Dengue virus (DENV), a mosquito-borne flavivirus, is a major public health threat. The virus poses risk to 2.5 billion people worldwide and causes 50 to 100 million human infections each year. Neither a vaccine nor an antiviral therapy is currently available for prevention and treatment of DENV infection. Here, we report a previously undescribed adenosine analog, NITD008, that potently inhibits DENV both in vitro and in vivo. In addition to the 4 serotypes of DENV, NITD008 inhibits other flaviviruses, including West Nile virus, yellow fever virus, and Powassan virus. The compound also suppresses hepatitis C virus, but it does not inhibit nonflaviviruses, such as Western equine encephalitis virus and vesicular stomatitis virus. A triphosphate form of NITD008 directly inhibits the RNA-dependent RNA polymerase activity of DENV, indicating that the compound functions as a chain terminator during viral RNA synthesis. NITD008 has good in vivo pharmacokinetic properties and is biologically available through oral administration. Treatment of DENV-infected mice with NITD008 suppressed peak viremia, reduced cytokine elevation, and completely prevented the infected mice from death. No observed adverse effect level (NOAEL) was achieved when rats were orally dosed with NITD008 at 50 mg/kg daily for 1 week. However, NOAEL could not be accomplished when rats and dogs were dosed daily for 2 weeks. Nevertheless, our results have proved the concept that a nucleoside inhibitor could be developed for potential treatment of flavivirus infections.

New chemotherapeutic compounds against multidrug-resistant Mycobacterium tuberculosis (Mtb) are urgently needed to combat drug resistance in tuberculosis (TB). We have identified and characterized the indolcarboxamides as a new class of antitubercular bactericidal agent. Genetic and lipid profiling studies identified the likely molecular target of indolcarboxamides as MmpL3, a transporter of trehalose monomycolate that is essential for mycobacterial cell wall biosynthesis. Two lead candidates, NITD-304 and NITD-349, showed potent activity against both drug-sensitive and multidrug-resistant clinical isolates of Mtb. Promising pharmacokinetic profiles of both compounds after oral dosing in several species enabled further evaluation for efficacy and safety. NITD-304 and NITD-349 were efficacious in treating both acute and chronic Mtb infections in mouse efficacy models. Furthermore, dosing of NITD-304 and NITD-349 for 2 weeks in exploratory rat toxicology studies revealed a promising safety margin. Finally, neither compound inhibited the activity of major cytochrome P-450 enzymes or the hERG (human ether-a-go-go related gene) channel. These results suggest that NITD-304 and NITD-349 should undergo further development as a potential treatment for multidrug-resistant TB.

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Dengue virus (DENV) is the most prevalent mosquito-borne viral pathogen that infects humans. Neither a vaccine nor an antiviral therapy is currently available for DENV. Here, we report an adenosine nucleoside prodrug that potently inhibits DENV replication both in cell culture and in a DENV mouse model. NITD449 (2-C-acetylene-7-deaza-7-carbamoyladenosine) was initially identified as a parental compound that inhibits all four serotypes of DENV with low cytotoxicity. However, in vivo pharmacokinetic studies indicated that NITD449 had a low level of exposure in plasma when dosed orally. To increase the oral bioavailability, we covalently linked isobutyric acids to the 3-and 5-hydroxyl groups of ribose via ester linkage to NITD449, leading to the prodrug NITD203 (3,5-O-diisobutyryl-2-C-acetylene-7-deaza-7-carbamoyl-adenosin). Pharmacokinetic analysis showed that upon oral dosing of the prodrug, NITD203 was readily converted to NITD449, resulting in improved exposure of the parental compound in plasma in both mouse and rat. In DENV-infected AG129 mice, oral dosing of the prodrug at 25 mg/kg of body weight reduced peak viremia by 30-fold. Antiviral spectrum analysis showed that NITD203 inhibited various flaviviruses (DENV, yellow fever virus, and West Nile virus) and hepatitis C virus but not Chikungunya virus (an alphavirus). Mode-of-action analysis, using a luciferase-reporting replicon, indicated that NITD203 inhibited DENV RNA synthesis. Although NITD203 exhibited potent in vitro and in vivo efficacies, the compound could not reach a satisfactory no-observableadverse-effect level (NOAEL) in a 2-week in vivo toxicity study. Nevertheless, our results demonstrate that a prodrug approach using a nucleoside analog could potentially be developed for flavivirus antiviral therapy.Dengue virus (DENV), the causative agent for dengue fever, is a mosquito-borne pathogen with significant impacts on public health and economy. It was confined to South East Asia in the 1950s, but since then, DENV has increased in its spread in geographic areas and in the number of infected patients (6). It is now estimated that 2.5 billion people are at risk for DENV infection, with about 50 million to 100 million human infections, leading to over 20,000 deaths each year. The disease spectrum ranges from mild undifferentiated fever to lifethreatening dengue hemorrhage fever (DHF) and dengue shock syndrome (DSS) (18). There is no clinically approved vaccine or antiviral therapy for DENV. Thus, DENV presents an increasingly unmet medical need to develop anti-DENV therapeutics.DENV belongs to the family of Flaviviridae, which contains three genera, Hepacivirus, Pestivirus, and Flavivirus. The genus Flavivirus contains many important human pathogens, such as West Nile virus (WNV), yellow fever virus (YFV), Japanese encephalitis virus (JEV), tick-borne encephalitis virus (TBEV), and DENV (4). Dengue virus is further subdivided into four serologically distinct serotypes, named dengue virus serotypes 1 to 4. The DENV genome consists of a positivestrand ...

The kinetics of distribution of lumiracoxib in synovial fluid are likely to extend the therapeutic action of the drug beyond that expected from plasma pharmacokinetics. These data support the use of lumiracoxib in a once-daily regimen for the treatment of rheumatoid arthritis.

Objective: Previous studies show conflicting results in wound healing outcomes based on angiosome direct perfusion (DP), but few have adjusted for wound characteristics in their analyses. We have previously shown that the Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification correlates with wound healing in diabetic foot ulcers (DFUs) treated by a multidisciplinary team. The aim of this study was to compare WIfI classification vs DP and pedal arch patency as predictors of wound healing in patients presenting with DFU and peripheral arterial disease. Methods: We performed a retrospective review of a prospectively maintained database of all patients with peripheral arterial disease presenting to our multidisciplinary DFU clinic who underwent angiography. An angiosome was considered directly perfused if the artery feeding the angiosome was revascularized or was completely patent. Wound healing time at 1 year was compared on the basis of DP vs indirect perfusion, Rutherford pedal arch grade, and WIfI classification using univariable statistics and Cox proportional hazards models. Results: Angiography was performed on 225 wounds in 99 patients (mean age, 63.3 6 1.2 years; 62.6% male; 53.5% black) during the entire study period. There were 33 WIfI stage 1, 33 stage 2, 51 stage 3, and 108 stage 4 wounds. DP was achieved in 154 wounds (68.4%) and indirect perfusion in 71 wounds (31.6%). On univariable analysis, WIfI classification was significantly associated with improved wound healing (57.2% for WIfI 3/4 vs 77.3% for WIfI 1/2; P ¼ .02), whereas DP and pedal arch patency were not (both, P $ .08). After adjusting for baseline patient and wound characteristics, WIfI stage remained independently predictive of wound healing (WIfI 3/4: hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.67-0.88), whereas DP (HR, 0.82; 95% CI, 0.55-1.21) and pedal arch grade (HR, 0.85; 95% CI, 0.70-1.03) were not. Conclusions: In our population of patients treated by a multidisciplinary diabetic foot service, the Society for Vascular Surgery WIfI classification system was a stronger predictor of diabetic foot wound healing than DP or pedal arch patency. Our results suggest that a measure of wound severity should be included in all future studies assessing wound healing as an outcome, as differences in patients' wound characteristics may be a strong contributor to the variation of angiosomedirected perfusion results previously observed.

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