Characterization of wet granulation process parameters using response surface methodology. 1. Top-spray fluidized bed.

Randomized full-factorial designs (3(2)) were used to investigate the effects of processing conditions in the top-spray fluidized bed (TSFB) on the granulation of acetaminophen powder (USP) using 5% polyvinylpyrrolidone (w/w) as the binder. Measured granule properties included the following: mean size and size distribution, specific surface area, bulk density, tapped density, flow rate through an orifice, angle of repose, residual moisture content, and percent overs (> 2 mm). The granules were then compressed (500, 1000, 1500 lbs) into tablets (9-mm shallow concave) using an instrumented rotary press and analyzed for both physical properties and drug-release characteristics. All experimental batches were run in triplicate to reduce the possibility of erroneous results and to increase the confidence in the resulting empirical relationships derived using response-surface methodology. Measured responses were then related to process parameters using two-factor and three-factor linear, interactions, and quadratic regression models. These models were used to generate three-dimensional response surfaces for use in the final analyses. Coefficients of determination (R2) ranging from 0.08 to 0.81 were obtained, indicating that only a portion of the variation in the data could be explained by the changes in process parameter settings during granulation and tableting. The best overall model fits were observed for mean granule size, size distribution, bulk density, tapped density, percent drug dissolution, tablet disintegration time, and tablet friability.

The v-sis oncogene product but not platelet-derived growth factor (PDGF) A homodimers activate PDGF alpha and beta receptors intracellularly and initiate cellular transformation.

The v-sis oncogene product p28v-sis and the platelet-derived growth factor (PDGF) B chain share 92% homology with each other and over 50% homology with the PDGF A chain. Exogenously added homodimers of PDGF A and PDGF B and of p28v-sis are potent mitogens but only PDGF B and p28v-sis induce transformation when endogenously expressed with a strong promoter. Because exogenous PDGF AA and PDGF BB both initiate a full mitogenic response, understanding the mechanisms underlying the difference in their transforming potential may clarify how growth factor genes act as oncogenes. In this work, we compared cells expressing high levels of PDGF A and v-sis. We observed that transformation by v-sis correlated directly with the rapid degradation (t1/2 approximately 20 min) of the alpha and beta PDGF receptors, with a failure of either the alpha or beta receptor to be fully processed and with the association of high levels of phosphatidylinositol (PI) 3-kinase with immunoprecipitates of the PDGF receptors. In contrast, in cells expressing essentially equal levels of PDGF A, transformation was not detected, alpha and beta PDGF receptor processing was normal, and association of PI 3-kinase with receptors in immunoprecipitates was not found above control values. The ability of v-sis to autoactivate PDGF receptors within processing compartments and to initiate activation of the PI 3-kinase signaling pathway coupled with the failure of PDGF A to activate its receptor intracellularly and to induce transformation when endogenously expressed at high levels suggests that the internal autoactivation of PDGF receptors may be essential for transformation by v-sis.

In vitro/in vivo evaluation of hydrochlorothiazide in experimental hydrochlorothiazide/triamterene combination tablets in beagle dogs.

The purpose of this study was to compare experimental formulations containing hydrochlorothiazide (CAS 58-93-5)/triamterene (HCT/TRI) in vitro and in vivo to a commercial tablet formulation (standard). The beagle dog was verified as a good model and was used for the in vivo studies. The commercial tablet and the experimental fast release formulation (FR) resulted in 100% release of HCT within 30 min in dissolution tests, whereas, the slow release formulation (SR) released only 54% HCT after 4 h. Relative bioavailability of the FR and SR formulations were 82 and 41%, respectively, compared to the commercial tablet. The experimental results indicate that HCT absorption occurs throughout the small intestine.

Nifedipine for intractable hiccups.

Seven patients with intractable hiccups were treated with a calcium channel blocker, nifedipine. A daily dose of 30 to 60 mg of this drug stopped hiccups in 4 patients and improved them in a 5th patient. In 2 patients hiccups recurred within 24 hours after stopping nifedipine. Nifedipine can be effective against intractable hiccups in some patients.