A single dose of raxibacumab improved survival in rabbits and monkeys with symptomatic inhalational anthrax. (ClinicalTrials.gov number, NCT00639678.)

We previously reported that the immunosuppressive malononitrileamides leflunomide and FK778 exert antiviral activity against cytomegalovirus (CMV). In the current investigation, we tested the hypothesis that leflunomide exerts concurrent antiviral activity and immune suppression in CMV-infected cardiac allograft recipients. Lewis rats were transplanted with Brown Norway hearts and then inoculated with rat CMV. Plaque assay demonstrated that leflunomide (30 mg/kg/day) reduced viral loads by 4-6 logs, and that the reduction in viral load was unaffected by administration of uridine. Leflunomide was as effective as cyclosporine A (CsA) or tacrolimus in preservation of allograft integrity through day 28. These studies directly demonstrate the bifunctionality of leflunomide as concurrently immunosuppressive and antiviral, enhancing the promise of this agent as a clinical option for treatment of transplant recipients.

No abstract

Appropriate animal models are required to test medical countermeasures to bioterrorist threats. To that end, we characterized a nonhuman primate (NHP) inhalational anthrax therapeutic model for use in testing anthrax therapeutic medical countermeasures according to the U.S. Food and Drug Administration Animal Rule. A clinical profile was recorded for each NHP exposed to a lethal dose of Bacillus anthracis Ames spores. Specific diagnostic parameters were detected relatively early in disease progression, i.e., by blood culture (ϳ37 h postchallenge) and the presence of circulating protective antigen (PA) detected by electrochemiluminescence (ECL) ϳ38 h postchallenge, whereas nonspecific clinical signs of disease, i.e., changes in body temperature, hematologic parameters (ca. 52 to 66 h), and clinical observations, were delayed. To determine whether the presentation of antigenemia (PA in the blood) was an appropriate trigger for therapeutic intervention, a monoclonal antibody specific for PA was administered to 12 additional animals after the circulating levels of PA were detected by ECL. Seventy-five percent of the monoclonal antibody-treated animals survived compared to 17% of the untreated controls, suggesting that intervention at the onset of antigenemia is an appropriate treatment trigger for this model. Moreover, the onset of antigenemia correlated with bacteremia, and NHPs were treated in a therapeutic manner. Interestingly, brain lesions were observed by histopathology in the treated nonsurviving animals, whereas this observation was absent from 90% of the nonsurviving untreated animals. Our results support the use of the cynomolgus macaque as an appropriate therapeutic animal model for assessing the efficacy of medical countermeasures developed against anthrax when administered after a confirmation of infection. Bacillus anthracis is a Gram-positive, rod-shaped, aerobic and/or facultative anaerobic, spore-forming bacterium that can cause human disease via the gastrointestinal, cutaneous, or inhalation (pulmonary) routes, each resulting in different clinical manifestations of disease (4,20). The pulmonary form of B. anthracis is the most lethal, and the incubation period usually varies from 1 to 6 days, depending upon the dose received (5). After inhalation exposure, some reports suggest a delayed onset of several weeks in low-dose exposure or after the removal of therapeutic intervention (4). In inhalation anthrax, the initial clinical signs and symptoms are nonspecific and may include malaise, headache, fever, nausea, and vomiting (4). These are followed by a sudden onset of respiratory distress with dyspnea, stridor, cyanosis, and chest pain. The onset of respiratory distress is followed by shock and often death, with close to 100% mortality in untreated cases (4).The mortality caused by B. anthracis is predominantly due to the three well-characterized virulence factors: the capsule and two toxins (23). The polyglutamate capsule prevents phagocytosis of the bacterium. Three polypeptides-protective antigen...