Novel therapeutic agents interfering in neutrophil migration

#The present invention relates to the field of diseases involving the immune system and, in particular, diseases involving neutrophil migration. A number of serious illnesses involve neutrophil transmigration at one stage or another. Such diseases include acute traumas (especially trauma to the brain), infections, ischemic neurological injury and other inflammatory diseases (such as autoimmune diseases).

#A very important disease for which no successful drug has been developed so far is bacterial meningitis. Bacterial meningitis is a serious illness, affecting annually in the United States about 3 individuals per 100,000. The case fatality rate is estimated at 25%, and a substantial percentage of the survivors will suffer permanent neurological impairment. Typically, a patient presents with serious clinical symptoms and a high leukocyte count in their cerebrospinal fluid (CSF). Extensive literature evidence suggests that these leukocytes, which are mainly neutrophil leukocytes, play an important adverse role in the pathogenesis of neurological damage.

#It has been demonstrated that a high influx of neutrophil leukocytes into the central nervous system (CNS) correlates with an unfavorable prognosis for neurological recovery. Therefore, several attempts have been made to reduce the inflammatory response. So far, the only studies published relating to adjuvant anti-inflammatory treatment in human bacterial meningitis are clinical trials with corticosteroids added to the antibiotic regimen. At least one of the proposed effects of corticosteroids involves the interference of neutrophil migration, although other mechanisms may play a role as well. Results of these clinical trials have been promising though controversial, and only in pediatric cases is the routine use of corticosteroid therapy currently recommended. In adult bacterial meningitis, more evidence of a positive effect of adjuvant corticosteroid treatment is needed.

#The invention will be explained in more detail in the following experimental part.

#Isolation of GXM.

#C. neoformans is autoclaved after growth in a chemically defined medium for 5 days. Polysaccharide is precipitated with calcium acetate and ethanol. After being dissolved in NaCl and undergoing brief ultrasonic irradiation, the polysaccharide is precipitated by differential complexation with hexadecyltrimethylammonium bromide. Purified GXM is precipitated by ethanol, dissolved, ultrasonically irradiated for 2 h, centrifuged, dialyzed, and finally recovered by lyophilization. Samples are analyzed through various methods to prove that none of the purified polysaccharides contain constituents other than those known to occur in GXM (37).