Toward the design of chemical libraries for mass screening biased against mutagenic compounds.

The ability to develop a chemical into a drug depends on multiple factors. Beyond potency and selectivity, ADME/PK and the toxicological profile of the compound play a significant role in its evaluation as a candidate for development. Those factors are being brought into bear earlier in the discovery process and even into the design of libraries for screening. The purpose of our study is the comparative analysis of simple physical characteristics of compounds that have been reported to be mutagens and nonmutagenic ones. The analysis of differences can lead to the development of knowledge-based biases in the libraries designed for massive screening. For each of four Salmonella strains, TA-98, TA-100, TA-1535, and TA-1537, an analysis of the statistical significance of the deviance of the averages for a number of global properties was carried out. The properties studied included parameters, such as topological indices, and bit strings representing the presence or absence of certain chemical moieties. The results suggest that mutagens display a larger number of hydrogen bond acceptor centers for most strains. Moreover, the use of bit strings points to the importance of certain molecular fragments, such a nitro groups, for the outcome of a mutagenicity study. Development of multivariate models based on global molecular properties or bit strings point to a small advantage of the latter for the prediction of mutagenicity. The benefits of the bit strings are in accord with the use of fragment-based approaches for the prediction of carcinogenicity and mutagenicity in methods described in the literature.

Modeling cyclooxygenase inhibition. Implication of active site hydration on the selectivity of ketoprofen analogues.

Molecular modeling studies performed on the two cyclooxygenase isozymes (COXs) suggest that active site hydration is crucial for understanding inhibitor selectivity. In this work, models have been constructed considering some implicit water molecules, placed in the position suggested by GRID, that participate in the dynamic hydrogen-bonding network at the polar active site entrance together with protein residues 355, 524, 120, and 513. The selectivity observed for ketoprofen (1) and the structural analogues 2 and 3 may be rationalized in terms of such implicit hydration.

Structural basis of the dynamic mechanism of ligand binding to cyclooxygenase.

Molecular modeling studies performed on the two cyclooxygenase (COX) isozymes suggest that the cavity at the mouth of the active site on the membrane domain that may act as an actual binding site of COX ligands. Actual docking of different inhibitors at this site provides a structural basis to explain the dynamics of COX inhibition.

New insights into the conformational requirements of B2 bradykinin antagonism.

The conformational profiles of a selected group of a new series of small linear and cyclic penta- and hexapeptides, inspired on the C-terminal segment of second-generation bradykinin (BK) antagonists, were independently computed in order to assess the chemical and geometrical requirements necessary for BK antagonism. Specifically, four cyclic peptides: cyclo-(Gly-Thi-D-Tic-Oic-Arg), cyclo-(Gly-Ala-D-Tic-Oic-Arg), cyclo-(Abu-Ala-Ser-D-Tic-Oic-Arg), cyclo-(Abu-D-Phe-Ala-D-Tic-Oic-Arg), and a linear peptide: Thi-Ser-D-Tic-Oic-Arg were selected for the present study. The first three BK analogs are capable to antagonize kinin-induced rabbit jugular vein and rabbit aorta smooth muscle contraction, while last two show no detectable affinity for the BK B2 receptor. The conformational space of the five peptides was thoroughly explored using simulated annealing (SA) in an iterative fashion as sampling technique. The bioactive conformation was assessed by pairwise cross comparisons between each of the unique low energy conformations found for each of the different peptides studied within a 5 kcal/mol threshold in respect to the global minimum. The conformational profile of the highly potent BK antagonist HOE-140, computed in an independent study, was also used in conjunction with the bioactive form assessed in the present study, to propose a pharmacophore that includes the stereochemical requirements for B2 BK antagonism.

Amygdalin binds to the CD4 receptor as suggested from molecular modeling studies.

The geometrical features of the proposed bioactive conformation of peptide T assessed by computational methods in a previous study, together with available structure-activity studies on peptide T, led us to propose a pharmacophore for the CD4-peptide T interaction. Subsequent, data base searching permitted us to identify amygdalin as a peptide T peptidomimetic.

[Factors determining infant mortality in Spain]. / Algunos factores determinantes de la mortalidad infantil en España.

We introduce an ecological research for Spain between the 1975 and 1979, trying to explain the variation of childhood mortality. The social-economical factor had an important weight, as the disposable familiar rent (R2 = 0.44) and the per capita rent, while the health factors had a least important influence. From this last group, the health resources utilization were the most important, as the consultation per habitant (partial regression coefficient -0.15 and -0.14 in 1977 and 1978 respectively) and the surgery activities. Every this reflect a country in change.

[Anxiety disorders. The variability and determinants of the therapeutic approach of primary care physicians]. / Trastornos de ansiedad. Variabilidad y condicionantes de la actitud terapéutica de los médicos de atención primaria.

OBJECTIVES: To analyse the influence of independent factors, relating to the characteristics of primary care doctors, patients and the illness, on therapeutic attitudes and their variability before anxiety disorders. DESIGN: Observational study of people attending primary care family medicine clinics who are identified as suffering anxiety disorders. SETTING: The autonomous Communities of Castilla and Leon, the Basque Country and the Valencian Community. PARTICIPANTS: 3247 patients over 18 classified by their doctors as suffering an anxiety disorder. MEASUREMENTS AND RESULTS: During 1995, 317 primary care doctors collected information from patients with anxiety disorders (CIE codes F40 and F41). The information was gathered with the same questionnaire in the three communities. The data were validated monthly before the final analysis. Women doctors gave less medical advice than male doctors (OR: 0.48, 95% CI: 0.36-0.65). Patients with anxiety in Castilla and Leon were at greater "risk" of receiving drugs treatment than those in the Basque Country (OR: 1.64, CI: 1.31-2.06). When the consultation was for any mental symptom or when the kind of anxiety was a panic disorder (OR: 2.39, CI: 1.53-3.65), phobic disorder (OR: 2.17, CI: 1.52-3.08) or mixed anxiety disorder (OR: 2.20, CI: 1.77-2.73), patients were more likely to be referred for specialist treatment. If it was decided to prescribe drugs treatment, women doctors used more often than their male colleagues a mixed treatment with anti-depressants, anxiolytic drugs and drugs for psychosis (OR: 1.60, CI: 160-4.28). Castilla and Leon, and the Valencian Community were less likely to use mixed treatment than the Basque Country reference group. CONCLUSIONS: This study shows the variability in the difficulties encountered in diagnosis and finding a common standard of conduct for primary care doctors faced with patients suffering anxiety disorders. Although the treatment used for anxiety can be considered adequate in most cases, there is high variability, which depends mainly on the type and other characteristics of the process, the patient and the professional.

[Fluoride levels in water for public use in the province of Valencia]. / Niveles de fluor en las aguas de consumo público de la provincia de Valencia.

It has been realized a description study about the fluorine content in the drinking waters from the province of Valencia and it has been looked for the relation with distinct variables in order to prevent possible risks for health. The fluoride level is very low in all the public consumption waters of the province. It has been recommended the fluoridation in order to get prophylaxis of the caries teeth. The structural and geological characteristics of the aquifer don't influence about the fluoride levels in it's water supplies. Fluorine level is lightly industrialized zones and supplies near dumping places of solid and liquid residues situated over vulnerable terrenes to contamination on account of porosity, immediately afterwards fissured zones and finally the mixed terrenes.

[Design and validation of the questionnaire on Women's Sexual Function (WSF)]. / Diseño y validación del cuestionario de Función Sexual de la Mujer (FSM).

OBJECTIVE: To design and validate a self-administered questionnaire to evaluate sexual function in women. DESIGN: Cross-sectional, multi-centre study. SETTING: Primary care, in 9 health centres of the Community of Valencia. PARTICIPANTS: Women not at risk of sexual dysfunction, selected by consecutive sampling. Initial sample 600, valid sample 212. INTERVENTIONS: Questionnaire of 14 questions to be filled out in 5-10 minutes, designed by a committee of experts. The participants filled it out on two occasions (test and retest) with an interval of 4 weeks. Diagnostic assessment by a committee of observers. MAIN MEASUREMENTS: Reliability between test and retest questions: - One to one: analysis of concordance: kappa index. Significant variations: 2 goodness of fit. - On the sum of replies: comparison of means (Wilcoxon) and subsequent analysis: intra-class correlation coefficient (ICC). Internal consistency: Cronbach's alpha. Validity of contents: consensus of experts. Inter-observer correlation: ICC and factor analysis. RESULTS: Reliability: one to one: Kappa from 0.597 to 0.743. 2 not significant (ns). Between total sums (Wilcoxon), ns (z=-0.312, P=.755) (95% confidence). ICC: r=0.9587 (95% CI, 0.9460-0.9685), significant correlation (99% confidence). Internal consistency: Cronbach's alpha test: 0.8954, retest: 0.8973. Inter-observer correlation: ICC: r=0.9498 (CI, 0.9386-0.9611) significant (confidence 99%). Factor analysis: groupings of items 9, 13, 14; 1, 2, 3, 10; 5, 6, 7, 8. CONCLUSIONS: The questionnaire is stable, valid and reliable. It evaluates the stages of sexual response, initiative and degree of sexual communication. It collects data on sexual performance. It is useful for exploring and diagnosing sexual dysfunction.

Identification of selective inhibitors of acetylcholinesterase from a combinatorial library of 2,5-piperazinediones.

The potentiation of central cholinergic activity has been proposed as a therapeutic approach for improving cognitive function in patients with Alzheimer's disease. Increasing the acetylcholine concentration in brain by modulating acetylcholinesterase (AChE) activity is among the most promising strategies. We have used a combinatorial approach to identify different 2,5-piperazinediones (DKP) with AChE inhibitory activity. Our goal was to find inhibitors exhibiting high AChE/BuChE (butyrylcholinesterase) selectivity, in order to reduce the undesirable side effects elicited by most of the inhibitors that have been developed to date. Screening of a DKP library constructed on solid-phase using the multiple parallel synthesis format, resulted in the identification of several compounds with moderate efficacy on AChE. In particular, DKP-80 had an IC50 = 2.2 microM with no significant inhibitory activity on BuChE. Moreover, estimated values of Clog P and log BB for the most active compounds fulfilled the bioavailability requirements for enzyme inhibitors acting on the central nervous system. In order to understand the inhibitory properties of the ligand at the molecular level, molecular dynamics simulations were computed on DKP-80 complexed to AChE, and the most relevant binding interactions of this inhibitor to the active center of the enzyme were characterized. Overall the present results indicate that the DKP-based compounds identified are novel AChE inhibitors which may be considered likely lead compounds for further development of drug candidates against Alzheimer's disease.

Synthesis and biological evaluation of 1,3,4-triaryl-3-pyrrolin-2-ones, a new class of selective cyclooxygenase-2 inhibitors.

The synthesis and structure activity relationships (SAR) of a series of novel selective COX-2 inhibitors are reported. The results show that some of the 1,3,4-triaryl-3-pyrrolin-2-ones 1 are more potent as COX-2 inhibitors than celecoxib, and that lactam Id has the same selectivity.