Pharmacological characterization of 3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (AM103), a novel selective 5-lipoxygenase-activating protein inhibitor that reduces acute and chronic inflammation.

Leukotrienes (LTs) are proinflammatory lipid mediators synthesized by the conversion of arachidonic acid (AA) to LTA(4) by the enzyme 5-lipoxygenase (5-LO) in the presence of 5-LO-activating protein (FLAP). 3-[3-tert-Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (AM103) is a novel selective FLAP inhibitor in development for the treatment of respiratory conditions such as asthma. In a rat ex vivo whole-blood calcium ionophore-induced LTB(4) assay, AM103 (administered orally at 1 mg/kg) displayed >50% inhibition for up to 6 h with a calculated EC(50) of approximately 60 nM. When rat lung was challenged in vivo with calcium ionophore, AM103 inhibited LTB(4) and cysteinyl leukotriene (CysLT) production with ED(50) values of 0.8 and 1 mg/kg, respectively. In this model, the EC(50) derived from plasma AM103 was approximately 330 nM for inhibition of both LTB(4) and CysLT. In an acute inflammation setting, AM103 displayed dose-dependent inhibition of LTB(4), CysLT, and plasma protein extravasation induced by peritoneal zymosan injection. In a model of chronic lung inflammation using ovalbumin-primed and challenged BALB/c mice, AM103 reduced the concentrations of eosinophil peroxidase, CysLTs, and interleukin-5 in the bronchoalveolar lavage fluid. Finally, AM103 increased survival time in mice exposed to a lethal intravenous injection of platelet-activating factor. In summary, AM103 is a novel, potent and selective FLAP inhibitor that has excellent pharmacodynamic properties in vivo and is effective in animal models of acute and chronic inflammation and in a model of lethal shock.

Treatment of anthracycline extravasation with Savene (dexrazoxane): results from two prospective clinical multicentre studies.

BACKGROUND: The purpose of this study was to assess the efficacy and tolerability of i.v. dexrazoxane [Savene (EU), Totect (US)] as acute antidote in biopsy-verified anthracycline extravasation. PATIENTS AND METHODS: Two prospective, open-label, single-arm, multicentre studies in patients with anthracycline extravasation were carried out. Patients with fluorescence-positive tissue biopsies were treated with a 3-day schedule of i.v. dexrazoxane (1000, 1000, and 500 mg/m(2)) starting no later than 6 h after the incident. Patients were assessed for efficacy (the possible need for surgical resection) and toxicity during the treatment period and regularly for the next 3 months. RESULTS: In 53 of 54 (98.2%) patients assessable for efficacy, the treatment prevented surgery-requiring necrosis. One patient (1.8%) required surgical debridement. Thirty-eight patients (71%) were able to continue their scheduled chemotherapy without postponement. Twenty-two patients (41%) experienced hospitalisation due to the extravasation. Mild pain (10 patients; 19%) and mild sensory disturbances (nine patients; 17%) were the most frequent sequelae. Haematologic toxicity was common as expected from the fact that the extravasation occurred during a chemotherapy course. Other toxic effects were transient elevation of alanine aminotransferases, nausea, and local pain at the dexrazoxane injection site. CONCLUSION: Dexrazoxane proved to be an effective and well-tolerated acute treatment with only one out of 54 assessable patients requiring surgical resection (1.8%).

The effect of a novel, dual function histamine H1 receptor antagonist/5-lipoxygenase enzyme inhibitor on in vivo dermal inflammation and extravasation.

Leukotrienes and histamine are thought to play important roles in the development of dermatitis. This study evaluated the in vivo efficacy of 5-{4-[(aminocarbonyl)(hydroxy)amino]but-1-ynyl}-2-(2-{4-[(R)-(4-chlorophenyl)(phenyl)methyl]piperazin-1-yl}ethoxy)benzamide (ucb 35440), a dual function histamine H1 receptor antagonist/5-lipoxygenase enzyme inhibitor, in mouse skin. A single application of phorbol 12-myristate 13-acetate (PMA) was used to induce an acute inflammatory response over a 6-h period. PMA was applied on days 0, 2, 4, 7 and 9 to generate a chronic inflammatory response measured on day 10. ucb 35440 was applied topically at 1 h pre-PMA challenge and 3 h post-PMA challenge in the acute model. In the chronic PMA model, ucb 35440 was applied topically twice a day (AM and PM) on days 7, 8 and 9. Dose-response studies revealed that ucb 35440 inhibited PMA-induced ear weight gain with a 57% inhibition measured using a 3% w/v topical solution in the acute model. The compound appeared less potent in the chronic model with 43% inhibition measured using a 3% w/v topical solution of ucb 35440. Qualitative histologic assessment in PMA challenged ears showed that ucb 35440 produced a moderate reduction of polymorphonuclear cell infiltration in the acute model whereas, a more substantial reduction in polymorphonuclear infiltration was noted in the chronic model. In addition, the oral efficacy of ucb 35440 was evaluated in vivo against histamine-induced extravasation in guinea pig skin. Single oral doses of ucb 35440 (10 mg/kg in 0.5% methylcellulose suspension) at 1, 2, 6 or 24 h pre-histamine challenge produced minimal inhibition of histamine-induced extravasation in the dermis. However, when ucb 35440 (10 mg/kg in a 0.5% methylcellulose suspension) was orally administered 24 and 2 h prior to dermal histamine challenge, significant inhibition of extravasation was observed. Similar inhibition of histamine-induced extravasation was observed when animals were orally dosed twice a day (AM and PM 10 mg/kg in a 0.5% methylcellulose suspension) for 5.5 days prior to dermal histamine challenge. Collectively, these results suggest that ucb 35440 may represent an important therapeutic class for the treatment of dermatologic inflammatory conditions.

Enzymatic digestion of the urethra after pancreatic transplantation: a case report.

The most common method of exocrine drainage in pancreatic transplantation is urinary drainage. With the shift from enteric drainage and duct occlusion techniques, there has been a concomitant shift from intraabdominal to urological complications. We present a case in which a simultaneous pancreas-kidney (SPK) transplant recipient developed urethral disruption and associated bladder outlet obstruction 11 months following surgery.

Neurogenic plasma extravasation in the rat nasal mucosa is potentiated by peptidase inhibitors.

The increase in vascular permeability associated with neurogenic inflammation in the nasal mucosa is mediated by neuropeptides such as substance P released from sensory nerves. Substance P is degraded by the peptidases neutral endopeptidase-24.11 (NEP-24.11) and angiotensin converting enzyme (ACE). In the present study, we used capsaicin to produce neurogenic inflammation in the nasal mucosa of rats, and we examined the effect of inhibition of NEP-24.11 by phosphoramidon, inhibition of ACE by captopril or inhibition of both enzymes by giving both inhibitors. Using as tracers intravenous Evans blue dye to quantify the extravasation and Monastral blue pigment to localize the sites of leakage, we examined the magnitude and distribution of capsaicin-induced plasma extravasation in the nasoturbinates, maxilloturbinates, ethmoidal turbinates and septum. Capsaicin caused a dose-dependent increase in Evans blue extravasation in the naso- and maxilloturbinates but had only a slight effect in the septum. The leaky blood vessels responsible for this plasma extravasation, as manifested by Monastral blue labeling, were most numerous in the naso- and maxilloturbinates, particularly near the front and free borders. After phosphoramidon, the leakage of Monastral blue was more widespread and extended in a more caudal direction. The response to capsaicin was augmented by phosphoramidon alone but not by captopril alone. However, in the presence of phosphoramidon, captopril further augmented the capsaicin-induced extravasation. We conclude that neurogenic inflammation in the rat nasal mucosa is greatest in the naso- and maxilloturbinates and can be modulated by NEP-24.11 and, to a lesser extent, by ACE.