No abstract

No abstract

Daily intravenous arsenic trioxide administered with all-trans retinoid acid, the standard-of-care for acute promyelocytic leukemia, is costly and challenging to administer. ORH-2014 is a novel, oral arsenic trioxide formulation, consisting of micron-size drug particles with rapid dissolution and high bioavailability. We conducted a multicenter phase 1 doseescalating study in patients with advanced hematologic malignancies. Twelve patients received ORH-2014 at 5 mg (n=3), 10 mg (n=6), or 15 mg (n=3) orally once a day (fasted state). Objectives were to assess the safety, tolerability and pharmacokinetics of ORH-2014 to support a dose recommendation for future trials. The median age of the patients was 77 years (range: 45-81) and they had received a median of two (range: 1-5) prior therapies. There were no dose limiting toxicities and no drug-related severe adverse events, except one grade III QT prolongation occurring beyond the dose limiting toxicity assessment period and resolving after treatment interruption. ORH-2014 steady-state plasma concentration was reached on day 15. ORH-2014, 15 mg C max was comparable to the calculated approved dose of intravenous arsenic trioxide (mean [% coefficient of variation]: 114 [21%] vs. 124 [60%] ng/mL) and area under the curve from 0 to 24 hours was 2,140 (36%) versus 1,302 (30%) h*ng/mL. These results indicate that ORH-2014 at 15 mg is safe, bioavailable, and provides the required arsenic exposure compared to intravenous arsenic trioxide at the approved dose (0.15 mg/kg); this ORH-2014 dose is recommended for future trials. (NCT03048344; www.clinicaltrials.gov).

No abstract

The integral heat of adsorption of water vapor on sodium benzoate samples was determined at various partial vapor pressures using a heat conduction microcalorimeter. An equation is presented to describe the calorimetric integral heat response (mJ/g of solid) as a function of relative humidity. This equation, although similar in principle to the well-known BET equation, relates the heat evolved (rather than volume or mass of gas adsorbed) upon adsorption to the partial pressure of the gas. It qualitatively describes the shape of the calorimetric isotherm and quantitatively allows the calculation of "monolayer capacity" or the apparent surface area with water as the adsorbate. The modified BET equation was applied to the calorimetric adsorption data available in the literature. The surface area or the monolayer coverage values of the solid samples used in these studies were calculated from data-fitted parameter estimates. Good agreement was found between Vm or surface area values obtained by the application of the model to the calorimetric data and those reported by the authors using conventional gravimetric or volumetric measurement of adsorption. The model satisfactorily described the experimental calorimetric data of water vapor adsorption on sodium benzoate. The model equation and the use of isothermal microcalorimetry provide a means to obtain the water adsorption surface area of solid materials. The method may also be useful in comparing the surface properties of drugs and excipients obtained by different methods or from different sources. The microcalorimetric method to characterize adsorption is more sensitive and convenient in comparison with some of the conventional techniques.