No abstract

A permanent, ordered collection of 23,000 recombinant DNA plasmids containing Drosophila melanogaster DNA has been established. Simple and practical methods for storing and manipulating this collection were developed. In addition, an improved, simple and inexpensive method for making paper filter replicas of such an ordered collection and of a high density (10,000 colonies/petri dish) unordered collection was developed. These filter replicas are suitable for nucleic acid hybridization screens of recombinant DNA colinies and each filter replica can be used for many (greater than 5) successive screens. The kinetics of this hybridization reaction were examined and allow design of experiments that detect colony complementarity to a nucleic acid that is 0.5% of the hybridization probe.

The effect of atovarstatin on digoxin pharmacokinetics was assessed in 24 healthy volunteers in two studies. Subjects received 0.25 mg digoxin daily for 20 days, administered alone for the first 10 days and concomitantly with 10 mg or 80 mg atorvastatin for the last 10 days. Mean steady-state plasma digoxin concentrations were unchanged by administration of 10 mg atorvastatin. Mean steady-state plasma digoxin concentrations following administration of digoxin with 80 mg atorvastatin were slightly higher than concentrations following administration of digoxin alone, resulting in 20% and 15% higher Cmax and AUC(0-24) values, respectively. Since tmax and renal clearance were not significantly affected, the results are consistent with an increase in the extent of digoxin absorption in the presence of atorvastatin. Digoxin is known to undergo intestinal secretion mediated by P-glycoprotein. Since atorvastatin is a CYP3A4 substrate and many CYP3A4 substrates are also substrates for P-glycoprotein transport, the influence of atorvastatin and its metabolites on P-glycoprotein-mediated digoxin transport in monolayers of the human colon carcinoma (Caco-2) cell line was investigated. In this model system, atorvastatin exhibited efflux or secretion kinetics with a K(m) of 110 microM. Atorvastatin (100 microM) inhibited digoxin secretion (transport from the basolateral to apical aspect of the monolayer) by 58%, equivalent to the extent of inhibition observed with verapamil, a known inhibitor of P-glycoprotein transport. Thus, the increase in steady-state digoxin concentrations produced by 80 mg atorvastatin coadministration may result from inhibition of digoxin secretion into the intestinal lumen.

Scanning electron microscopic observations of the pulsed carbon dioxide laser effect on human enamel support microradiographic findings and indicate that this laser is significantly more efficient than the ruby laser within the limits of this investigation. Surface changes which were suggestive of fusion occurred between energy densities of 13 to 50 joules per square centimeter.There may be several potential applications of laser energy to dentistry. Initially, the use of the laser as a replacement for the dental drill was a popular idea,' but because of the high energy densities required this does not seem practical and has not been explored scientifically. Laser application to spectroscopic analysis of the chemical composition of substances related dentally has been attempted2?3 but still seems to be premature. The dental laboratory use of laser energy to solder and weld is in an early stage of development.4 In studying the effect of low laser energy densities, our interest has been ap-

No abstract

No abstract

In vitro and clinical studies were conducted to characterize the potential of avasimibe, an acyl-CoA/cholesterol acyltransferase inhibitor to cause drug-drug interactions. Clinically, 3-and 6-fold increases in midazolam (CYP3A4 substrate) oral clearance were observed after 50 and 750 mg of avasimibe daily for 7 days, respectively. A 40% decrease in digoxin (P-glycoprotein substrate) area under the curve was observed with 750 mg of avasimibe daily for 10 days. In vitro studies were conducted to define the mechanisms of these interactions. Induction was observed in CYP3A4 activity and immunoreactive protein (EC 50 of 200 -400 nM) in primary human hepatocytes treated with avasimibe. Rifampin treatment yielded similar results. Microarray analysis revealed avasimibe (1 M) increased CYP3A4 mRNA 20-fold, compared with a 23-fold increase with 50 M rifampin. Avasimibe induced P-glycoprotein mRNA by about 2-fold and immunoreactive protein in a dose-dependent manner. Transient transfection assays showed that avasimibe is a potent activator of the human pregnane X receptor (hPXR) and more active than rifampin on an equimolar basis. Drug-drug interaction studies for CYP3A4 using pooled human hepatic microsomes and avasimibe at various concentrations, revealed IC 50 values of 20.7, 1.6, and 3.1 M using testosterone, midazolam, and felodipine as probe substrates, respectively. Our results indicate that avasimibe causes clinically significant drug-drug interactions through direct activation of hPXR and the subsequent induction of its target genes CYP3A4 and multiple drug resistance protein 1.Avasimibe is a sulfamic acid phenyl ester that inhibits acyl-CoA/cholesterol acyltransferase (ACAT), an enzyme that catalyzes the intracellular esterification of cholesterol, thereby reducing intracellular cholesterol ester content. This class of inhibitors reduces the absorption of dietary cholesterol, the secretion of hepatic very low-density lipoproteins into the plasma, and the extent of atherosclerosis (Lee et al., 1996). Avasimibe is currently in clinical trials and the doses being administered to patients are between 50 to 750 mg daily. Avasimibe has been shown to reduce triglycerides at doses between 50 and 500 mg daily (Insull et al., 2001). The pharmacokinetics of avasimibe is characterized by less than proportional increases in systemic exposure with increasing dose, as measured by maximum plasma concentrations (C max ) and the plasma concentration-time area under the curve (AUC). C max values of avasimibe were approximately 0.5 and 1.5 M after multiple oral doses of 50 and 750 mg daily, respectively (Vora et al., 1997). The lack of dose proportionality was most likely due to the poor solubility of the compound. In general, a reduction in AUC after multiple dose administration is consistent with autoinduction of the metabolic pathways of a compound and/or induction of the MDR1 gene product P-glycoprotein.Enzyme induction often results in decreasing plasma drug concentrations and the attenuation of the effect of concomitan...

The third-order elastic moduli of several isotropic polycrystalline metals have been determined from measurements of the velocities of both longitudinal and shear ultrasonic waves in uniaxially stressed specimens. In each case, the wave-propagation direction was chosen normal to the applied stress, and the shear waves were polarized either normal or parallel to the stress direction. Hence, a unique evaluation of all three thirdorder moduli was possible using the recent theory of Thurston and Brugger, specialized for isotropic symmetry. The measuring equipment is based on a new variation of the pulse-echo interferometric technique and is capable of resolving velocity changes of a few parts in 106. Results are presented for several steels, aluminum alloys, magnesium, tungsten, and molybdenum, and are shown to be in good agreement with alternative nonlinear elasticity data, including static measurement of the pressure derivatives of the bulk and shear moduli.