Efficacy of NVC-422 in the treatment of dermatophytosis caused by Trichophyton mentagrophytes using a guinea pig model.

OBJECTIVES: Dermatophytes, belonging to genera including Trichophyton, Epidermophyton, and Microsporum, are the causative agents of superficial fungal infections, prevalences of which are estimated to be as high as 25% in the worldwide population. This study evaluated the activity of topical formulations of NVC-422 (sodium 2-[dichloroamino]-2-methylpropane-1-sulfonate), the lead compound in a new class of antimicrobials that consist of broad-spectrum, fast-acting, nonantibiotic antimicrobial molecules based on the endogenously produced N-chlorotaurines. METHODS: The antifungal efficacy of NVC-422 was investigated using a guinea pig model of infection with Trichophyton mentagrophytes. Infected guinea pigs were randomly assigned to four treatment and two control groups. The efficacy of the treatments was assessed clinically and mycologically at 72 hours after the final topical dose. RESULTS: The test compound 2% NVC-422 in 1% Noveon Gel demonstrated the highest level of clinical efficacy. Outcomes of treatment with all other test compounds differed significantly from outcomes in the untreated control group (P = 0.003, P = 0.029, P = 0.012, and P < 0.0001, respectively). Fungal elements were detectable in skin sections from untreated guinea pigs but not in skin sections obtained from any of the treatment groups. CONCLUSIONS: Evaluation of the efficacy of NVC-422 in the treatment of dermatophytosis using an experimental guinea pig model showed that this compound possesses potent antifungal efficacy as measured by mycological and clinical endpoints. The highest degree of clinical and mycological efficacy was demonstrated by 2% NVC-422 in 1% Noveon Gel. These data show that NVC-422 has potent antifungal activity in vivo. Clinical evaluation of NVC-422 in the treatment of superficial infections caused by dermatophytes, including onychomycosis, is warranted.

Virucidal mechanism of action of NVC-422, a novel antimicrobial drug for the treatment of adenoviral conjunctivitis.

Human adenoviral conjunctivitis is a highly contagious eye infection affecting millions of people world-wide. If untreated, it can further develop into keratitis, corneal ulceration, scarring and possible blindness. Despite the significant patient morbidity and socio-economic costs, it is an unmet medical need with no FDA approved treatment. Here, we demonstrate the virucidal activity of NVC-422 (N,N-dichloro-2,2-dimethyltaurine) against adenovirus type 5 (Ad5) and investigated its mechanism of action of Ad5 inactivation. NVC-422 inhibits Ad5-induced loss of cell viability in vitro with 50% inhibitory concentration (IC(50)) ranging from 9 to 23 µM. NVC-422 does not cause any cytotoxicity at concentrations as high as 250 µM. Invitro, NVC-422 inactivates Ad5 but does not interfere with viral replication, indicating that NVC-422 acts on the extracellular adenovirus as a virucidal agent. NVC-422 inactivates Ad5 by oxidative inactivation of key viral proteins such as fiber and hexon as evidenced by SDS-PAGE, Western blotting and reversed-phase HPLC. These data, combined with measurements of the kinetics of the NVC-422 reactivity with selected amino acids, indicate that the changes in the viral proteins are caused by the selective oxidation of sulfur-containing amino acids. The conformational changes of the viral proteins result in the destruction of the viral morphology as shown by transmission electron microscopy. In summary, NVC-422 exhibits virucidal activity against Ad5 by the oxidative inactivation of key viral proteins, leading to the loss of viral integrity and infectivity.

NVC-422 topical gel for the treatment of impetigo.

Impetigo is a highly contagious bacterial skin infection affecting children worldwide that is caused by the Gram-positive bacteria Staphylococcus aureus, Streptococcus pyogenes, or both. Staphylococcus species can quickly develop drug resistance rendering mupirocin, fusidic acid, and erythromycin ineffective. Preclinical and clinical studies demonstrated that NVC-422 (N, N-dichloro-2, 2-dimethyltaurine) rapidly kills pathogens without the development of drug resistance. 129 patients with clinically diagnosed impetigo were randomized to three dose groups (0.1, 0.5, or 1.5% NVC-422 topical gel) in a study conducted at 2 centers; 125 patients (97%) had microbiologically confirmed infection. Treatment was administered three times a day (TID) for 7 days to all randomized subjects. Response was measured at the completion of treatment (Day 8) and 1 week post treatment (Day 15) by the Skin Infection Rating Scale (SIRS) and by microbiological response. A total of 120 subjects (96%) completed all 7 days of treatment and were assessed at end of treatment (EOT). Clinical response rate at EOT in the PPC population was excellent in each of the dose groups (84.6%, 87.2%, and 92.3% in the 0.1%, 0.5% and 1.5% dose groups respectively). The majority of the infections were caused by S. aureus, alone (106/125, 85%) of which approximately 10% were MRSA. There were no clinical recurrences in any treatment groups. Treatment-emergent adverse events were seen in 5.4% of the subjects (7/129) and were mild to moderate and resolved. NVC-422 topical gel administered TID was well tolerated, with high rates of clinical and microbiological responses for treating impetigo.

Identification of pretreatment agents to enhance adenovirus infection of bladder epithelium.

Adenovirus has been used widely as a gene transfer vector in the laboratory and clinic for the purpose of gene therapy. Conditionally replication-competent oncolytic adenoviruses are capable of multiplying up to a thousand old in target cells, a property that might prove to be of tremendous potential in the area of cancer therapy. Intravesicular therapy of refractory superficial bladder cancer employing an oncolytic adenovirus would allow for local administration and efficient delivery of virus to bladder tumor. The glycosaminoglycan layer on the surface of the bladder urothelium acts as a nonspecific antiadherence barrier and may be a significant roadblock to efficient infection of the urothelium by adenoviruses. Several laboratories have investigated the potential utility of bladder pretreatment with chemical agents to enhance the adenovirus infection of bladder urothelium but with limited success. A class of compounds has been identified that is effective for pretreatment of urothelium, permitting efficient adenoviral infection. In a murine model, pretreatment of the bladder with 0.1% dodecyl-beta-D-maltoside (DDM) or sodium dodecyl sulfate (SDS) for 5 min resulted in >90% transduction of the urothelial layer within 15 min after exposure to a replication-defective adenovirus compared to