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Prediction of intestinal absorption and blood-brain barrier penetration by computational methods.

This review surveys the computational methods that have been developed with the aim of identifying drug candidates likely to fail later on the road to market. The specifications for such computational methods are outlined, including factors such as speed, interpretability, robustness and accuracy. Then, computational filters aimed at predicting "drug-likeness" in a general sense are discussed before methods for the prediction of more specific properties--intestinal absorption and blood-brain barrier penetration--are reviewed. Directions for future research are discussed and, in concluding, the impact of these methods on the drug discovery process, both now and in the future, is briefly considered.

Animals↗

Vapor-to-droplet transition in a Lennard-Jones fluid: simulation study of nucleation barriers using the ghost field method.

We report a comprehensive Monte Carlo (MC) simulation study of the vapor-to-droplet transition in Lennard-Jones fluid confined to a spherical container with repulsive walls, which is a case study system to investigate homogeneous nucleation. The focus is made on the application of a modified version of the ghost field method (Vishnyakov, A.; Neimark, A. V. J. Chem. Phys. 2003, 119, 9755) to calculate the nucleation barrier. This method allows one to build up a continuous trajectory of equilibrium states stabilized by the ghost field potential, which connects a reference droplet with a reference vapor state. Two computation schemes are employed for free energy calculations, direct thermodynamic integration along the constructed trajectory and umbrella sampling. The nucleation barriers and the size dependence of the surface tension are reported for droplets containing from 260 to 2000 molecules. The MC simulation study is complemented by a review of the simulation methods applied to computing the nucleation barriers and a detailed analysis of the vapor-to-droplet transition by means of the classical nucleation theory.

Journal Article↗

Outer membranes of gram-negative bacteria. XIX. Isolation from Pseudomonas aeruginosa PAO1 and use in reconstitution and definition of the permeability barrier.

A method for separating the outer and inner membranes of Pseudomonas aeruginosa PAO1 in the absence of added ethylenediaminetetraacetic acid was devised. The method yields two outer membrane fractions which show the same protein pattern on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, but differ substantially in their relative contents of phospholipids. One of these outer membrane fractions and the inner membrane fraction are less than 4% cross-contaminated, as judged by the content of typical inner and outer membrane markers. The outer membrane contains four major protein bands with apparent molecular weights of 37,000, 35,000, 21,000 and 17,000. Vesicles reconstituted from lipopolysaccharide and phospholipids were impermeable to all saccharides included in the vesicles during vesicle formation. When the vesicles contained outer membrane proteins, they fully retained only those saccharides of greater than 9,000 molecular weight, suggesting that the exclusion limit of the outer membrane of P. aeruginosa for saccharides is substantially larger than the figure (500 to 600 daltons) obtained for certain enteric bacteria. The advantages and potential disadvantages of having an outer membrane with a higher exclusion limit for hydrophilic substances are discussed.

Bacterial Proteins↗

Permeability of a capsaicin derivative, [14C]DA-5018 to blood-brain barrier corrected with HPLC method.

In the present work, the transport mechanism of a capsaicin derivative, DA-5018, through blood-brain barrier (BBB) has been investigated to evaluate the feasibility of potential drug development. The result of pharmacokinetic parameters obtained from the intravenous injection of plasma volume marker, [3H]RSA and [14C]DA-5018, indicated that both AUC, area under the plasma concentration curve and VD, volume of distribution in brain of [3H]RSA agreed with those reported (1620 +/- 10 percentage injected dose minute per milliliter (%IDmin/ml) and 12.0 +/- 0.1 microliters/g, respectively). Elimination half-life and AUC of [14C]DA-5018 is corrected by the HPLC analysis, 19.6 +/- 1.2 min and 7.69 +/- 0.85% IDmin/ml, respectively. The metabolic rate of [14C] DA-5018 was very rapid. The blood-brain barrier permeability surface area (PS) product of [14C]DA-5018 was calculated to be 0.24 +/- 0.05 microliter/min/g. The result of internal carotid artery perfusion and capillary depletion suggested that [14C]DA-5018 pass through BBB with the time increasingly. Investigation of transport mechanism of [14C]DA-5018 using agonist and antagonist suggested that vanilloid (capsaicin) receptor did not exist in the BBB, and nutrient carrier system in the BBB has no effect on the transport of DA-5018. In conclusion, despite the fact that penetration of DA-5018 through BBB is significant, the intact drug found in the brain tissue is small because of a rapid metabolism. Therefore, for the central analgesic effect of DA-5018, the method to increase the metabolic stability in plasma and the brain permeability should be considered.

Analgesics, Non-Narcotic↗

Vaginal mechanical contraceptive devices.

The alleged adverse effects of oral contraceptives and intrauterine devices have led to increased consumer and physician demand for vaginal contraceptive devices. The efficacy and the advantages and disadvantages of vaginal sponges, cervical caps and diaphragms are discussed and compared in this article.

Contraceptive Agents, Female↗

[Contraception].

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Contraception↗

Diffusion barriers in skin--a new method of comparison.

Using a method which allows the net barrier potential of skin to be expressed in terms of a 'penetration half-life', skin barriers to nandrolone and allyl oestrenol penetration were compared in human, rat and hamster skin. The ranking order in terms of the net barrier was: human = haired rat greater than or equal to hairless rat greater than hairless hamster. Using the same principles, the net barrier effects of the various layers in whole human skin were also compared. The dermis was only slightly less effective than the stratum corneum as a barrier to diffusion.

Allylestrenol↗

A daughter's journey promoting geriatric self-care: promoting positive health care interactions.

Love for my parents leads me to promoting geriatric self-care. Methods of empowerment, identification of barriers and methods of overcoming them, and tools for the health care provider in promoting positive health care interactions is the focus of this article. When the older adult and the health care provider work together, the barrier of knowledge regarding chronic conditions is more likely to be overcome, allowing for the best alternatives in assessment, medication, treatment, and referral. Beginning with the material available from the National Institute of Aging (NIA) Web site, both the older adult and health care provider can promote positive health care interactions. Care and concern for the older adult is needed by all in the health care field. We are the older adults of tomorrow.

Aged↗

Contraceptive failure in the United States: an update.

This report provides an update of the authors' previous estimates of first-year probabilities of contraceptive failure for all methods of contraception. Estimates are provided of failure during typical use (which includes both incorrect and inconsistent use) and during perfect use (correct use at every act of intercourse). The difference between these two probabilities provides a measure of how forgiving of imperfect use each method is. These revisions are prompted by recent studies that provide the first estimates of failure during perfect use for periodic abstinence and the cervical cap, by more complete evaluations of implants, and by the appearance of the Copper T 380A and disappearance of other IUDs from the US market. Also provided is a more complete explanation of how the previous estimate of the probability of becoming pregnant while relying solely on chance should be interpreted, and this estimate is revised slightly downward.

Clinical Trials as Topic↗