Molecular pharmacological profile of a novel thiazolinone-based direct and selective 5-lipoxygenase inhibitor.

BACKGROUND AND PURPOSE: The potency of many 5-lipoxygenase (5-LOX) inhibitors depends on the cellular peroxide tone and the mechanism of 5-LOX enzyme activation. Therefore, new inhibitors that act regardless of the mode of enzyme activation need to be developed. Recently, we identified a novel class of thiazolinone-based compounds as potent 5-LOX inhibitors. Here, we present the molecular pharmacological profile of (Z)-5-(4-methoxybenzylidene)-2-(p-tolyl)-5H-thiazol-4-one, compound C06. EXPERIMENTAL APPROACH: Inhibition of 5-LOX product formation was determined in intact cells [polymorphonuclear leukocytes (PMNL), rat basophilic leukaemia-1, RAW264.7] and in cell-free assays [homogenates, 100, 000×g supernatant (S100), partially purified 5-LOX] applying different stimuli for 5-LOX activation. Inhibition of peroxisome proliferator-activated receptor (PPAR), cytosolic phospholipase A(2) (cPLA(2) ), 12-LOX, 15-LOX-1 and 15-LOX-2 as well as cyclooxygenase-2 (COX-2) were measured in vitro. KEY RESULTS: C06 induced non-cytotoxic, direct 5-LOX inhibition with IC(50) values about 0.66 µM (intact PMNL, PMNL homogenates) and approximately 0.3 µM (cell-free PMNL S100, partially purified 5-LOX). Action of C06 was independent of the stimulus used for 5-LOX activation and cellular redox tone and was selective for 5-LOX compared with other arachidonic acid binding proteins (PPAR, cPLA(2) , 12-LOX, 15-LOX-1, 15-LOX-2, COX-2). Experimental results suggest an allosteric binding distinct from the active site and the C2-like domain of 5-LOX. CONCLUSIONS AND IMPLICATIONS: C06 was identified as a potent selective direct 5-LOX inhibitor exhibiting a novel and unique mode of action, different from other established 5-LOX inhibitors. This thiazolinone may possess potential for intervention with inflammatory and allergic diseases and certain types of cancer.

Screening of herbal extracts for activation of the human peroxisome proliferator-activated receptor.

The peroxisome proliferator-activated receptors play a pivotal role in metazoan lipid and glucose homeostasis. Synthetic activators of PPARalpha (fibrates) and PPARgamma (glitazones) are therefore widely used for treatment of dislipidemia and diabetes, respectively. There is growing evidence for herbal compounds to influence nuclear receptor signalling e.g. the PPARs. We recently reported carnosic acid and carnosol, both being diterpenes found in the labiate herbs sage and rosemary, to be activators of PPARgamma. The subsequent screening of a variety of ethanolic extracts, obtained from traditionally used herbs, for PPAR activation, led to an exceptionally high hit rate. Among 52 extracts nearly the half significantly activated PPARgamma and 14 activated PPARalpha in addition, whereas three of them were pan-PPAR activators, which also activated PPARdelta. The most active extracts, for which a concentration dependent effect could be shown, were the extracts of Alisma plantago aquatica (ze xie/european waterplantain), Catharanthus roseus (madagascar periwinkle), Acorus calamus (sweet calamus), Euphorbia balsamifera (balsam spurge), Jatropha curcas (barbados nut), Origanum majorana (marjoram), Zea mays (corn silk), Capsicum frutescens (chilli) and Urtica dioica (stinging nettle). The results of the present study provide a possible rationale for the traditional use of many herbs as antidiabetics.

[Idiopathic retroperitoneal fibrosis (Ormond's disease)]. / Die idiopathische retroperitoneale Fibrose (Morbus Ormond).

INTRODUCTION: Idiopathic retroperitoneal fibrosis (RPF) represents a rare inflammatory disease, which leads to extensive fibrosis of the retroperitoneal space. In the course of the progressive fibrosis, fibrous tissue compresses the retroperitoneal structures with the development of consecutive ureteral obstruction. Because of the unknown aetiology, no consensus between conservative and surgical treatment exists. CASE REPORT: A 60-year-old patient was admitted to hospital with left-sided flank pain, hydronephrosis, and retroperitoneal tumour. A CT scan-guided biopsy revealed RPF. The hydronephrosis was treated by endoluminal urinary diversion. Under simultaneous administration of steroids, an almost complete regression of the RPF was noted. CONCLUSIONS: First goal in the treatment of RPF is urinary diversion to protect the renal function. A simultaneous therapy with steroids can cause a complete regression of the RPF. Surgical intervention is only recommended in refractory cases.

[Correction of endotoxicosis in alcoholic pancreatitis in elderly and senile patients using discrete plasmapheresis].

The majority of critical conditions in man occur in diseases accompanied with development of endogenic intoxication syndrome. The search for universal criterion and design of highly effective programs for correction of this condition are of great importance for internal medicine and surgical practice. Discrete plasmapheresis for endotoxicosis in elderly and gerontological patients has its specific features which should be taken into consideration because of low adaptation abilities of such group of patients.

[V.A.C. (Vacuum Assisted Closure) therapy as a treatment option in complications following lymphadenectomy in patients with penile cancer]. / Die V.A.C. (Vacuum Assisted Closure) Therapie als Behandlungsalternative bei Komplikationen nach Durchführung einer Lymphadenektomie bei fortgeschrittenen Peniskarzinomen.

INTRODUCTION: Penile cancer is a rare tumor entity. Primary therapy consists of tumor excision (laser therapy, circumcision, partial or complete penectomy). Therapy of advanced or metastasized penile cancer is still challenging due to high morbidity with postoperative lymph edema, fistula, wound infection and resulting secondary wound healing. METHODS: In this series we retrospectively investigated clinical and diagnostic data from 28 patients (1995-2005) with penile cancer regarding their follow-up, especially in respect to morbidity after lymphadenectomy and the resulting therapy. We evaluated the efficacy of V.A.C. therapy as an alternative in this setting regarding costs and duration of hospital stay. RESULTS: 11/28 pats. underwent lymphadenectomy (LA) because of tumor stage or suspicious lymph node status. Eight of those pats. developed complications, as there were: lymph edema, and/or secondary wound healing with fistula. 4/8 pats. were treated with V.A.C. therapy. In this group a significant advantage regarding cost and time of hospitalization was observed. DISCUSSION: Despite higher primary introduction costs an early V.A.C. therapy in patients with secondary wound healing and lymph obstruction is advisable and resulted in a shortened hospitalization and reduced overall costs per patient.

Identification of aromatic dihydroxy acids in biological fluids.

3,5-Dihydroxyphenylpropionic acid, 3,5-dihydroxycinnamic acid and 2,3-dihydroxycinnamic acid were detected for the first time to be components of human urine. In the course of this investigation all constitutional isomers of dihydroxy-benzoic, -phenylpropionic, -phenylacetic and -cinnamic acid were synthesized. Mass spectra and retention indices of methyl and trimethylsilyl (TMS) derivatives were determined. In contrast to many other substituted aromatic compounds the mass spectra of methyl and TMS derivatives of dihydroxy aromatic acids often allow a firm distinction to be made between constitutional isomers: TMS derivatives of aromatic acids containing two hydroxy groups located in the ortho position to each other can be recognized by ions resulting from a primary cleavage reaction mainly in the side chain or ester group, followed by loss of tetramethylsilane. In methyl derivatives of 1,2,3-trisubstituted isomers, methoxy groups are lost much more easily from the ions corresponding to the benzylic cleavage than in other isomers. Methyl derivatives of dihydroxycinnamic acids containing at least one methoxy group in the ortho position to the side chain are characterized by a fragmentation reaction, corresponding to the loss of dimethyl ether. TMS and methyl derivatives of 3,5-dihydroxy aromatic acids show unique structure-specific fragmentation reactions.