Quality by design in lead optimization: a new strategy to address productivity in drug discovery.

The constant decline in drug discovery productivity despite the continuous growth in R&D investments has been on the table for many years and is driving changes in the current business model. We have focused our attention on what appears to be by far the major cause of attrition, the intrinsic quality of drug candidates; with the assumption that candidate quality can be designed and assessed at a rather early stage in drug discovery we have developed tools such as CNS chemical space mapping through PLS analysis, Drug Efficiency (DRUG(eff)) and the mechanistic PK/PD hypothesis. We also introduced best practices that were found extremely valuable which will be discussed in this article.

Cigarette smoke combined with staining beverages decreases luminosity and increases pigmentation in composite resin restorations.

This study evaluated the effect of cigarette smoke combined or not with colored beverages on the color change of a composite resin before and after repolishing procedures. Composite specimens were allocated into six groups (N = 10): 1) control (no colorant); 2) cigarette smoke; 3) coffee; 4) coffee and cigarette smoke; 5) red wine; and 6) red wine and cigarette smoke. During 21 days, groups 2, 4, and 6 were exposed daily to the smoke from 20 cigarettes, and groups 3, 4, 5, and 6 were immersed in coffee or red wine for 4 minutes each day.

Capsule endoscopy in patients with cardiac pacemakers and implantable cardioverter-defibrillators - a retrospective multicenter investigation.

Background & Aims: Capsule endoscopy (CE) is an established tool for the investigation of the small intestine. The Food and Drug Administration, Given Imaging and Olympus have not recommended the use of capsule endoscopy in patients with cardiac pacemakers and implantable cardioverter defibrillators (ICDs). The aim of this retrospective study was to investigate the safety of capsule endoscopy systems (Given Imaging and Olympus) when applied in patients with different types of pacemakers/ICDs in vivo.

Epidemiological and molecular assessment of a measles outbreak in a highly vaccinated population of northeast Italy.

Two distinct measles outbreaks, unrelated from the epidemiological point of view but caused by genetically related strains, occurred in the Friuli Venezia Giulia region of northeastern Italy. Forty-two cases were reported during the period April-May 2008. In the first outbreak the index case was a teacher who introduced the virus into the Pordenone area, involving eight adolescents and young adults.

The pathogenesis of retinal damage in blunt eye trauma: finite element modeling.

Purpose: To test the hypothesis that blunt trauma shockwave propagation may cause macular and peripheral retinal lesions, regardless of the presence of vitreous. The study was prompted by the observation of macular hole after an inadvertent BB shot in a previously vitrectomized eye.

Methods: The computational model was generated from generic eye geometry.

Intracoital subfoveal hemorrhage after tadalafil (cialis) premedication: a case report.

Purpose: The purpose of this study is to report the first case, to our knowledge, of intracoital subfoveal hemorrhage occurring 1 hour after tadalafil premedication in a patient with previously undiagnosed retinal angiomatous proliferation and erectile dysfunction.

Methods: This is an interventional case report. The patient underwent Snellen vision acuity measurement, anterior and posterior segment biomicroscopy, and indirect ophthalmoscopy.

Epidemiological and molecular assessment of a rubella outbreak in North-Eastern Italy.

From January to June 2008, a rubella outbreak involving 111 laboratory confirmed cases occurred in the Friuli Venezia Giulia (FVG) region of North-Eastern Italy. The outbreak occurred initially in two residential homes for young adults disabled mentally and physically. Subsequently, the epidemic spread to the general population.

Morphologic texture characterization allied to cigarette smoke increase pigmentation in composite resin restorations.

Statement Of The Problem: The staining effect of tobacco smoke on resin color is clinically observed. However, there is no evidence determining whether this staining is increased on texturized surfaces or if the color change is superficial and can be removed by repolishing procedures.

Objective: To evaluate the effect of tobacco smoke on the color of a composite with smooth or texturized surfaces, before and after repolishing.

Drug efficiency: a new concept to guide lead optimization programs towards the selection of better clinical candidates.

As a result of their wide acceptance and conceptual simplicity, drug-like concepts are having a major influence on the drug discovery process, particularly in the selection of the 'optimal' absorption, distribution, metabolism, excretion and toxicity and physicochemical parameters space. While they have an undisputable value when assessing the potential of lead series or in evaluating inherent risk of a portfolio of drug candidates, they result much less useful in weighing up compounds for the selection of the best potential clinical candidate. We introduce the concept of drug efficiency as a new tool both to guide the drug discovery program teams during the lead optimization phase and to better assess the developability potential of a drug candidate.

Application of LC-NMR to the identification of bulk drug impurities in NK1 antagonist GW597599 (vestipitant).

Liquid chromatography-NMR (LC-NMR) spectroscopy was used to obtain detailed information regarding the structure of the major bulk drug impurities present in GW597599 (vestipitant). The one-dimensional (1)H LC-NMR experiments were performed in both continuous and stop-flow modes on a sample of GW597599 (vestipitant) enriched with mother liquor impurities. The information derived from both LC-NMR and LC-MS data provided the structural information of all major impurities.

Parenteral fish oil-associated burr cell anemia.

We report the development of burr cell anemia in an infant with short bowel syndrome who received parenteral fish oil (Omegaven, Fresenius-Kabi, Graz, Austria) after development of total parenteral nutrition-associated liver disease. Parenteral fish oil was discontinued, and the burr cell anemia disappeared, suggesting that parenteral fish oil might be associated with hemolytic anemia.

Role of the pharmaceutical excipients in the tamoxifen activity on MCF-7 and vero cell cultures.

Background: Microparticles are used for controlled drug delivery. With the aim of improving both bioavailability and tamoxifen selective toxicity, the activity of tamoxifen embedded in calcium alginate/chitosan microparticles was studied.

Materials And Methods: Tamoxifen alone and embedded in microparticles prepared with sodium alginate from Kelco (62% mannuronic acid and 38% guluronic acid) and from Fluka (30% mannuronic acid and 70% guluronic acid) was added to MCF-7 and Vero cultures and evaluated for antiproliferative activity by the MTT test.

The use of Lactobacillus rhamnosus in the therapy of bacterial vaginosis. Evaluation of clinical efficacy in a population of 40 women treated for 24 months.

Background: Bacterial vaginosis (BV) is the most prevalent vaginal disorder in adult women worldwide. A number of clinical studies indicate that re-establishment of the physiological ecosystem by re-colonization of vaginal mucosa by lactobacilli may be an effective therapy for BV both after initial antimicrobial therapy or when given alone. A vaginal pH <4.

Scleral buckle removal associated with pars plana vitrectomy for recurrent retinal detachment.

Purpose: Scleral buckle (SB) removal is rarely performed due to extrusion, infection, or diplopia. We report a series of patients with recurrent retinal detachment (RRD) after primary SB due to new breaks occurring at sites where the presence of a pre-existing SB was judged counterproductive. All patients were treated by means of pars plana vitrectomy (PPV) and SB removal with the sole purpose of achieving a more favorable retinal profile.

Cellular uptake and toxicity of microparticles in a perspective of polymyxin B oral administration.

Alginate/chitosan microparticles with a mean size less than 1 microm, designed in a previous work for the targeting of polymyxin B to M-cells and, then, to the lymphatic system, were assayed for transport ability by enterocytes. Caco-2 cell monolayer model, combined with confocal microscopy, showed that microparticles were endocytosed by the cells through an energy-dependent process, being the process saturable at 6 h incubation. Furthermore, microparticles maintained the biological activity of the antibiotic and decreased the antibiotic cytotoxicity against Vero cell cultures.

Human semen hyperviscosity: prevalence, pathogenesis and therapeutic aspects.

The aims of this study were (a) to determine the prevalence of subjects with semen hyperviscosity (SHV) in a large population of male partners of subfertile couples; (b) to identify any correlation between SHV and infections or inflammation of the genital tract; (c) to assess the effects of therapeutic approaches for treating SHV; and (d) to assess sperm kinetic parameters after successful treatment of SHV. A retrospective study of 1 833 male partners of subfertile couples was conducted. Next, clinical, seminal, bacteriological and ultrasound studies involving 52 subjects suffering from SHV were performed, and the SHV was classified as being mild (length of thread > 2 cm and 4 cm and 6 cm).

Dopamine D3 receptor antagonists: the quest for a potentially selective PET ligand. Part 3: Radiosynthesis and in vivo studies.

Compound 1 is a potent and selective antagonist of the dopamine D(3) receptor. With the aim of developing a carbon-11 labeled ligand for the dopamine D(3) receptor, 1 was selected as a potential PET probe. [(11)C]1 was obtained by palladium catalyzed cross coupling using [(11)C]cyanide and 4 with a specific activity of 55.

Discovery process and pharmacological characterization of 2-(S)-(4-fluoro-2-methylphenyl)piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethylphenyl)ethyl]methylamide (vestipitant) as a potent, selective, and orally active NK1 receptor antagonist.

In an effort to discover novel druglike NK(1) receptor antagonists a new series of suitably substituted C-phenylpiperazine derivatives was identified by an appropriate chemical exploration of related N-phenylpiperazine analogues, with the specific aim to maximize their in vitro affinity and optimize in parallel their pharmacokinetic profile. Among the compounds synthesized, 2-(S)-(4-fluoro-2-methylphenyl)piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethylphenyl)ethyl]methylamide (vestipitant) was identified as one of the most in vitro potent and selective NK(1) receptor antagonists ever discovered, showing appropriate pharmacokinetic properties and in vivo activity. On the basis of its preclinical profile, this compound was selected as a drug candidate.

Mast cell tryptase in sera of patients with Crohn's disease and mastocytosis.

Introduction: The pathogenesis of Crohn's disease is unclear, but an abnormal immune response seems to play an important role. This study investigated whether serum tryptase could be shown in Crohn's disease as a marker of disease.

Materials And Methods: Mast cell tryptase was detected in sera of 48 patients with active Crohn's disease, 31 patients with inactive Crohn's disease, 17 patients with mastocytosis, and 50 controls.

MBL2 gene polymorphisms are correlated with high-risk human papillomavirus infection but not with human papillomavirus-related cervical cancer.

We investigated whether there is a correlation between MBL2 polymorphisms and the host susceptibility to human papillomavirus (HPV) infection and cancer development. Toward this end, we analyzed MBL2 exon 1 polymorphisms in 172 women infected by strains of HPV that are associated with high-risk of cervical cancer development (or "high-risk" HPV infection), 105 of whom had HPV-related squamous cell carcinoma of the cervix (SCC), as well as 105 women not infected by HPV. We demonstrated an association of MBL2 polymorphisms with high-risk HPV infection in women without SCC who showed increased presence of the mutant MBL2 0 allele and 0/0 genotype as compared with women with SCC and healthy controls.

Long-term partial remission of autoimmune thrombocytopenia in a patient treated with the anti-tumor necrosis factor-alpha antibody infliximab for refractory fistulizing Crohn's disease.

Background: Up to the present date, the treatment of recurrent chronic fistulas occurring with Crohn's disease represents a challenging task for both internists and surgeons alike.

Methods: Conservative methods of treatment using steroids, dietotherapy, antibiotics or immunosuppressive agents are not particularly effective in treating fistulas. Treatment with anti-tumor necrosis factor-alpha (TNFalpha) antibodies results in more remissions of fistulas.

An enhanced memetic differential evolution in filter design for defect detection in paper production.

This article proposes an Enhanced Memetic Differential Evolution (EMDE) for designing digital filters which aim at detecting defects of the paper produced during an industrial process. Defect detection is handled by means of two Gabor filters and their design is performed by the EMDE. The EMDE is a novel adaptive evolutionary algorithm which combines the powerful explorative features of Differential Evolution with the exploitative features of three local search algorithms employing different pivot rules and neighborhood generating functions.

Mepacrine antagonises tumour cell growth induced by natural polyamines.

Background: Mepacrine is an antiproliferative agent, characterised by an aliphatic chain similar to that of natural polyamines whose activation is closely associated with cell proliferation and may lead to malignant transformation and neurodegenerative diseases. This study aims to investigate a possible antagonism between mepacrine and polyamines in tumour proliferation.

Materials And Methods: MCF-7 and Vero cells were cultured in Eagle's minimum essential medium and then subjected to graded concentrations of putrescine, spermine and spermidine alone and in combination with mepacrine.