunteers, the three galenical formulations are considered to be equivalent.

Pharmacokinetics of lornoxicam in man.

Clinical phase I pharmacokinetic studies with lornoxicam were performed with the 4 mg dose of lornoxicam. Lornoxicam was administered as an aqueous solution both orally and intravenously to young, healthy, male volunteers. The total excretion of lornoxicam via urine and faeces after oral administration was determined by administering 14C-labelled compound. The results show that the parent compound and the main metabolite, 5'-hydroxy-lornoxicam, were found in plasma. However, in urine, no lornoxicam was detected, only 5'-hydroxy-lornoxicam. After oral as well as intravenous administration, a short terminal half-life of lornoxicam in the range of 4-5 hours was found. Given orally as solution, lornoxicam was rapidly and almost completely absorbed.

Overview of the pharmacological properties, pharmacokinetics and animal safety assessment of lornoxicam.

Lornoxicam is a new, highly potent antirheumatic agent which is an oxicam derivative. Although highly potent as a cyclo-oxygenase inhibitor, the compound does not cause inhibition of 5-lipoxygenase and does not appear to shunt arachidonic acid through this cascade. This powerful inhibition of cyclo-oxygenase has manifested itself as highly potent analgesic and anti-inflammatory effects in animal studies and also prevented the bone destruction which normally occurs in the adjuvant polyarthritic rat. To explain this finding, studies have demonstrated that lornoxicam inhibits polymorphonuclear (PMN)-leukocyte migration; inhibits the release of superoxide from human PMN-leukocytes; inhibits the release of platelet derived growth factor (PDGF) from human platelets and stimulates the synthesis of proteoglycans in cartilage in tissue culture. Lornoxicam is well absorbed and has a plasma t1/2 in man of 4 hours which is distinctly different from other oxicams. It is metabolized in animals and in man to the 5'-hydroxy-metabolite which is inactive in pharmacological tests. In vitro and in vivo animal safety studies have demonstrated both subchronically and chronically that lornoxicam manifests no unusual toxicity, is not a mutagen nor is it tumorigenic and causes no fetal teratogenicity in reproduction studies.