Model-based drug development: strengths, weaknesses, opportunities, and threats for broad application of pharmacometrics in drug development.

Systematic implementation of model-based drug development (MBDD) to drug discovery and development has the potential to significantly increase the rate of medical breakthroughs and make available new and better treatments to patients. An analysis of the strengths, weaknesses, opportunities, and threats (ie, SWOT) was conducted through focus group discussions that included 24 members representing 8 pharmaceutical companies to systematically assess the challenges to implementing MBDD into the drug development decision-making process. The application of the SWOT analysis to the successful implementation of MBDD yielded 19 strengths, 27 weaknesses, 34 opportunities, and 22 threats, which support the following conclusions.

Model-based drug development survey finds pharmacometrics impacting decision making in the pharmaceutical industry.

During the past decade, the pharmaceutical industry has seen the increasing application of pharmacometrics approaches in drug development. However, the full potential of incorporating model-based approaches in drug development and its impact on decision making has not been fully realized to date. In 2009, a survey on model-based drug development (MBDD) was conducted (1) to further understand the current state of MBDD in the pharmaceutical industry and (2) to identify opportunities to realize the full potential of MBDD.

Thermosensitive gating effect and selective gas adsorption in a porous coordination nanocage.

A porous coordination nanocage functionalized with 24 triisopropylsilyl groups exhibits a remarkable thermosensitive gate opening phenomenon and demonstrates a molecular sieving effect at a certain temperature range, which can be used for gas separation purposes.

Recurrent lower gastrointestinal bleeding from idiopathic ileocolonic varices: a case report.

Introduction: Varices of the colon are a rare cause of lower gastrointestinal bleeding, usually associated with portal hypertension due to liver cirrhosis or other causes of portal venous obstruction. Idiopathic colonic varices are extremely rare. Recognition of this condition is important as idiopathic colonic varices may be a cause of recurrent lower gastrointestinal bleeding.

Distance and angular holonomic constraints in molecular simulations.

Finding the energy minima of systems with constraints is a challenging problem. We develop a minimization method based on the projection operator technique to enforce distance and angle constraints in minimization and reaction-path dynamics. The application of the projection operator alone does not maintain the constraints, i.

Comparison of laterally condensed, vertically compacted thermoplasticized, cold free-flow GP obturations - A volumetric analysis using spiral CT.

Aim/objective: To compare the laterally condensed gutta-percha, vertically compacted thermoplastized gutta-percha (E and Q Plus system) and cold free-flow gutta-percha (GuttaFlow). This is a volumetric analysis using spiral CT, an in vitro study.

Materials And Methods: Access cavities were prepared in 60 single rooted anterior teeth; cleaning and shaping was done and obturated with three of the different techniques: group A: cold lateral; group B: vertically compacted thermoplasticized and group C: cold free-flow obturation techniques.

Insight into residues involved in the structure and function of the breast cancer associated protein human gamma synuclein.

Aberrantly expressed human gamma synuclein (SNCG) interacts with BubR1 and heat shock protein 70 (Hsp70) in late stages of breast and ovarian cancer. This interaction is essential for progression, development and survival of cancer cells. A short, synthetically designed ankyrin-repeat-containing peptide (ANK peptide) was proven to inhibit the activity of SNCG.

Hydrogen bonding effects in adsorption of water-alcohol mixtures in zeolites and the consequences for the characteristics of the Maxwell-Stefan diffusivities.

This work highlights a variety of peculiar characteristics of adsorption and diffusion of polar molecules such as water, methanol and ethanol in zeolites. These peculiarities are investigated with the aid of configurational-bias Monte Carlo (CBMC) simulations of adsorption isotherms, and molecular dynamics (MD) simulations of diffusivities in FAU, MFI, DDR, and LTA zeolites. Because of strong hydrogen bonding, significant clustering of the guest molecules occurs in all investigated structures.

Coats' disease, Turner syndrome, and von Willebrand disease in a patient with Wildtype Norrie disease pseudoglioma.

The authors describe a girl diagnosed as having Coats' disease, Turner syndrome (45X karyotype), and type 1 von Willebrand disease. She tested negative for the Norrie disease pseudoglioma (NDP) gene located on the X-chromosome, which has been suspected of contributing to Coats' disease.

Highlighting a variety of unusual characteristics of adsorption and diffusion in microporous materials induced by clustering of guest molecules.

In this work, we highlight several unusual characteristics of adsorption and diffusion of a variety of guest molecules, such as linear and branched alkanes with a number of C atoms in the 1-6 range, CO(2), and Ar in microporous structures such as zeolites (FAU, NaY) and metal organic frameworks (IRMOF-1, CuBTC, MIL-47, MIL-53 (Cr)-lp, PCN-6') that have channel or cavity sizes larger than about 0.75 nm. Clustering of guest molecules is found to manifest at temperatures below the critical temperature, T(c), of the guest species.

Characteristics of inflammation common to both diabetes and periodontitis: are predictive diagnosis and targeted preventive measures possible?

Diabetes and periodontitis are chronic inflammatory disorders that contribute to each others' severity and worsen each others' prognosis. Studies have shown that patients with diabetes are at increased risk of developing periodontitis, and that diabetics with untreated periodontitis have more difficulty controlling serum glucose. Periodontal treatment that reduces gingival inflammation aids in the control of hyperglycemia.

A temporal precedence based clustering method for gene expression microarray data.

Background: Time-course microarray experiments can produce useful data which can help in understanding the underlying dynamics of the system. Clustering is an important stage in microarray data analysis where the data is grouped together according to certain characteristics. The majority of clustering techniques are based on distance or visual similarity measures which may not be suitable for clustering of temporal microarray data where the sequential nature of time is important.

Ethyl 6-amino-5-cyano-2,4-bis-(4-methyl-phen-yl)-4H-pyran-3-carboxyl-ate.

In the title compound, C(23)H(22)N(2)O(3), the pyran ring adopts a twisted boat conformation. The tolyl rings and carboxyl-ate group are attached to the pyran ring with torsion angles of -77.1 (2), 59.

3-Benzyl-6-benzyl-amino-1-methyl-5-nitro-1,2,3,4-tetra-hydro-pyrimidine.

In the title compound, C(19)H(22)N(4)O(2), the tetra-hydro-pyrimidine ring adopts an envelope conformation (with the N atom connected to the benzyl group representing the flap). This benzyl group occupies a quasi-axial position. The two benzyl groups lie over the tetra-hydro-pyridimidine ring.

Ethyl 2-(6-amino-5-cyano-3,4-dimethyl-2H,4H-pyrano[2,3-c]pyrazol-4-yl)acetate.

In he title compound, C(13)H(16)N(4)O(3), the pyrazole ring is planar (r.m.s.

Bis(μ-phenyl-tellurido-κTe:Te)bis-[tetra-carbonyl-rhenium(I)].

The title compound, [Re(2)(C(6)H(5)Te)(2)(CO)(8)], crystallizes with two mol-ecules in the asymmetric unit, in which two Re atoms are coordinated in a slightly distorted octa-hedral environment and are bridged by two Te atoms, which show a distorted trigonal-pyramidal geometry. The torsion angles for the Te-Re-Te-Re sequence of atoms are 19.29 (18) and 16.

Heptacarbonyl-1κC,2κC-(4-phenyl-pyridine-1κN)di-μ-phenyltellurido-1:2κTe:Te-dirhenium(I).

In the title complex, [Re(2)(C(6)H(5)Te)(2)(C(11)H(9)N)(CO)(7)], two Re atoms are coordinated in slightly distorted octa-hedral coordination environments and are bridged by two Te atoms, which are coordinated in trigonal-pyramidal environments. The torsion angle for the Te-Re-Te-Re sequence of atoms is 17.06 (3)°.

Interaction of ocular hypotensive agents (PGF2 alpha analogs-bimatoprost, latanoprost, and travoprost) with MDR efflux pumps on the rabbit cornea.

Purpose: The objectives of this work were (i) to screen ocular hypotensive prostaglandin (PGF2 alpha) analogs--bimatoprost, latanoprost, and travoprost as well as their free acid forms--for interaction with efflux pumps on the cornea and (ii) to assess the modulation of efflux upon co-administration of these prostaglandin analogs.

Methods: Cultured rabbit primary corneal epithelial cells (rPCEC) were employed as an in vitro model for rabbit cornea. Transporter-specific interaction studies were carried out using Madin-Darby canine kidney (MDCK) cells overexpressing MDR1, MRP1, MRP2, MRP5, and BCRP.

Metabolism and excretion of anacetrapib, a novel inhibitor of the cholesteryl ester transfer protein, in humans.

Anacetrapib is a novel cholesteryl ester transfer protein inhibitor being developed for the treatment of primary hypercholesterolemia and mixed dyslipidemia. The absorption, distribution, metabolism, and excretion of anacetrapib were investigated in an open-label study in which six healthy male subjects received a single oral dose of 150 mg and 165 microCi of [(14)C]anacetrapib. Plasma, urine, and fecal samples were collected at predetermined times for up to 14 days postdose and were analyzed for total radioactivity, the parent compound, and metabolites.

Quantified gene expression levels for phase I/II metabolizing enzyme and estrogen receptor levels in benign prostate from cohorts designated as high-risk (UK) versus low-risk (India) for adenocarcinoma at this organ site: a preliminary study.

Risk of clinically significant prostate adenocarcinoma (CaP) varies worldwide, although there is a uniform prevalence of latent disease. A hormone-responsive tissue, the prostate possesses the metabolizing capacity to biotransform a variety of environmental procarcinogens or endogenous hormones. Whether such metabolizing capacity or estrogen receptor (ER) status underlies these demographic differences in susceptibility to CaP remains unclear.

Investigating cluster formation in adsorption of CO2, CH4, and Ar in zeolites and metal organic frameworks at subcritical temperatures.

The critical temperatures, T(c), of CO(2), CH(4), and Ar are 304 K, 191 K, and 151 K, respectively. This paper highlights some unusual characteristics of adsorption and diffusion of these molecules in microporous structures such as zeolites and metal organic frameworks at temperatures T < T(c). Published experimental adsorption data for T < T(c) show that the isotherms invariably display stepped characteristics.