Assessing the Safety, Tolerability, Pharmacokinetics, and Biodistribution of Novel Oral Formulations of Amphotericin B following Single- and Multiple-Dose Administration to Beagle Dogs.

The purpose of this study was to assess the safety, tolerability, pharmacokinetics (PK), and biodistribution of novel oral amphotericin B (AmpB) formulations following single- and multiple-oral-dose administration to healthy beagle dogs. The liquid formulation of AmpB was administered to three male dogs, and the capsule formulations of AmpB were administered to each of two groups of six male dogs. Blood was collected for pharmacokinetic evaluation on days 1, 2, and 3 (up to 72 h postdosing). Dogs receiving the capsule formulations further received a single oral dose of 100 mg once daily for three more days, and on the 4th day, blood samples were taken at 24 h postdosing and the dogs were humanely sacrificed with the removal of organs, from which tissue samples were taken for analysis of the AmpB content. Multiple-dose studies were completed for 7 or 14 days with daily doses of up to 1,000 mg/day with the capsule formulations. All oral formulations of AmpB following both single- and multiple-dose administration were well tolerated in the dogs, and there were no relevant adverse signs observed, such as changes in hematologic, coagulation, or biochemistry parameters; loss of weight; changes in food or water intake; or signs of gastrointestinal distress. The oral absorption of AmpB from the liquid formulation and the capsule formulations were similar, with no significant differences. The tissue distributions of AmpB were similar following repeated doses of the two capsule formulations to dogs. Following 14 days of treatment with the iCo-010 liquid formulation and the iCo-019 and iCo-022 capsule formulations, the range of values of the maximum observed plasma concentration (Cmax) was 53.2 to 62.3, 24.9 to 66.4, and 36.7 to 85.2 ng/ml, respectively; the range of values of the time to Cmax was 4 to 12, 4 to 24, and 2 to 24 h, respectively; and the range of values of the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration was 2,635 to 3,071, 1,053 to 2,517, and 1,443 to 3,713 ng · h/ml, respectively. We have developed a safe novel oral AmpB formulation suitable for future efficacy studies.

Safety, Tolerability, and Pharmacokinetics of a Novel Oral Amphotericin B Formulation (iCo-019) following Single-Dose Administration to Healthy Human Subjects: an Alternative Approach to Parenteral Amphotericin B Administration.

This study evaluated the safety, tolerability, and pharmacokinetics of a novel oral amphotericin B (AmB) formulation (iCo-019) following single doses to healthy humans. The data from this study suggest that iCo-019 has a long circulation time and systemic exposure without the associated gastrointestinal, liver, and kidney toxicity associated with AmB. This novel oral AmB formulation can serve as a new treatment strategy to overcome the limitations of the use of parenterally administered AmB products.

Antisense oligonucleotide therapy in diabetic retinopathy.

Diabetic retinopathy is one of the leading causes of blindness in the United States and other parts of the world. Historically, laser photocoagulation and vitrectomy surgery have been used for the treatment of diabetic retinopathy, including diabetic macular edema. Both procedures have proven to be useful under certain conditions but have their limitations. New pathways and processes that promote diabetic retinopathy have been identified, and several new therapeutic approaches are under investigation. These new therapies may be beneficial in the treatment of diabetic retinopathy and include antivascular endothelial growth factor agents, corticosteroids, and therapies that may potentially target a number of additional diabetic retinopathy-related factors and processes, including antisense oligonucleotides. Second-generation antisense oligonucleotides, such as iCo-007, may offer a significant advantage in the treatment of diabetic retinopathy by downregulating the signal pathways of multiple growth factors that seem to play a critical role in the process of ocular angiogenesis and vascular leakage. Benefits of such molecules are expected to include the specificity of the kinase target and an extended half-life, resulting in less frequent intravitreal drug administration, resistance to molecule degradation, and a good safety profile.

Verteporfin therapy of subfoveal occult choroidal neovascularization in AMD using delayed light application: one-year results of the VALIO Study.

PURPOSE: To compare photodynamic therapy (PDT) with verteporfin (Visudyne; Novartis Pharma AG, Basel, Switzerland) using either standard or delayed light application. DESIGN: Phase II, multicenter, masked, randomized clinical trial. METHODS: Sixty patients with occult with no classic choroidal neovascularization (CNV) resulting from age-related macular degeneration were assigned randomly (1:1) to verteporfin infusion followed by light application either at 15 minutes (standard light) or 30 minutes (delayed light) after the start of the infusion. The assigned treatment was repeated every three months if fluorescein leakage was detected. RESULTS: At month 12, patients lost a mean of 15.7 letters and 11.4 letters from baseline in the standard and delayed light groups, respectively (P = .38). Twelve (52%) of 23 patients in the standard light group and 11 (42%) of 26 in the delayed light group lost at least 15 letters of visual acuity (P = .57). CONCLUSIONS: There were no statistically significant differences between verteporfin therapy using the delayed light regimen of 30 minutes or the standard light regimen of 15 minutes in eyes with occult with no classic CNV.