Towards strain gauges based on a self-assembled nanoparticle monolayer--SAXS study.

An in situ small-angle x-ray scattering study of the nanoparticle displacement in a self-assembled monolayer as a function of a supporting membrane strain is presented. The average nanoparticle spacing is 6.7 nm in the unstrained state and increases in the applied force direction, following linearly the membrane strain which reaches the maximum value of 11%. The experimental results suggest a continuous mutual shift of the nanoparticles and their gradual separation with the growing stress rather than nanoparticle islands formation. No measurable shift of the nanoparticles was observed in the direction perpendicular to the applied stress.

Characterization of the highly variable bioavailability of tiludronate in normal volunteers using population pharmacokinetic methodologies.

Currently, the use of classical bioequivalence criteria is being called into question for certain classes of drugs such as bisphosphonates. These compounds typically possess a wide therapeutic index but may be characterized by low and variable absorption. The purpose of this communication was to characterize the highly variable bioavailability of tiludronate using a population pharmacokinetic method (NONMEM program) and compare the results to a standard 2 way cross-over bioequivalence trial in healthy subjects. Over 3500 plasma samples from 153 healthy subjects, representing 12 different clinical trials were pooled for mixed effect modeling purposes (complete data set). These studies, conducted under single and multiple dose conditions, contained all the directly comparable data available in healthy subjects administered a 400 mg dose of tiludronate. A two compartment model with first order absorption was fit to the plasma concentration-time data and a term for relative bioavailability (BA) was included. Intersubject and residual variability were modeled using a constant coefficient of variation (CCV) model. A pilot model development data set was obtained from a 24 subject cross-over bioequivalence study. Population estimates of BA and its associated 90% confidence interval of 1.12 and 0.89-1.35 compared favorably to standard bioequivalence methodology (1.15 and 0.93-1.42, respectively). Since a good fit of predicted and observed plasma concentrations as well as estimates of BA were obtained, a two compartment model with a term for BA was then applied to the complete data set. Under these conditions, BA and its 90% confidence interval were found to be 1.17 and 0.98-1.36. Intersubject variability of 31%, compared with 38% in the pilot model development data set and residual variability of 38% were seen. No differences in absorption characteristics as measured by Ka were found. Good agreement between the population pharmacokinetic parameters were observed when the pilot data set was compared with the full data set. The proposed model was confirmed by creating 10 additional smaller data sets that were matched for the number of subjects given both formulations under single and multiple dose conditions. No change in the estimate of BA was observed under these study conditions. This study demonstrated that population pharmacokinetic methodology can be applied successfully to problematical bioequivalence issues that may occur during the development process. Increasing the number of subjects in the overall analysis did not alter the estimate of BA or its 90% confidence interval, when compared to the original cross-over bioequivalence study. Bayesian approaches can be of value in large clinical trials where typically relatively few plasma samples are obtained from individual subjects.

Passive transfer of hepatitis antibodies during intravenous administration of immune globulin.

We studied the effect of intravenous immune globulin (IVIG) infusion on the levels of hepatitis B and C antibodies in 10 premature babies. All four tested lots of a commercially purchased IVIG preparation were found to contain substantial amounts of hepatitis B core and hepatitis C antibodies. Our results show that passive transfer of hepatitis B and C virus antibodies occurred after IVIG infusion, and that the levels were dependent on the quantity of IVIG given. When assessing neonates for hepatitis, the factor of receipt of blood products, including IVIG, needs to be considered to interpret laboratory results.

Post-antibiotic effect of ceftazidime, ciprofloxacin, imipenem, piperacillin and tobramycin for Pseudomonas cepacia.

The post-antibiotic effects (PAE) of ceftazidime, ciprofloxacin, imipenem, piperacillin and tobramycin were studied for ten strains of Pseudomonas cepacia isolated from patients with cystic fibrosis. Antibiotic concentrations used for exposure were either the MIC of each agent for the sensitive isolates or the recommended sensitivity breakpoint concentrations for the resistant isolates. After 2 h of exposure, cultures were rapidly diluted 1000-fold to eliminate the antibiotic. Out of the ten isolates, there were eight sensitive to ceftazidime, six to ciprofloxacin, six to imipenem, nine to piperacillin and five to tobramycin. All antibiotics tested demonstrated PAE for some isolates of P. cepacia, however, each antibiotic failed to produce a PAE for at least one isolate. The mean PAE was 1.35 h for ceftazidime, 2.38 h for ciprofloxacin, 2.39 h for imipenem, 2.16 h for piperacillin and 1.77 h for tobramycin. Imipenem demonstrated PAE of > or = 0.5 h for all sensitive isolates tested; ceftazidime, piperacillin, ciprofloxacin and tobramycin demonstrated PAE of > or = 0.5 h for 6/8, 8/9, 5/6 and 2/5 sensitive isolates, respectively. These data indicate that several antibiotics have significant (> or = 0.5 h) PAE for isolates of P. cepacia.

Cytomegalovirus infection and excretion in residents of a nursing home.

Cytomegalovirus (CMV), following primary infection, usually remains latent with the potential for reactivation and excretion in saliva and urine. The prevalence of CMV excretion has not been studied among the elderly. This study followed 54 nursing home residents (mean age 83 years and medically stable, but with a wide spectrum of medical conditions). Over a 6 month period these subjects were serially tested for viral excretion in saliva and urine and for CMV antibody. While approximately 93% of the residents tested were sero-positive, indicating previous CMV infection, there was no evidence of viral excretion in any resident during the study period. Therefore, it is unlikely that the elderly nursing home residents will prove to be a source of CMV to the health care workers or to their family members.

Pharmacokinetics of nitroglycerin after parenteral and oral dosing in the rat.

The pharmacokinetics of nitroglycerin was characterized in detail using venous plasma after different intravenous bolus doses (0.15-2.48 mg/kg), intra-arterial infusion (8.2 micrograms/min over 5 h), and oral doses (7-100 mg/kg). Venous plasma clearance was found to be approximately 650 mL/kg and was independent of the intravenous or intra-arterial dose. This confirmed earlier reports that the venous plasma clearance of nitroglycerin in rats exceeded the value of normal cardiac output. A terminal half-life of approximately 15 min was observed after high intravenous bolus doses of nitroglycerin. This slow disappearance phase was likely rate limited by redistribution of drug back into the plasma. The bioavailability of oral nitroglycerin (F) showed an apparent Michaelis-Menten dependency on dose. F was less than 5% at doses less than 20 mg/kg, but increased to a plateau of approximately 20% from 50-100 mg/kg. First-pass metabolism of nitroglycerin is thus apparently controlled by at least two systems (sites or enzymes). Coadministration of mannitol hexanitrate, a potential competitive inhibitor of first-pass metabolism, did not increase F.