A phase 2, double-blind, multicenter, randomized, placebo-controlled, dose­ranging study of the efficacy and safety of Astodrimer Gel for the treatment of bacterial vaginosis.

BACKGROUND: Astodrimer Gel contains a novel dendrimer intended to treat and prevent bacterial vaginosis. We assessed the efficacy and safety of Astodrimer Gel for treatment of bacterial vaginosis. METHODS: 132 women with bacterial vaginosis were randomized 1:1:1:1 to Astodrimer 0.5% (N = 34), 1% (N = 33), or 3% (N = 32) Gel or hydroxyethyl cellulose placebo gel (N = 33) at a dose of 5 g vaginally once daily for 7 days at 6 centers in the United States. The primary endpoint was clinical cure (no bacterial vaginosis vaginal discharge and no more than one of 1) vaginal pH ≥4.5; 2) ≥20% clue cells; or 3) positive whiff test) at study days 21-30. Secondary analyses included clinical cure at study days 9-12, patient-reported symptoms, acceptability and adverse events. RESULTS: The Astodrimer 1% Gel dose was superior to placebo for the primary and selected secondary efficacy measures in the modified intent-to-treat population. Clinical cure rates at day 9-12 were superior to placebo for the Astodrimer 3%, 1% and 0.5% Gel groups (62.5% [15/24; P = .002], 74.1% [20/27; P < .001], and 55.2% [16/29; P = .001], respectively, vs. 22.2% [6/27]). At day 21-30, clinical cure rates were 46.2% (12/26) for the 1% dose vs. 11.5% for placebo (3/26; P = .006). A greater proportion of patients reported absence of vaginal discharge and vaginal odor at day 9-12 and day 21-30 for Astodrimer Gel groups compared with placebo. Adverse events considered potentially treatment-related occurred in only 25% of Astodrimer Gel-treated patients vs. 22% of placebo patients. CONCLUSION: Astodrimer Gel once daily for 7 days was superior to placebo for treatment of bacterial vaginosis and was well-tolerated. The 1% dose consistently showed the strongest efficacy across endpoints. These results support a role for Astodrimer Gel, 1%, as an effective treatment for bacterial vaginosis.

Expression of the IGF system in normal and diabetic transgenic (mRen-2)27 rat eye.

PURPOSE: In the present study, a recently described model of diabetic eye disease was used to investigate the distribution of the insulin-like growth factor (IGF) system in the eyes of transgenic (mRen-2)27 rats (exhibiting hypertension and elevated serum and ocular renin levels) with streptozotocin-induced diabetes. METHODS: Female transgenic (mRen-2)27 rats were randomized to receive either streptozotocin (diabetic) or citrate buffer (control). After 10 months, the rats were killed and the eyes fixed and embedded in paraffin. In situ hybridization (ISH) was used to document the cellular distribution of mRNAs for components of the IGF system (IGF-I, IGF-I receptor [IGFIR] and IGF binding proteins [IGFBP]1 to -6) in the eyes. RESULTS: In nondiabetic rats, mRNA for IGFBP-1, -5, and -6; IGF-I; and IGFIR were detected in the retina. In addition, IGF-I mRNA was present in the cornea, IGFBP-1 mRNA was observed in the cornea and iris, and IGFBP-5 and -6 mRNAs were identified in the ciliary body, iris, and cornea. mRNAs for IGFBP-2, -3, and -4 were not found in the eyes. In diabetic rats, reduced levels of IGFBP-6 mRNA were detectable, whereas levels of IGFBP-5 mRNA were increased in the inner and outer retina, rods and cones, iris, cornea, and ciliary body. Other components of the IGF system in the eye were unchanged with diabetes. CONCLUSIONS: In the diabetic (mRen-2)27 rat, IGFBP-6 is downregulated and IGFBP-5 is upregulated by induction of diabetes. Because these IGFBPs may respectively have IGF-enhancing and IGF-inhibitory effects, these findings suggest a possible net IGF-enhancing effect induced by diabetes, providing further evidence for a role of the IGF system in the development of diabetic retinopathy.

UV induced responses of the human epidermal IGF system: impaired anti-apoptotic effects of IGF-I in HaCaT keratinocytes.

The insulin-like growth factor receptor (IGF-IR) is critical in epidermal development and IGF binding protein-3 (IGFBP-3), a modulator of cellular activity with or without IGF-dependence, co-localises with epidermal IGF-IRs. We have investigated whether the greater UV susceptibility of a human keratinocyte cell line (HaCaT) in comparison to normal human keratinocytes (NHKs) may involve differences in the IGF system. At 24 h after UV (960 mJ/cm(2) UVB), in comparison to NHKs, HaCaT keratinocytes exhibited significantly higher levels of apoptosis, refractoriness to IGF-I treatment and reduced IGF-IR phosphorylation. Secreted, intact IGFBP-3 (38-42 kDa) and IGFBP-3 mRNA abundance were reduced in HaCaT keratinocytes, but not consistently altered in NHKs. Immunoreactive IGFBP-3 fragments (16-11 kDa) were detected in both UV-exposed cultures. These data suggest that an altered IGF system contributes to HaCaT keratinocyte UV susceptibility and that following UV insult the IGF system may enhance keratinocyte viability and contribute to a return to epidermal homeostasis.

Epidermal homeostasis: the role of the growth hormone and insulin-like growth factor systems.

GH and IGF-I and -II were first identified by their endocrine activity. Specifically, IGF-I was found to mediate the linear growth-promoting actions of GH. It is now evident that these two growth factor systems also exert widespread activity throughout the body and that their actions are not always interconnected. The literature highlights the importance of the GH and IGF systems in normal skin homeostasis, including dermal/epidermal cross-talk. GH activity, sometimes mediated via IGF-I, is primarily evident in the dermis, particularly affecting collagen synthesis. In contrast, IGF action is an important feature of the dermal and epidermal compartments, predominantly enhancing cell proliferation, survival, and migration. The locally expressed IGF binding proteins play significant and complex roles, primarily via modulation of IGF actions. Disturbances in GH and IGF signaling pathways are implicated in the pathophysiology of several skin perturbations, particularly those exhibiting epidermal hyperplasia (e.g., psoriasis, carcinomas). Additionally, many studies emphasize the potential use of both growth factors in the treatment of skin wounds; for example, burn patients. This overview concerns the role and mechanisms of action of the GH and IGF systems in skin and maintenance of epidermal integrity in both health and disease.