Discovery of 2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyl)oxy)methyl)cyclohexyl)methoxy)acetate (Ralinepag): An Orally Active Prostacyclin Receptor Agonist for the Treatment of Pulmonary Arterial Hypertension.

The design and synthesis of a new series of potent non-prostanoid IP receptor agonists that showed oral efficacy in the rat monocrotaline model of pulmonary arterial hypertension (PAH) are described. Detailed profiling of a number of analogues resulted in the identification of 5c (ralinepag) that has good selectivity in both binding and functional assays with respect to most members of the prostanoid receptor family and a more modest 30- to 50-fold selectivity over the EP3 receptor. In our hands, its potency and efficacy are comparable or superior to MRE269 (the active metabolite of the clinical compound NS-304) with respect to in vitro IP receptor dependent cAMP accumulation assays. 5c had an excellent PK profile across species. Enterohepatic recirculation most probably contributes to a concentration-time profile after oral administration in the cynomolgus monkey that showed a very low peak-to-trough ratio. Following the identification of an acceptable solid form, 5c was selected for further development for the treatment of PAH.

Targeted transarterial therapy of Vx-2 rabbit liver tumor with Yttrium-90 labeled ferromagnetic particles using an external magnetic field.

BACKGROUND: Our goal was to study the efficacy of liver cancer embolization with magnetically targeted Yttrium-90 labeled ferromagnetic particles and establish the biodistribution profile of these particles. MATERIALS AND METHODS: Of twenty rabbits, nine underwent transarterial radioembolization of implanted Vx-2 tumor with increasing 90Y-MTC doses, three were treated with carrier particles alone, four remained untreated and four were sacrificed early to document biodistribution. At various intervals, animals were sacrificed and biodistribution, liver cancer viability and toxicity were measured. RESULTS: There was a dose related degree of tumor necrosis, with greater than 90 Gy yielding 100% necrosis (baseline 50%). Blood radioactivity one hour post-radioembolization was less than 0.0275 microCi/g. No hematological toxicity was observed. Except for the non-targeted right liver lobe, organ radioactivity levels were within tolerance levels. Significant left (targeted) hepatic lobe necrosis was seen in subjects receiving high doses. CONCLUSION: Hepatic arterial radioembolization with 9Y-MTC bolstered by external magnetic field has significant tumoricidal effect and a favorable biodistribution profile.

Immunomodulatory effect of endotoxin on the development of latex allergy.

BACKGROUND: Although numerous studies have been conducted delineating the clinical manifestations of latex allergy and characterizing the protein allergens, little is known regarding the natural history of the disease. OBJECTIVE: These studies were undertaken to investigate the immunomodulatory role of inhaled endotoxin on the development of latex-specific IgE-mediated responses to natural rubber latex (NRL) proteins by using a mouse model. METHODS: Female BALB/c mice were exposed to 25 microg of NRL proteins with or without increasing concentrations of endotoxin (50-25,000 EU) through the respiratory tract. Serum antibody levels were evaluated biweekly during the study. After sensitization, mice were challenged with methacholine or NRL proteins, and airway hyperreactivity (AHR) was evaluated with whole-body plethysmography. After NRL challenge, lungs were excised for histopathology, and lung-associated lymph nodes were removed for cytokine mRNA evaluation. RESULTS: When compared with mice exposed to latex alone, mice exposed to latex and endotoxin demonstrated up to 50% lower levels of latex-specific IgE and decreased latex-specific AHR and mucin production. Conversely, these same animals demonstrated increased levels of latex-specific serum IgG2a and IgA antibodies and an increase in IFN-gamma and IL-12 mRNA levels in the draining lymph node cells. Concurrent exposure to LPS with nonammoniated latex resulted in increased alveolitis and nonspecific AHR on respiratory challenge with methacholine. CONCLUSION: Coexposure with LPS and allergen decreased latex-specific IgE but augmented nonspecific AHR. These studies demonstrate that endotoxin associated with NRL gloves can modulate the development of allergic responses to NRL proteins.

Intravesical administration of doxorubicin to swine bladder using magnetically targeted carriers.

PURPOSE: The feasibility of using magnetic targeted carriers (MTC) to deliver doxorubicin intravesically was studied in normal swine bladder. MTCs are microparticles consisting of metallic iron and activated carbon. Doxorubicin is adsorbed to the activated carbon component of the MTCs (MTC-DOX) while the iron component provides magnetic susceptibility. This technology is designed for site-specific delivery of a drug to a tumor in the presence of an externally applied magnetic field in order to achieve prolonged release of high localized drug concentrations by retention of MTCs in the region of interest. An intravesical route of administration was evaluated as intravesical chemotherapy is used in the treatment of bladder cancer. METHODS: The urethras of six swine were catheterized and Foley catheters were placed in their bladders. The effects of doses ranging from 10 to 80 mg doxorubicin adsorbed onto 300 to 800 mg MTCs were studied. A 30-min period of magnetic targeting immediately followed dosing, in which an external magnet was placed on the skin surface over a predetermined site on the bladder. The subsequent retention and distribution of test material was evaluated by measurement of doxorubicin levels in plasma and histopathological examination of the bladder following treatment. Blood samples were taken prior to treatment and at 15 and 30 min after infusion for measurement of doxorubicin. The bladder was drained and rinsed thoroughly following the procedure. RESULTS: Plasma doxorubicin concentrations were less than the assay limit of detection (10 ng/ml) during the 30 min following dosing. MTCs were found within the bladder walls, predominantly at the targeted site where they were present at greater depths within the layers of the epithelium. The study results show that MTC-DOX can be targeted and retained within specific locations in the bladder using magnetic targeting. CONCLUSIONS: MTC delivery may allow greater exposure and specific deposition of drug at a defined site over intravesical administration of doxorubicin alone. The feasibility of this novel method of drug delivery was demonstrated and the results support further study for its potential use in treating bladder cancer.