The novel inosine analogue INO-2002 exerts an anti-inflammatory effect in a murine model of acute lung injury

Endogenous purines, including inosine, have been shown to exert immunomodulatory and anti-inflammatory effects in a variety of disease models. The dosage of inosine required for these effects has been shown to be between 200 and 600 mg kg(−1) because of the rapid metabolism of inosine in vivo. The aim of this study was to determine whether a metabolic resistant purine analog, INO-2002, exerts anti-inflammatory effects in an animal model of acute respiratory distress syndrome. Mice challenged with intratracheal LPS (50 μg) were treated with INO-2002 (30 or 100 mg kg(−1), i.p.) in divided doses at either 1 and 12 h or at 5 and 16 h. After 24 h, bronchoalveolar lavage fluid was obtained to measure leukocyte infiltration by myeloperoxidase levels, lung edema by protein levels, and proinflammatory chemokine (macrophage inflammatory protein 1α) and cytokine (TNF-α, IL-1, and IL-6) levels. INO-2002 (30 and 100 mg kg(−1)) reduced the LPS-mediated infiltration of leukocytes and edema as evidenced by bronchoalveolar lavage fluid reduction in levels of myeloperoxidase and protein. INO-2002 also downregulated expression of the proinflammatory mediators macrophage inflammatory protein 1α, TNF-α, IL-1, and IL-6. Delaying the start of treatment by 5 h after LPS administration affected the potency of INO-2002 protective effects, with 100 but not 30 mg kg(−1) having anti-inflammatory effects. The inosine analog INO-2002 largely suppressed LPS-induced inflammation in vivo at doses lower than those needed for the naturally occurring purine inosine. These data support the proposal that purine analogs, resistant to metabolic breakdown, may represent a useful addition to the therapy of acute respiratory distress syndrome

The novel inosine analogue INO-2002 protects against diabetes development in multiple low-dose streptozotocin and non-obese diabetic mouse models of type 1 diabetes

Endogenous purines including inosine have been shown to exert immunomodulatory and anti-inflammatory effects in a variety of disease models. The dosage of inosine required for protection is very high because of the rapid metabolism of inosine in vivo. The aim of this study was to determine whether a metabolic-resistant purine analogue, INO-2002, exerts anti-inflammatory effects in two animal models of type I diabetes. Type I diabetes was induced chemically with streptozotocin or genetically using the non-obese diabetic (NOD) female mouse model. Mice were treated with INO-2002 or inosine as required at 30, 100, or 200 mg/kg per day, while blood glucose and diabetes incidence were monitored. The effect of INO-2002 on the pancreatic cytokine profile was also determined. INO-2002 reduced both the hyperglycaemia and incidence of diabetes in both streptozotocin-induced and spontaneous diabetes in NOD mice. INO-2002 proved to be more effective in protecting against diabetes than the naturally occurring purine, inosine, when administered at the same dose. INO-2002 treatment decreased pancreatic levels of interleukin (IL)-12 and tumour necrosis factor-α, while increasing levels of IL-4 and IL-10. INO-2002 also reduced pancreatic levels of the chemokine MIP-1α. The inosine analogue, INO-2002, was protected more effectively than the naturally occurring purine, inosine, against development of diabetes in two separate animal models. INO-2002 exerts protective effects by changing the pancreatic cytokine expression from a destructive Th1 to a protective Th2 profile. The use of analogues of inosine such as INO-2002 should be considered as a potential preventative therapy in individuals susceptible to developing type I diabetes

Topical administration of a novel nitric oxide donor, linear polyethylenimine-nitric oxide/nucleophile adduct (DS1), selectively increases vaginal blood flow in anesthetized rats

The aim of the present study was to test the effects of a topical administration of a novel nitric oxide donor, linear polyethylenimine-nitric oxide/nucleophile adduct (DS1), on vaginal blood flow and hemodynamics in rats. Laser Doppler flowmetry was used to measure blood flow changes following topical application of DS1 (0.3 or 1.5 mg in 0.15 ml saline) into the vagina of anesthetized Wistar rats. In vivo hemodynamic parameters were measured with Millar-tip-catheter placed in the left ventricle. DS1 (1.5 mg) increased vaginal blood flow by 191+/-24, 226+/-22 and 166+/-23% of the baseline value (at 5, 15 and 30 min, respectively, after application) without affecting systemic blood pressure, heart rate and cardiac function. The increased vaginal blood flow following DS1 application returned to baseline between 45 and 60 min. Thus, topical application of nitric oxide donors such as DS1 may be useful for the treatment of female sexual dysfunction that develops due to an impairment of local blood flow supply to the vaginal tissue