Computational modeling of drug dissolution in the human stomach: Effects of posture and gastroparesis on drug bioavailability.

The oral route is the most common choice for drug administration because of several advantages, such as convenience, low cost, and high patient compliance, and the demand and investment in research and development for oral drugs continue to grow. The rate of dissolution and gastric emptying of the dissolved active pharmaceutical ingredient (API) into the duodenum is modulated by gastric motility, physical properties of the pill, and the contents of the stomach, but current in vitro procedures for assessing dissolution of oral drugs are limited in their ability to recapitulate this process. This is particularly relevant for disease conditions, such as gastroparesis, that alter the anatomy and/or physiology of the stomach. In silico models of gastric biomechanics offer the potential for overcoming these limitations of existing methods. In the current study, we employ a biomimetic in silico simulator based on the realistic anatomy and morphology of the stomach (referred to as "StomachSim") to investigate and quantify the effect of body posture and stomach motility on drug bioavailability. The simulations show that changes in posture can potentially have a significant (up to 83%) effect on the emptying rate of the API into the duodenum. Similarly, a reduction in antral contractility associated with gastroparesis can also be found to significantly reduce the dissolution of the pill as well as emptying of the API into the duodenum. The simulations show that for an equivalent motility index, the reduction in gastric emptying due to neuropathic gastroparesis is larger by a factor of about five compared to myopathic gastroparesis.

The impact of airbags and seat belts on the incidence and severity of maxillofacial injuries in automobile accidents in New York State.

OBJECTIVE: To evaluate the effect driver-side and passenger-side airbags have had on the incidence and severity of maxillofacial trauma in victims of automobile accidents. DESIGN: Retrospective analysis of all automobile (passenger cars and light trucks) accidents reported in 1994. SETTING: New York State. PATIENTS: Of the 595910 individuals involved in motor vehicle accidents in New York in 1994, 377054 individuals were initially selected from accidents involving cars and light trucks. Of this subset, 164238 drivers and 62755 right front passengers were selected for analysis. MAIN OUTCOME MEASURES: Each case is described in a single record with approximately 100 variables describing the accident, eg, vehicle, safety equipment installed and utilized or deployed, occupant position, patient demographics, International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnoses, and procedural treatments rendered. A maxillofacial trauma severity scale was devised, based on the ICD-9-CM diagnoses. RESULTS: Individuals using airbags and seat belts sustained facial injuries at a rate of 1 in 449, compared with a rate of 1 in 40 for individuals who did not use seat belts or airbags (P<.001). Those using airbags alone sustained facial injuries at the intermediate rate of 1 in 148, and victims using seat belts without airbags demonstrated an injury rate of 1 in 217 (P<.001). CONCLUSION: Use of driver-side airbags, when combined with use of seat belts, has resulted in a decrease in the incidence and severity of maxillofacial trauma.

Changing patterns of gene expression define four stages of cerebellar granule neuron differentiation.

Among CNS neuronal populations, the cerebellar granule cell provides a simple model for analysing the molecular regulation of CNS neurogenesis. In this study, polyclonal antisera raised against immature granule cell precursors, purified from early postnatal mouse cerebellum, were used to isolate 39 unique cDNA clones from a lambda gt11 cDNA expression library made from the same cell population. Northern blot analysis revealed developmental stage and tissue-specific expression of 28 of the clones. In situ localization of mRNAs encoded by these novel cDNAs, as well as those encoding the axonal glycoprotein TAG-1 and the alpha 6 subunit of the GABAA receptor, reveal four distinct stages in cerebellar granule cell differentiation. The developmentally transient and spatially restricted expression of clones GC9 and GC44 identify a previously unrecognized step in cerebellar histogenesis.

T antigen and p53 in pre- and post-crisis simian virus 40-transformed human cell lines.

Infection of normal human diploid fibroblasts (HF) with the DNA tumor virus simian virus 40 (SV) leads to an extension of lifespan and concomitant increase in the levels of the viral large tumor antigen (T antigen) and the cellular protein p53. The intracellular localization of T antigen and p53 was mostly nuclear in both SVpre-crisis and SVpost-crisis cells, however certain population doubling (PD) of the SVpre-crisis cells exhibited some cytoplasmic staining. The DNA content of SVpre-crisis cells shifted to tetraploidy and the SVpost-crisis cells were near-tetraploid. Quantitation of T antigen and p53 in single cells by flow cytometry demonstrated that for all antibodies tested the levels of T antigen were higher in the SVpre-crisis HF than in the SVpost-crisis. The quantity of p53 increased with increasing age of SVpre-crisis HF, and the levels of p53 were higher in the SVpost-crisis HF populations. Immunoprecipitation of p53, T antigen and complexes demonstrated that all p53 was bound to T antigen in SVpre-crisis HF and SVpost-crisis HF. The SVpre-crisis HF cells showed that 33% of all T antigen was bound to p53, while 67% was free, and the SVpost-crisis HF exhibited 50% free T antigen and 50% bound to p53. The half-life of p53 was similar in all SVpre-crisis HF; however, the half-life was 2-3 times greater in SVpost-crisis HF than in SVpre-crisis HF. These results suggest that the interaction of DNA (ploidy), T antigen, p53 and complexes may be involved in formation of a stable SV40-transformed human cell line.

Synthesis and biological activity of 5-fluoro- and 5-methyl-1,3-oxazine-2,6(3H)-dione.

5-Fluoro-1,3-oxazine-2,6(3H)-dione (3-oxa-FU) was synthesized by reacting 3-oxauracil with fluoroxytrifluoromethane and decomposing the adduct in the presence of a catalytic amount of Et3N. 5-Methyl-1,3-oxazine-2,6(3H)-dione (3-oxathymine) was prepared by polyphosphoric acid catalyzed ring closure of beta-(N-ethoxycarbonylamino)-2-methacrylic acid and by treatment of citraconimide with sodium hypochlorite. As determined in vitro, 3-oxa-FU was markedly inhibitory to S. faecium (ID50 = 9 X 10(-8) M) and E. coli (ID50 = 1 X 10(-7) M) but was less active against leukemia L-1210 cells (ID50 = 1 X 10(-5) M). At 1 x 10(-4) M, 3-oxathymine was inactive in these cell systems. Inhibition of the growth of S. faecium by 3-oxa-FU was reversed competitively by the natural pyrimidines. The relatively rapid hydrolysis of the compounds in the growth media is a major factor in determining their biological effectiveness.