Suppression of respiratory syncytial virus infection in cotton rats by bis(5-amidino-2-benzimidazolyl)methane.

Intraperitoneal administration of bis(5-amidino-2-benzimidazolyl)methane at well-tolerated daily doses of 25 mg/kg subsequent to challenge and for 3 days thereafter effected over a 1-log reduction in the amount of virus recovered from lungs of cotton rats inoculated intratracheally with respiratory syncytial virus. When animals were immunosuppressed to prolong virus shedding, the reduction in recovered virus achieved with a 7-day dosing schedule of bis(5-amidino-2-benzimidazolyl)methane exceeded 2 logs

Enhancement of respiratory syncytial virus-induced cytopathology by trypsin, thrombin, and plasmin.

A series of proteases of diverse substrate specificity were tested for their effect on respiratory syncytial virus-induced cytopathology. Three of the enzymes, thrombin, plasmin, and trypsin, were able to augment significantly the fusion of virus-infected A549 cells. On a concentration basis, thrombin was the most active promoter, followed by plasmin and then trypsin. Hirudin, a specific thrombin inhibitor, blocked the fusion-enhancing property of thrombin, yet had no influence on the basal rate of fusion in the absence of the enzyme. By contrast, the amidine-type inhibitors of trypsin-like proteases, bis(5-amidino-2-benzimidazolyl)-methane (BABIM), blocked not only the thrombin effect, but also the fusion in the thrombin-free controls. The suppressive activity of BABIM was observed at concentrations so low as to exclude any direct inhibitory effect on thrombin itself. These results make it seem very likely that thrombin advances cell fusion by activating a BABIM-sensitive protease. Plasmin and trypsin can be expected to act in a similar manner

Effect of synthetic protease inhibitors of the amidine type on cell injury by Rickettsia rickettsii.

To evaluate the importance of proteolytic activity in the pathogenesis of cell injury by Rickettsia rickettsii, a series of four aromatic amidine inhibitors of trypsin-like proteases were introduced into the plaque model. The compounds were shown to be active toward plaque reduction with their order of effectiveness parallel to their antitrypsin activity. One of the compounds, bis(5-amidino-2-benzimidazolyl)-methane, at a concentration of 10(-5) M demonstrated complete inhibition of plaque formation on day 6. Bis(5-amidino-2-benzimidazolyl)methane at the same concentration reduced cell injury even when added to the system after 72 h of rickettsial infection. The reduction in morbidity in guinea pigs experimentally infected with R. rickettsii and treated with bis(5-amidino-2-benzimidazolyl)methane as compared with morbidity in infected, untreated animals, comprised delay in the onset of fever and slightly fewer febrile animals. Because bis(5-amidino-2-benzimidazolyl)methane had no effect on phospholipase A2, the enzyme activity associated with penetration-induced cell injury, it is likely that a trypsin-like protease also plays an essential role either in the physiology of R. rickettsii or as its pathogenic mechanism

Suppression of respiratory syncytial virus infection in cotton rats by bis(5-amidino-2-benzimidazolyl)methane.

Intraperitoneal administration of bis(5-amidino-2-benzimidazolyl)methane at well-tolerated daily doses of 25 mg/kg subsequent to challenge and for 3 days thereafter effected over a 1-log reduction in the amount of virus recovered from lungs of cotton rats inoculated intratracheally with respiratory syncytial virus. When animals were immunosuppressed to prolong virus shedding, the reduction in recovered virus achieved with a 7-day dosing schedule of bis(5-amidino-2-benzimidazolyl)methane exceeded 2 logs

Sequential events in the pathogenesis of streptococcal cell wall-induced arthritis and their modulation by bis(5-amidino-2-benzimidazolyl)methane (BABIM).

This report builds on the authors' earlier discovery of bis(5-amidino-2-benzimidazolyl)methane (BABIM) as a strong suppressive agent for streptococcal cell wall fragment-induced arthritis in the Lewis rat. As a synthetic inhibitor of trypsinlike proteases, BABIM opens up a new route to the control of inflammatory joint disease. To gain a deeper insight into the function of the compound, the authors have now studied its influence on the sequential development of the joint changes and the associated lesions in spleen and liver. Bis(5-amidino-2-benzimidazolyl)methane is shown to block acute synovitis, to retard and reduce granuloma formation in spleen and liver, to decrease neutrophilic leukocytosis, and to diminish hemopoietic hyperplasia in the bone, and thus also to mitigate the distinctive osteoclastic and chondroclastic events. The compound does not interfere with the splenic immune response, the temporary rise in hepatocytic mitotic activity, or the organ deposition of streptococcal cell walls