Hyekyung Yang

Oral Efficacy of a Respiratory Syncytial Virus Inhibitor in Rodent Models of Infection

ABSTRACT BMS-433771 is a potent inhibitor of respiratory syncytial virus (RSV) replication in vitro. Mechanism of action studies have demonstrated that BMS-433771 halts virus entry through inhibition of F protein-mediated membrane fusion. BMS-433771 also exhibited in vivo efficacy following oral administration in a mouse model of RSV infection (C. Cianci, K. Y. Yu, K. Combrink, N. Sin, B. Pearce, A. Wang, R. Civiello, S. Voss, G. Luo, K. Kadow, E. Genovesi, B. Venables, H. Gulgeze, A. Trehan, J. James, L. Lamb, I. Medina, J. Roach, Z. Yang, L. Zadjura, R. Colonno, J. Clark, N. Meanwell, and M. Krystal, Antimicrob. Agents Chemother. 48:413-422, 2004). In this report, the in vivo efficacy of BMS-433771 against RSV was further examined in the BALB/c mouse and cotton rat host models of infection. By using the Long strain of RSV, prophylactic efficacy via oral dosing was observed in both animal models. A single oral dose, administered 1 h prior to intranasal RSV inoculation, was as effective against infection as a 4-day b.i.d. dosing regimen in which the first oral dose was given 1 h prior to virus inoculation. Results of dose titration experiments suggested that RSV infection was more sensitive to inhibition by BMS-433771 treatment in the BALB/c mouse host than in the cotton rat. This was reflected by the pharmacokinetic and pharmacodynamic analysis of the efficacy data, where the area under the concentration-time curve required to achieve 50% of the maximum response was ∼7.5-fold less for mice than for cotton rats. Inhibition of RSV by BMS-433771 in the mouse is the result of F1-mediated inhibition, as shown by the fact that a virus selected for resistance to BMS-433771 in vitro and containing a single amino acid change in the F1 region was also refractory to treatment in the mouse host. BMS-433771 efficacy against RSV infection was also demonstrated for mice that were chemically immunosuppressed by cyclophosphamide treatment, indicating that compound inhibition of the virus did not require an active host immune response.

Prolonged and potent therapeutic and prophylactic effects of (S)-1-[(3-hydroxy-2-phosphonylmethoxy)propyl]cytosine against herpes simplex virus type 2 infections in mice.

The acyclic nucleotide analog (S)-1-[(3-hydroxy-2-phosphonylmethoxy)propyl]cytosine (HPMPC) is a potent and selective inhibitor of herpesviruses. Cells preincubated with HPMPC are refractory to herpes simplex virus type 2 (HSV-2) infection for several days after removal of the drug from the medium. A single administration of 30 mg of HPMPC per kg of body weight 4 days prior to virus infection intraperitoneally with HSV-2 (strain G) completely protected mice from death, and the protective effect was dose dependent. HPMPC was equally efficacious in protecting mice when the same total amount of the drug was administered as a single dose as when it was given daily in several smaller doses (5 mg/kg with treatment initiation at 3 h postinfection [p.i.], 90 versus 80% survival, respectively). In contrast, ganciclovir [9(1,3-dihydroxy-2-propoxymethyl)guanine] was more efficacious when it was given daily than it was when it was given less than daily in a late stage of HSV-2 infection (100 mg/kg; when mice were treated 96 h p.i., 80 versus 50% survival, respectively; when mice were treated 120 h p.i., 60 versus 20% survival, respectively). Therefore, single doses of HPMPC were more effective than ganciclovir in protecting mice from death (80 versus 20% survival, respectively; P less than 0.05), whereas there was no difference when the drugs were given daily (50 versus 60% survival, respectively). Our studies suggest a potential of HPMPC for conventional and prophylactic treatments of herpesvirus infections with infrequent drug administration.

Bactericidal Activities of BMS-284756, a Novel Des-F(6)-Quinolone, against Staphylococcus aureus Strains with Topoisomerase Mutations

ABSTRACT The antistaphylococcal activities of BMS-284756 (T-3811ME), levofloxacin, moxifloxacin, and ciprofloxacin were compared against wild-type and grlA and grlA/gyrA mutant strains of Staphylococcus aureus. BMS-284756 was the most active quinolone tested, with MICs and minimal bactericidal concentrations against S. aureus wild-type strain MT5, grlA mutant MT5224c4, and grlA/gyrA mutant EN8 of 0.03 and 0.06, 0.125 and 0.125, and 4 and 4 μg/ml, respectively. In the time-kill studies, BMS-284756 and levofloxacin exhibited rapid killing against all strains. Ciprofloxacin, however, was not bactericidal for the double mutant, EN8. BMS-284756 and levofloxacin were bactericidal (3 log10 decrease in CFU/ml) against the MT5 and MT5224c4 strains at two and four times the MIC within 2 to 4 h. Against EN8, BMS-284756 was bactericidal within 4 h at two and four times the MIC, and levofloxacin achieved similar results within 4 to 6 h. Both the wild-type strain MT5 and grlA mutant MT5224c4 should be considered susceptible to both BMS-284756 and levofloxacin, and both quinolones are predicted to have clinical efficacy. The in vivo efficacy of BMS-284756, levofloxacin, and moxifloxacin against S. aureus strain ISP794 and its single mutant 2C6(1)-1 directly reflected the in vitro activity: increased MICs correlated with decreased in vivo efficacy. The 50% protective doses of BMS-284756 against wild-type and mutant strains were 2.2 and 1.6 mg/kg of body weight/day, respectively, compared to the levofloxacin values of 16 and 71 mg/kg/day and moxifloxacin values of 4.7 and 61.6 mg/kg/day. BMS-284756 was more potent than levofloxacin and equipotent with moxifloxacin against ISP794 both in vitro and in vivo, while BMS-284756 was more potent than levofloxacin and moxifloxacin against 2C6(1)-1.

Efficacy of BMS-180194 against experimental cytomegalovirus infections in immunocompromised mice

A new antiviral nucleoside, BMS-180194 [1R-(1 alpha, 2 beta, 3 alpha)]- 2-amino-9[2,3-bis(hydroxymethyl)cyclobutyl]-1,9dihydro-6H-purin-6- one, is a broad spectrum antiviral agent. The antiviral effectiveness of BMS-180194 against murine cytomegalovirus (MCMV) infection in immunocompromised C57BL/6 mice was investigated and was compared to that of ganciclovir (GCV). LP-BM5 murine retrovirus complex-induced immunocompromised C57BL/6 mice were challenged with MCMV then treated intraperitoneally or per os with various doses of BMS-180194 ranging from 30 to 3 mg/kg/day. When administered intraperitoneally, BMS-180194 was effective against MCMV-mediated mortality in a dose-dependent manner demonstrating a 50% protective dose (PD50) of 3.12 mg/kg/day which was comparable to that of GCV. There was a marked reduction in organ MCMV titers in BMS-180194-treated animals (10-10,000- fold lower than the placebo controls). Similar findings were observed when the compound was administered orally. Interestingly, oral BMS-180194 demonstrated a similar antiviral efficacy as that obtained by the parental route of administration suggesting a high oral bioavailability of the compound. Oral ganciclovir treatment, however, required more than a 4-fold higher amount of GCV to confer the same degree of protection obtained by a parenteral route of administration. Oral BMS-180194 was also effective in reducing the organ MCMV titer in genetically severe combined immunodeficient (SCID) mice. The parenteral or oral antiviral efficacy of BMS-180194 was comparable to that of parenteral ganciclovir against MCMV infection in the present study. Doses of BMS-180194 employed in the present study showed no toxicity to mice. These results suggest that BMS-180194 may be of value as an oral antiviral agent for treatment of opportunistic CMV infections in immunocompromised individuals.

In Vitro and In Vivo Activities of a Novel Cephalosporin, BMS-247243, against Organisms other than Staphylococci

ABSTRACT BMS-247243, a novel cephalosporin inhibitory for methicillin-resistant staphylococci, primarily has activity against gram-positive bacteria. The activities of BMS-247243, cefotaxime, and ceftriaxone against streptococci and Streptococcus pneumoniae were similar. BMS-247243 inhibits Enterococcus faecalis but not Enterococcus faecium. BMS-247243 also inhibits many inherently vancomycin-resistant species (Leuconstoc, Lactobacillus, Pediococcus) and anaerobic gram-positive bacteria.