GLC and NMR analysis of isomeric impurities in the new anti-inflammatory agent benoxaprofen

GLC and NMR methods are described for the determination of four possible isomeric impurities in the novel anti-inflammatory agent benoxaprofen. The 2- and 3-chlorophenyl isomers were determined by GLC after alkaline hydrolysis and subsequent methylation. A rapid NMR procedure, using the lanthanide shift reagent tris- (1, 1, 1, 2, 2, 3, 3-heptafluoro- 7, 7-dimethyl- 4, 6-octanedionato)-europium, was developed for the 6- and 7- (alpha-methylacetic acid) isomers. Similar methodolology, with tris-(3-heptafluorobutyryl-d-camphorato)europium, enabled the determination of the enantiomer ratio for benoxaprofen. For the positional isomers, the limits of detection were 0.05% by GLC and 0.2% by NMR.     

Selected treatment strategies for septic shock based on proposed mechanisms of pathogenesis

PURPOSE: To review selected new therapies for septic shock designed to inhibit bacterial toxins or endogenous mediators of inflammation. DATA SOURCES: Scientific journals, scientific meeting proceedings, and Food and Drug Administration advisory committee proceedings. STUDY SELECTION AND EXTRACTION: Preclinical and clinical data from trials using core-directed antiendotoxin antibodies and anticytokine therapies for sepsis and studies in animal models of sepsis from our laboratory. RESULTS OF DATA SYNTHESIS: Ten clinical trials using core-directed antiendotoxin antibodies produced inconsistent results and did not conclusively establish the safety or benefit of this approach. Both anti-interleukin-1 and anti-tumor necrosis factor (TNF) therapies have been beneficial in some animal models of sepsis but did not clearly improve survival in initial human trials, and one anti-TNF therapy actually produced harm. Neutrophils, another target for therapeutic intervention, protect the host from infection but may also contribute to the development of tissue injury during sepsis. In a canine model of septic shock, granulocyte colony-stimulating factor increased the number of circulating neutrophils and improved survival, but an anti-integrin (CD11/18) antibody that inhibits neutrophil function worsened outcome. Nitric oxide, a vasodilator produced by the host, causes hypotension during septic shock but may also protect the endothelium and maintain organ blood flow. In dogs challenged with endotoxin, the inhibition of nitric oxide production decreased cardiac index and did not improve survival. CONCLUSIONS: No new therapy for sepsis has shown clinical efficacy. Perhaps more accurate clinical and laboratory predictors are needed to identify patients who may benefit from a given treatment strategy. On the other hand, the therapeutic premises may be flawed. Targeting a single microbial toxin such as endotoxin may not represent a viable strategy for treating a complex inflammatory response to diverse gram-negative bacteria. Similarly, the strategy of inhibiting the host inflammatory response may not be beneficial because immune cells and cytokines play both pathogenic and protective roles. Finally, our scientific knowledge of the complex timing of mediator release and balance during sepsis may be insufficient to develop successful therapeutic interventions for this syndrome.     

Long term follow-up of prophylactic caval clipping

120 high risk patients who underwent prophylactic inferior vena cava clipping were retrospectively evaluated to determine the incidence of post clipping leg swelling and pulmonary embolism. Each one of those patients had at least two criteria for the clipping. These criteria of high risk factors were precisely identified. There were two patients who had postoperative pulmonary embolism but none of them was fatal, i.e. less than two per cent. Two patients developed severe leg swelling (less than two per cent) and six had mild leg swelling (less than six per cent). Prophylactic inferior vena cava clipping is a safe and effective mean to prevent post-operative pulmonary embolism.     

Current study of Cushing's syndrome, apropos of 3 cases

The authors describe three cases of Cushing' syndrome, due to nodular hyperplasia, simple hyperplasia and adenocarcinoma respectively, and the most useful approaches (dexamethasone, metopirona, insulinic hypoglycemia, cortisol rhythm, catheterism and assessment of urinary free cortisol) for diagnosis and etiology of Cushing's syndrome.