The immunosuppressor st1959, a 3,5-diaryl-s-triazole derivative, inhibits T cell activation by reducing NFAT nuclear residency.

3-(2-ethylphenyl)-5-(3-methoxyphenyl)-1H-1,2,4-triazole (ST1959) has shown therapeutic effects in several animal models of autoimmune diseases. In this study the effects of ST1959 were further investigated in a murine model of colitis. The evidence obtained indicates that the beneficial effects exerted by ST1959 rely upon a decreased local immunological response. The cellular effects of ST1959 were additionally investigated on human peripheral blood mononuclear cells and Jurkat T cells by measuring cytokine production, cell proliferation and activation of a set of transcription factors. ST1959 decreases human T cell proliferation and inhibits cytokine expression at the transcriptional level. Moreover, at doses inhibiting cytokine production, ST1959 blocks phorbol 12-myristate 13-acetate (PMA) and ionomycin-induced nuclear factor protein of activated T cell (NFAT1) activity, without impairing AP-1- and NF-kB-dependent transcription. Immunofluorescence data show that ST1959 inhibits the nuclear residency of NFAT1 in both Jurkat and human peripheral blood mononuclear cells activated with PMA/ionomycin. leptomycin B, an inhibitor of CRM1/exportin-1alpha-dependent nuclear export, reverted the inhibitory effect of ST1959 on NFAT1 nuclear localization. This indicates that ST1959 may increase the nuclear export of NFAT1, downregulating NFAT1 activity via a mechanism different from that of cyclosporin A, since it does not affect NFAT phosporylation/dephosphorylation steps. These findings provide new insights into the molecular mechanisms underlying the immunomodulatory activity of ST1959.

Tratamiento con caspofungina de endocarditis por Candida tropicalis resistente a fluconazol / Treatment with caspofungin of Candida tropicalis endocarditis resistant to fluconazol

Fungal endocarditis, in particular due to Candida species, requires medical and surgical treatment and amphotericin B is the drug of choice. Caspofungin is an echinocandin very effective against Candida and Aspergillus. We present a patient with Candida tropicalis endocarditis, fluconazol resistant, treated with caspofungin, on a compassional basis as a result of adverse effects with amphotericin B. The patient had a microbiological response.

Las endocarditis causadas por hongos, (Candida en particular), requieren tratamiento médico-quirúrgico,siendo la anfotericina B la droga de elección. Caspofungina es una equinocandina con gran actividadsobre Candida y Aspergillus. Se presenta un paciente con una endocarditis por Candida tropicalis resistente a fluconazol tratado con caspofungina bajo un esquema de salvataje, luego de haber presentado efectos adversos por anfotericina B. El paciente tuvo respuesta microbiológica.

Tratamiento con caspofungina de endocarditis por Candida tropicalis resistente a fluconazol / Treatment with caspofungin of Candida tropicalis endocarditis resistant to fluconazol

Fungal endocarditis, in particular due to Candida species, requires medical and surgical treatment and amphotericin B is the drug of choice. Caspofungin is an echinocandin very effective against Candida and Aspergillus. We present a patient with Candida tropicalis endocarditis, fluconazol resistant, treated with caspofungin, on a compassional basis as a result of adverse effects with amphotericin B. The patient had a microbiological response.(AU)

Las endocarditis causadas por hongos, (Candida en particular), requieren tratamiento médico-quirúrgico,siendo la anfotericina B la droga de elección. Caspofungina es una equinocandina con gran actividadsobre Candida y Aspergillus. Se presenta un paciente con una endocarditis por Candida tropicalis resistente a fluconazol tratado con caspofungina bajo un esquema de salvataje, luego de haber presentado efectos adversos por anfotericina B. El paciente tuvo respuesta microbiológica.(AU)

[Quantitative cultures from catheters, using the Brun Buisson technique]. / Cultivos cuantitativos de catéteres por la técnica de Brun Buisson.

The objective of this collaborative work carried out in the Fundación Favaloro and the Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia, was to determine optimal conditions for incubation (time and atmosphere) of quantitative cultures of catheters processed according to the technique of vortex agitation (Brun Buisson method). From 689 processed catheters, 551 yielded negative cultures. From the 138 positive cultures, 125 yielded monomicrobial cultures and 13 polimicrobial cultures (total number of microorganisms was 151). In the last situation each micoorganism was considered on an individual basis. A total of 58 episodes of catheter related bacteremias occurred, being 52 monomicrobial and 6 polimicrobial (total number of microorganisms was 64). When colony counts were compared in aerobic and in 5-10% CO2 atmospheres, a very good correlation was obtained (p = 0.27; r2 = 0.9268). No advantage was observed by incubating plates for more than 48 hours. Colony counts performed at the second versus the third day, and at the second day versus the seventh, gave very good correlation (p = 0.10 and r2 = 0.9996; p = 0.31 and r2 = 0.9995, respectively).

Cultivos cuantitativos de catéteres por la técnica de Brun Buisson / Quantitative cultures from catheters, using the Brun Buisson technique

The objective of this collaborative work carried out in the Fundación Favaloro and the Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia, was to determine optimal conditions for incubation (time and atmosphere) of quantitative cultures of catheters processed according to the technique of vortex agitation (Brun Buisson method). From 689 processed catheters, 551 yielded negative cultures. From the 138 positive cultures, 125 yielded monomicrobial cultures and 13 polimicrobial cultures (total number of microorganisms was 151). In the last situation each micoorganism was considered on an individual basis. A total of 58 episodes of catheter related bacteremias occurred, being 52 monomicrobial and 6 polimicrobial (total number of microorganisms was 64). When colony counts were compared in aerobic and in 5-10 CO2 atmospheres, a very good correlation was obtained (p = 0.27; r2 = 0.9268). No advantage was observed by incubating plates for more than 48 hours. Colony counts performed at the second versus the third day, and at the second day versus the seventh, gave very good correlation (p = 0.10 and r2 = 0.9996; p = 0.31 and r2 = 0.9995, respectively).

Cultivos cuantitativos de catéteres por la técnica de Brun Buisson / Quantitative cultures from catheters, using the Brun Buisson technique

The objective of this collaborative work carried out in the Fundación Favaloro and the Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia, was to determine optimal conditions for incubation (time and atmosphere) of quantitative cultures of catheters processed according to the technique of vortex agitation (Brun Buisson method). From 689 processed catheters, 551 yielded negative cultures. From the 138 positive cultures, 125 yielded monomicrobial cultures and 13 polimicrobial cultures (total number of microorganisms was 151). In the last situation each micoorganism was considered on an individual basis. A total of 58 episodes of catheter related bacteremias occurred, being 52 monomicrobial and 6 polimicrobial (total number of microorganisms was 64). When colony counts were compared in aerobic and in 5-10 CO2 atmospheres, a very good correlation was obtained (p = 0.27; r2 = 0.9268). No advantage was observed by incubating plates for more than 48 hours. Colony counts performed at the second versus the third day, and at the second day versus the seventh, gave very good correlation (p = 0.10 and r2 = 0.9996; p = 0.31 and r2 = 0.9995, respectively).(AU)

Cultivos cuantitativos de catéteres por la técnica de Brun Buisson. / [Quantitative cultures from catheters, using the Brun Buisson technique]

The objective of this collaborative work carried out in the Fundación Favaloro and the Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia, was to determine optimal conditions for incubation (time and atmosphere) of quantitative cultures of catheters processed according to the technique of vortex agitation (Brun Buisson method). From 689 processed catheters, 551 yielded negative cultures. From the 138 positive cultures, 125 yielded monomicrobial cultures and 13 polimicrobial cultures (total number of microorganisms was 151). In the last situation each micoorganism was considered on an individual basis. A total of 58 episodes of catheter related bacteremias occurred, being 52 monomicrobial and 6 polimicrobial (total number of microorganisms was 64). When colony counts were compared in aerobic and in 5-10

CO2 atmospheres, a very good correlation was obtained (p = 0.27; r2 = 0.9268). No advantage was observed by incubating plates for more than 48 hours. Colony counts performed at the second versus the third day, and at the second day versus the seventh, gave very good correlation (p = 0.10 and r2 = 0.9996; p = 0.31 and r2 = 0.9995, respectively).

[Utility of prolonged incubation and terminal subcultures of blood cultures from immunocompromised patients]. / Utilidad de la incubación prolongada y de los subcultivos terminales de hemocultivos de pacientes inmunocomprometidos.

The value of blind terminal subcultures (7 and 30 days) and prolonged incubation (30 days) of blood cultures from immunosuppressed patients was analyzed in the Fundación Favaloro, the Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia and the Hospital de Niños Ricardo Gutiérrez. A total of 2707 blood cultures and 369 patients were included (transplantation of solid organs 154, oncohematologic disorders 106 and solid tumors 109). Bact-Alert bottles were incubated at 35 degrees C for 30 days in the Bact-Alert System. Bottles with positive signals were routinely removed, and aliquots of the broth were Gram stained and subcultured aerobically in chocolate agar and Sabouraud agar. A total of 136 bacteremic episodes were obtained. The positivization time of blood cultures was 81.6% at 24 h, 93.3% at 48 h, 94.5% at 72 h and 97.7% within 7 days. Only 3 (2.2%) episodes were positive by blind terminal subcultures and 1 (0.75%) by prolonged incubation (14 days). The median time and range of positivization in hours were 13.8 and 2.2-168, respectively. The microorganisms isolated were coagulase negative staphylococci (n = 24), Klebsiella pneumoniae (n = 22), Staphylococcus aureus (n = 21), Escherichia coli (n = 18), Acinetobacter spp (n = 9), Candida spp (n = 8), Pseudomonas aeruginosa (n = 6), Enterobacter cloacae (n = 5), Stenotrophomonas maltophilia (n = 5), Enterococcus faecalis, Salmonella spp and Capnocytophaga sputigena (n = 2), Enterobacter aerogenes, Enterococcus faecium, Citrobacter diversus, Candida albicans, Klebsiella oxytoca, Chryseomonas luteola, Serratia marcescens, Abiotrophia spp, Campylobacter jejuni, Moraxella catarrhalis, Moraxella urethralis, Neisseria sicca, beta hemolytic group G streptococci, Rhodococcus equi, Micrococcus spp, Cryptococcus neoformans and Streptococcus mitis (n = 1). In our experience, blind terminal subcultures and prolonged incubation of blood cultures from immunosuppressed patients are unnecessary and cost expensive.

Utilidad de la incubación prolongada y de los subcultivos terminales de hemocultivos de pacientes inmunocomprometidos / Utility of prolonged incubation and terminal subcultures of blood cultures from immunocompromised patients

The value of blind terminal subcultures (7 and 30 days) and prolonged incubation (30 days) of blood cultures from immunosuppressed patients was analyzed in the Fundación Favaloro, the Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia and the Hospital de Niños Ricardo GutiÚrrez. A total of 2707 blood cultures and 369 patients were included (transplantation of solid organs 154, oncohematologic disorders 106 and solid tumors 109). Bact-Alert bottles were incubated at 35 degrees C for 30 days in the Bact-Alert System. Bottles with positive signals were routinely removed, and aliquots of the broth were Gram stained and subcultured aerobically in chocolate agar and Sabouraud agar. A total of 136 bacteremic episodes were obtained. The positivization time of blood cultures was 81.6 at 24 h, 93.3 at 48 h, 94.5 at 72 h and 97.7 within 7 days. Only 3 (2.2) episodes were positive by blind terminal subcultures and 1 (0.75) by prolonged incubation (14 days). The median time and range of positivization in hours were 13.8 and 2.2-168, respectively. The microorganisms isolated were coagulase negative staphylococci (n = 24), Klebsiella pneumoniae (n = 22), Staphylococcus aureus (n = 21), Escherichia coli (n = 18), Acinetobacter spp (n = 9), Candida spp (n = 8), Pseudomonas aeruginosa (n = 6), Enterobacter cloacae (n = 5), Stenotrophomonas maltophilia (n = 5), Enterococcus faecalis, Salmonella spp and Capnocytophaga sputigena (n = 2), Enterobacter aerogenes, Enterococcus faecium, Citrobacter diversus, Candida albicans, Klebsiella oxytoca, Chryseomonas luteola, Serratia marcescens, Abiotrophia spp, Campylobacter jejuni, Moraxella catarrhalis, Moraxella urethralis, Neisseria sicca, beta hemolytic group G streptococci, Rhodococcus equi, Micrococcus spp, Cryptococcus neoformans and Streptococcus mitis (n = 1). In our experience, blind terminal subcultures and prolonged incubation of blood cultures from immunosuppressed patients are unnecessary and cost expensive.

Utilidad de la incubación prolongada y de los subcultivos terminales de hemocultivos de pacientes inmunocomprometidos / Utility of prolonged incubation and terminal subcultures of blood cultures from immunocompromised patients

The value of blind terminal subcultures (7 and 30 days) and prolonged incubation (30 days) of blood cultures from immunosuppressed patients was analyzed in the Fundación Favaloro, the Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia and the Hospital de Niños Ricardo GutiUrrez. A total of 2707 blood cultures and 369 patients were included (transplantation of solid organs 154, oncohematologic disorders 106 and solid tumors 109). Bact-Alert bottles were incubated at 35 degrees C for 30 days in the Bact-Alert System. Bottles with positive signals were routinely removed, and aliquots of the broth were Gram stained and subcultured aerobically in chocolate agar and Sabouraud agar. A total of 136 bacteremic episodes were obtained. The positivization time of blood cultures was 81.6 at 24 h, 93.3 at 48 h, 94.5 at 72 h and 97.7 within 7 days. Only 3 (2.2) episodes were positive by blind terminal subcultures and 1 (0.75) by prolonged incubation (14 days). The median time and range of positivization in hours were 13.8 and 2.2-168, respectively. The microorganisms isolated were coagulase negative staphylococci (n = 24), Klebsiella pneumoniae (n = 22), Staphylococcus aureus (n = 21), Escherichia coli (n = 18), Acinetobacter spp (n = 9), Candida spp (n = 8), Pseudomonas aeruginosa (n = 6), Enterobacter cloacae (n = 5), Stenotrophomonas maltophilia (n = 5), Enterococcus faecalis, Salmonella spp and Capnocytophaga sputigena (n = 2), Enterobacter aerogenes, Enterococcus faecium, Citrobacter diversus, Candida albicans, Klebsiella oxytoca, Chryseomonas luteola, Serratia marcescens, Abiotrophia spp, Campylobacter jejuni, Moraxella catarrhalis, Moraxella urethralis, Neisseria sicca, beta hemolytic group G streptococci, Rhodococcus equi, Micrococcus spp, Cryptococcus neoformans and Streptococcus mitis (n = 1). In our experience, blind terminal subcultures and prolonged incubation of blood cultures from immunosuppressed patients are unnecessary and cost expensive.(AU)

[Characterization and distribution of Citrobacter species in a university hospital]. / Caracterización y distribución de especies de Citrobacter en un hospital universitario.

OBJECTIVE: [corrected] a) To identify Citrobacter strains following the conventional biochemical reaction of Brenner and col; b) to evaluate the sensitivity and specificity of the O'Hara's method compared with Brenner's method, and c) to determine the rate and distribution of the strains in the clinical isolates. MATERIAL AND METHODS: One hundred and twenty two clinical isolates, characterized as Citrobacter spp. were collected between May of 1994 and August of 1997. Clinical isolates included inpatients and outpatients from Hospital de Clínicas. Strains were identified following the methods of Brenner and O'Hara. RESULTS: Methods of Brenner identified 111 of 122 strains: C. freundii 59 of 111; C. koseri 18 of 111; C. werkmanii 15 of 111; C. braakii 9 of 111; C. youngae 6 of 111 and C. amalonaticus 4 of 111. O'Hara's methods identified 104 of 111 strains (94%). C. freundii was recovered most frequently from urine and feces (p Fisher < 0.026 and 0.039 respectively), while C. koseri was isolated from urine principally (p Fisher < 0.0372). CONCLUSIONS: The genus Citrobacter is an important opportunistic pathogen that can be identified in clinical microbiology laboratories using O'Hara's method.

Utilidad de la incubación prolongada y de los subcultivos terminales de hemocultivos de pacientes inmunocomprometidos. / [Utility of prolonged incubation and terminal subcultures of blood cultures from immunocompromised patients]

The value of blind terminal subcultures (7 and 30 days) and prolonged incubation (30 days) of blood cultures from immunosuppressed patients was analyzed in the Fundación Favaloro, the Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia and the Hospital de Niños Ricardo Gutiérrez. A total of 2707 blood cultures and 369 patients were included (transplantation of solid organs 154, oncohematologic disorders 106 and solid tumors 109). Bact-Alert bottles were incubated at 35 degrees C for 30 days in the Bact-Alert System. Bottles with positive signals were routinely removed, and aliquots of the broth were Gram stained and subcultured aerobically in chocolate agar and Sabouraud agar. A total of 136 bacteremic episodes were obtained. The positivization time of blood cultures was 81.6

at 24 h, 93.3

at 48 h, 94.5

at 72 h and 97.7

within 7 days. Only 3 (2.2

) episodes were positive by blind terminal subcultures and 1 (0.75

) by prolonged incubation (14 days). The median time and range of positivization in hours were 13.8 and 2.2-168, respectively. The microorganisms isolated were coagulase negative staphylococci (n = 24), Klebsiella pneumoniae (n = 22), Staphylococcus aureus (n = 21), Escherichia coli (n = 18), Acinetobacter spp (n = 9), Candida spp (n = 8), Pseudomonas aeruginosa (n = 6), Enterobacter cloacae (n = 5), Stenotrophomonas maltophilia (n = 5), Enterococcus faecalis, Salmonella spp and Capnocytophaga sputigena (n = 2), Enterobacter aerogenes, Enterococcus faecium, Citrobacter diversus, Candida albicans, Klebsiella oxytoca, Chryseomonas luteola, Serratia marcescens, Abiotrophia spp, Campylobacter jejuni, Moraxella catarrhalis, Moraxella urethralis, Neisseria sicca, beta hemolytic group G streptococci, Rhodococcus equi, Micrococcus spp, Cryptococcus neoformans and Streptococcus mitis (n = 1). In our experience, blind terminal subcultures and prolonged incubation of blood cultures from immunosuppressed patients are unnecessary and cost expensive.

[Evaluation of the reincubation of positive blood cultures for detection in the BACT-ALERT system for the detection of polymicrobial bacteremia]. / Evaluación de la reincubación de hemocultivos positivos por el sistema BACT-ALERT para la detección de bacteriemias polimicrobianas.

Between February and September 1997, 6588 blood cultures at the Instituto de Cardiología y Cirugía Cardiovascular and Hospital de Niños Ricardo Gutiérrez were studied by using the Bact-Alert system (Organon Teknika) 341 contaminants and 294 episodes of bacteremia (600 samples) were analyzed. From these samples, 280 (95.3%) were monomicrobial episodes and 14 (4.7%) polymicrobial episodes. Positive blood cultures detected by the Bact-Alert system were processed and then reincubated during 7 days, when they were Gram stained and subcultured in blood agar, chocolate agar (both in 5-10% CO2), laked blood agar supplemented with hemin and vitamin K in anaerobic atmosphere (only anaerobic bottles) and CLDE (aerobic conditions). Following reincubation, 3 out of 14 polymicrobial bacteremias were detected, rising the level of detection from 3.7% to 4.7%. Taking into account the total number of bacteremias, only in 3 out of 294 (1%), a second microorganism was detected. Otherwise, in blood cultures where a contaminating microorganism was initially isolated, no further isolates representing a true bacteremia were recovered. Reincubation and terminal subculture of initially positive blood cultures did not provide relevant data in order to change therapeutic measures in the studied population. Due to the increase in costs and labor we consider that this methodology is not routinely advised.

Evaluación de la reincubación de hemocultivos positivos por el sistema BACT-ALERT para la detección de bacteriemias polimicrobianas / Evaluation of the reincubation of positive blood cultures for detection in the BACT-ALERT system for the detection of polymicrobial bacteremia

Between February and September 1997, 6588 blood cultures at the Instituto de CardiologÝa y CirugÝa Cardiovascular and Hospital de Niños Ricardo GutiÚrrez were studied by using the Bact-Alert system (Organon Teknika) 341 contaminants and 294 episodes of bacteremia (600 samples) were analyzed. From these samples, 280 (95.3) were monomicrobial episodes and 14 (4.7) polymicrobial episodes. Positive blood cultures detected by the Bact-Alert system were processed and then reincubated during 7 days, when they were Gram stained and subcultured in blood agar, chocolate agar (both in 5-10 CO2), laked blood agar supplemented with hemin and vitamin K in anaerobic atmosphere (only anaerobic bottles) and CLDE (aerobic conditions). Following reincubation, 3 out of 14 polymicrobial bacteremias were detected, rising the level of detection from 3.7 to 4.7. Taking into account the total number of bacteremias, only in 3 out of 294 (1), a second microorganism was detected. Otherwise, in blood cultures where a contaminating microorganism was initially isolated, no further isolates representing a true bacteremia were recovered. Reincubation and terminal subculture of initially positive blood cultures did not provide relevant data in order to change therapeutic measures in the studied population. Due to the increase in costs and labor we consider that this methodology is not routinely advised.

Evaluación de la reincubación de hemocultivos positivos por el sistema BACT-ALERT para la detección de bacteriemias polimicrobianas / Evaluation of the reincubation of positive blood cultures for detection in the BACT-ALERT system for the detection of polymicrobial bacteremia

Between February and September 1997, 6588 blood cultures at the Instituto de CardiologYa y CirugYa Cardiovascular and Hospital de Niños Ricardo GutiUrrez were studied by using the Bact-Alert system (Organon Teknika) 341 contaminants and 294 episodes of bacteremia (600 samples) were analyzed. From these samples, 280 (95.3) were monomicrobial episodes and 14 (4.7) polymicrobial episodes. Positive blood cultures detected by the Bact-Alert system were processed and then reincubated during 7 days, when they were Gram stained and subcultured in blood agar, chocolate agar (both in 5-10 CO2), laked blood agar supplemented with hemin and vitamin K in anaerobic atmosphere (only anaerobic bottles) and CLDE (aerobic conditions). Following reincubation, 3 out of 14 polymicrobial bacteremias were detected, rising the level of detection from 3.7 to 4.7. Taking into account the total number of bacteremias, only in 3 out of 294 (1), a second microorganism was detected. Otherwise, in blood cultures where a contaminating microorganism was initially isolated, no further isolates representing a true bacteremia were recovered. Reincubation and terminal subculture of initially positive blood cultures did not provide relevant data in order to change therapeutic measures in the studied population. Due to the increase in costs and labor we consider that this methodology is not routinely advised.(AU)

Evaluación de la reincubación de hemocultivos positivos por el sistema BACT-ALERT para la detección de bacteriemias polimicrobianas. / [Evaluation of the reincubation of positive blood cultures for detection in the BACT-ALERT system for the detection of polymicrobial bacteremia]

Between February and September 1997, 6588 blood cultures at the Instituto de Cardiología y Cirugía Cardiovascular and Hospital de Niños Ricardo Gutiérrez were studied by using the Bact-Alert system (Organon Teknika) 341 contaminants and 294 episodes of bacteremia (600 samples) were analyzed. From these samples, 280 (95.3

) were monomicrobial episodes and 14 (4.7

) polymicrobial episodes. Positive blood cultures detected by the Bact-Alert system were processed and then reincubated during 7 days, when they were Gram stained and subcultured in blood agar, chocolate agar (both in 5-10

CO2), laked blood agar supplemented with hemin and vitamin K in anaerobic atmosphere (only anaerobic bottles) and CLDE (aerobic conditions). Following reincubation, 3 out of 14 polymicrobial bacteremias were detected, rising the level of detection from 3.7

to 4.7

. Taking into account the total number of bacteremias, only in 3 out of 294 (1

), a second microorganism was detected. Otherwise, in blood cultures where a contaminating microorganism was initially isolated, no further isolates representing a true bacteremia were recovered. Reincubation and terminal subculture of initially positive blood cultures did not provide relevant data in order to change therapeutic measures in the studied population. Due to the increase in costs and labor we consider that this methodology is not routinely advised.

Beneficial effects of a novel platelet-activating factor receptor antagonist, ST 899, on endotoxin-induced shock in mice.

The effect of ST 899, a novel platelet-activating factor (PAF) receptor antagonist, on serum tumor necrosis factor (TNF), interleukin-6 (IL-6), and interferon-gamma (IFN-gamma) production as well as on lethality in an experimental endotoxin shock model was investigated in C57BL/6 mice. In this model, animals receiving 40 mg/kg lipopolysaccharide (LPS) (Escherichia coli 055:B5) intraperitoneally were pretreated with ST 899 administered according to two different schedules. ST 899 pretreatment dose dependently reduced the mortality induced by LPS injection. The PAF receptor antagonist was also able to reduce significantly the LPS-induced increase in serum TNF. Although serum IL-6 levels were not affected, we found that ST 899, when administered intraperitoneally 60 min and intravenously 10 min prior to LPS challenge, had a tendency (at higher doses) to decrease circulating IFN-gamma levels. It is suggested that ST 899 may be beneficial, in combination with current therapies, in the treatment of diseases that involve overproduction of PAF, TNF, and IFN-gamma such as septic shock.

Modulation of splenic lymphocyte activities by a new hypoxanthine derivative (ST 789) in immunosuppressed mice.

Splenic lymphocytes of experimentally-immunosuppressed mice of different age (10 weeks and 6 months) were studied to evaluate their functional response following subcutaneous and intraperitoneal treatment with the hypoxanthine derivative N-alpha-5-(1,6-dihydro-6-oxo-9-purinyl)pentyloxy-carbonyl-L- arginine (ST 789). Experimental immunosuppression was carried out by injecting hybrid B6D2F1 mice with a single dose of cyclophosphamide (100 mg/kg, i.p.) 2 hours prior to treatment with ST 789. In the young, we found that ST 789 markedly restored the splenocyte proliferative response, assessed as total amount of 3H-thymidine incorporated by mitogen-stimulated cells. In the adult, however, the ST 789-induced recovery was less pronounced. Finally, the effects of ST 789 treatment on Con A-induced IL-2 production by splenocytes were studied in normal and immunosuppressed mice of 10 weeks.