The echinocandins are an important class of antifungal agents. However, instability and, in some cases, lack of solubility have restricted their use to situations in which daily infusions are acceptable. CD101 is a novel echinocandin in development for topical and weekly i.v. administration that exhibits prolonged stability in plasma and aqueous solutions up to 40°C. After incubation for 44 h in rat, dog, monkey and human plasma at 37°C, the percent of CD101 remaining (91%, 79%, 94% and 93%, respectively) was consistently greater than that of anidulafungin (7%, 15%, 14% and 7%, respectively). Similarly, after incubation in phosphate-buffered saline at 37°C, the CD101 remaining (96%) was greater than that of anidulafungin (42%). CD101 exhibited o2% degradation after long-term storage at 40°C as a lyophilized powder (9 months) and at room temperature in 5% dextrose (15 months), 0.9% saline (12 months) and sterile water (18 months). Degradation was o7% at 40°C in acetate and lactate buffers (6 to 9 months at pH 4.5-5.5). The chemical stability and solubility of CD101 contribute to dosing, pharmacokinetic, formulation and safety advantages over other echinocandins and should expand utility beyond daily i.v. therapy.
Background-The objective of this study was to address the feasibility and the biological activity of orally administered human brain natriuretic peptide (hBNP). Proprietary technology has been developed in which short, amphiphilic oligomers are covalently attached to peptides. The conjugated peptides are intended to have an improved pharmacokinetic profile and to enable oral administration. We hypothesized that novel oral conjugated hBNP (CONJ-hBNP) increases plasma hBNP, activates cGMP, and reduces mean arterial pressure (MAP). Methods and Results-This randomized crossover-designed study tested the biological activity of oral CONJ-hBNP compared with oral native hBNP in normal conscious dogs. Measurements of MAP, plasma hBNP, and cGMP were made at baseline (BL) and repeated at 10, 30, 60, 120, 180, and 240 minutes after oral administration. Plasma hBNP was not detectable in dogs at BL. Plasma hBNP was detected after native hBNP and CONJ-HBNP administration. However, plasma hBNP concentration was significantly higher after CONJ-hBNP than after native hBNP administration (Pϭ0.0374 between groups). Plasma cGMP increased after CONJ-hBNP for 60 minutes (from 10.8Ϯ3 to 36.8Ϯ26 pmol/mL; PϽ0.05), whereas it did not change after native hBNP (Pϭ0.001 between groups). MAP decreased at 10 minutes and remained decreased for 60 minutes after CONJ-hBNP (from 113Ϯ8 to 101Ϯ12 mm Hg after 10 minutes to 97.5Ϯ10 mm Hg after 30 minutes to 99Ϯ13 mm Hg after 60 minutes) while remaining unchanged after native hBNP (Pϭ0.0387 between groups). BNP is an endogenous peptide produced by the heart as a nonactive 108 -amino acid hormone. [1][2][3] It is cleaved and activated into its 32-amino acid mature form by the transmembrane enzyme corin. 4 -6 BNP has natriuretic, diuretic, vasorelaxant, lusitropic, and antialdosterone properties, as well as direct and indirect antifibrotic actions. 7 BNP binds to the natriuretic peptide receptor-A (NPR-A), which is a membrane-bound receptor located on cardiomyocytes, vascular endothelium, smooth muscle, kidneys, and lungs, resulting in activation of its second messenger, cGMP. Conclusions-ThisWe recently reported that exogenous administration of BNP has favorable effects in experimental congestive heart failure (CHF). 8 Furthermore, recent studies have demonstrated the efficacy of intravenous administration of recombinant hBNP in decreasing cardiac filling pressures and improving symptoms in the setting of acute decompensated CHF. 9 -12 In experimental hypertension, administration of long-acting BNP synthesized as a fusion peptide with albumin sustained blood pressure-lowering actions, supporting a strategy for longer-term BNP therapy in cardiovascular dis- eases. 13 Although these are important advances for hypertension and CHF therapy, the current use of BNP is limited to acute intravenous administration. Recently, proprietary technology (Nobex) has been developed in which short, amphiphilic oligomers are covalently attached to peptides. In contrast to standard PEGylation technology, this technique u...
Echinocandins are a first-line therapy for candidemia and invasive candidiasis. They are generally safe with few drug interactions, but the stability and pharmacokinetic properties of currently approved echinocandins are such that each was developed for daily intravenous infusion. We sought to discover a novel echinocandin with properties that would enable more flexible dosing regimens, alternate routes of delivery, and expanded utility. Derivatives of known echinocandin scaffolds were generated, and an iterative process of design and screening led to the discovery of CD101, a novel echinocandin that has since demonstrated improved chemical stability and pharmacokinetics. Here, we report the structure-activity relationships (including preclinical efficacy and pharmacokinetic data) for the series of echinocandin analogs from which CD101 was selected. In a mouse model of disseminated candidiasis, the test compounds displayed clear dose responses and were generally associated with lower fungal burdens than that of anidulafungin. Single-dose pharmacokinetic studies in beagle dogs revealed a wide disparity in the half-lives and volumes of distribution, with one compound (now known as CD101) displaying a half-life that is nearly 5-fold longer than that of anidulafungin (53.1 h versus 11.6 h, respectively). In vitro activity data against panels of Candida spp. and Aspergillus spp. demonstrated that CD101 behaved similarly to approved echinocandins in terms of potency and spectrum of activity, suggesting that the improved efficacy observed in vivo for CD101 is a result of features beyond the antifungal potency inherent to the molecule. Factors that potentially contribute to the improved in vivo efficacy of CD101 are discussed.
Background-We previously reported the feasibility of an acute, orally delivered, newly developed, conjugated form of human B-type natriuretic peptide (hBNP) in normal animals. The objective of the present study was to extend our findings and to define the chronic actions of an advanced oral conjugated hBNP (hBNP-054) administered for 6 days on sodium excretion and blood pressure. We also sought to establish the ability of this new conjugate to acutely activate cGMP and to reduce blood pressure in an experimental model of angiotensin II (ANG II) -mediated hypertension. Methods and Results-First, we developed additional novel conjugated forms of oral hBNP that were superior to our previously reported hBNP-021 in reducing blood pressure in 6 normal dogs. We then tested the new conjugate, hBNP-054, chronically in 2 normal dogs to assess its biological actions as a blood pressure-lowering agent and as a natriuretic factor. Second, we investigated the effects of acute oral hBNP-054 or vehicle in 6 dogs that received continuous infusion of ANG II to induce hypertension. After baseline determination of mean blood pressure (MAP) and blood collection for plasma hBNP and cGMP, all dogs received continuous ANG II infusion (20 ng · kg Ϫ1 · min
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