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Foram analisados os resultados preventivos da aplicação tópica semestral de gel com flúor-fosfato acidulado em 998 crianças, de 6, 8 e 10 anos, provenientes de famílias de baixa renda. Utilizou-se a metodologia de aplicação em massa sem profilaxia prévia desenvolvida no contexto do Programa Nacional de Prevenção da Cárie Dental. Após um ano, constatou-se em localidades sem fluoretação da água de consumo público redução na incidência de cárie da ordem de 31,6% em crianças de 6 anos, 24,9% aos 8 anos e 39,5% aos 10 anos, segundo o índice CPO-S. Nas localidades com flúor na água, as reduções foram, respectivamente, de 24,3%, 26,6% e 27,7%, em todos os casos com significância estatística ao nível de 95%. Face aos resultados positivos e à segurança, custo reduzido e praticidade do método, recomenda-se que os programas de saúde bucal em todos os níveis desenvolvam ação preventiva permanente, abrangente e sem solução de continuidade para as crianças sob sua responsabilidade.

Kramers' rate for the passage of trajectories X(t) over an energy barrier due to thermal or other fluctuations is usually associated with additive noise. We present a generalization of Kramers' rate for systems with multiplicative noise. We show that the expression commonly used in the literature for multiplicative noise is not correct, and we present results of numerical integrations of the Langevin equation for dX(t)/dt evolving in a quartic bistable potential which corroborate our claim.

Granular systems present surprisingly complicated dynamics. In particular, nonlinear interactions and energy dissipation play important roles in these dynamics. Usually (but admittedly not always), constant coefficients of restitution are introduced phenomenologically to account for energy dissipation when grains collide. The collisions are assumed to be instantaneous and to conserve momentum. Here, we introduce the dissipation through a viscous (velocity-dependent) term in the equations of motion for two colliding grains. Using a first-order approximation, we solve the equations of motion in the low viscosity regime. This approach allows us to calculate the collision time, the final velocity of each grain, and a coefficient of restitution that depends on the relative velocity of the grains. We compare our analytic results with those obtained by numerical integration of the equations of motion and with exact ones obtained by other methods for some geometries.

We consider an array of units each of which can be in one of three states. Unidirectional transitions between these states are governed by Markovian rate processes. The interactions between units occur through a dependence of the transition rates of a unit on the states of the units with which it interacts. This coupling is nonlocal, that is, it is neither an all-to-all interaction (referred to as global coupling), nor is it a nearest neighbor interaction (referred to as local coupling). The coupling is chosen so as to disfavor the crowding of interacting units in the same state. As a result, there is no global synchronization. Instead, the resultant spatiotemporal configuration is one of clusters that move at a constant speed and that can be interpreted as traveling waves. We develop a mean field theory to describe the cluster formation and analyze this model analytically. The predictions of the model are compared favorably with the results obtained by direct numerical simulations.

Infinite arrays of coupled two-state stochastic oscillators exhibit well-defined steady states. We study the fluctuations that occur when the number N of oscillators in the array is finite. We choose a particular form of global coupling that in the infinite array leads to a pitchfork bifurcation from a monostable to a bistable steady state, the latter with two equally probable stationary states. The control parameter for this bifurcation is the coupling strength. In finite arrays these states become metastable: The fluctuations lead to distributions around the most probable states, with one maximum in the monostable regime and two maxima in the bistable regime. In the latter regime, the fluctuations lead to transitions between the two peak regions of the distribution. Also, we find that the fluctuations break the symmetry in the bimodal regime, that is, one metastable state becomes more probable than the other, increasingly so with increasing array size. To arrive at these results, we start from microscopic dynamical evolution equations from which we derive a Langevin equation that exhibits an interesting multiplicative noise structure. We also present a master equation description of the dynamics. Both of these equations lead to the same Fokker-Planck equation, the master equation via a 1/N expansion and the Langevin equation via standard methods of Itô calculus for multiplicative noise. From the Fokker-Planck equation we obtain an effective potential that reflects the transition from the monomodal to the bimodal distribution as a function of a control parameter. We present a variety of numerical and analytic results that illustrate the strong effects of the fluctuations. We also show that the limits N → ∞ and t → ∞ (t is the time) do not commute. In fact, the two orders of implementation lead to drastically different results.

We implement a binary collision approximation to study pulse propagation in a chain of o-rings. In particular, we arrive at analytic results from which the pulse velocity is obtained by simple quadrature. The predicted pulse velocity is compared to the velocity obtained from the far more resource-intensive numerical integration of the equations of motion. We study chains without precompression, chains precompressed by a constant force at the chain ends (constant precompression), and chains precompressed by gravity (variable precompression). The application of the binary collision approximation to precompressed chains provides an important generalization of a successful theory that had up to this point only been implemented to chains without precompression, that is, to chains in a sonic vacuum.

Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa inhibitors, incorporating neutral and basic monoaryl P4 groups, ultimately producing potent inhibitors with effective levels of anticoagulant activity and extended oral pharmacokinetic profiles. However, time dependant inhibition of Cytochrome P450 3A4 was a particular issue with this series., (Copyright 2009 Elsevier Ltd. All rights reserved.)

We study heat conduction in one-dimensional granular gases. In particular, we consider two mechanisms of viscous dissipation during intergrain collisions. In one, the dissipative force is proportional to the grain's velocity and dissipates not only energy but also momentum. In the other, the dissipative force is proportional to the relative velocity of the grains and therefore conserves momentum even while dissipating energy. This allows us to explore the role of momentum conservation in the heat conduction properties of this one-dimensional nonlinear system. We find normal thermal conduction whether or not momentum is conserved.

Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating biaryl P4 groups, producing highly potent inhibitors with encouraging oral pharmacokinetic profiles and significant but sub-optimal anticoagulant activities.

Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating basic biaryl P4 groups, producing highly potent inhibitors with significant anticoagulant activities and encouraging oral pharmacokinetic profiles.

Modification of the pyrimidone 5-substituent in clinical candidate SB-435495 has given a series of inhibitors of recombinant lipoprotein-associated phospholipase A(2) with sub-nanomolar potency. Cyclopentyl fused derivative 21, SB-480848, showed an enhanced in vitro and in vivo profile versus SB-435495 and has been selected for progression to man.

The introduction of a functionalised amido substituent into a series of 1-(biphenylmethylacetamido)-pyrimidones has given a series of inhibitors of recombinant lipoprotein-associated phospholipase A(2) with sub-nanomolar potency and very encouraging developability properties. Diethylaminoethyl derivative 32, SB-435495, was selected for progression to man.

A series of 1-(biphenylmethylamidoalkyl)-pyrimidones has been designed as nanomolar inhibitors of recombinant lipoprotein-associated phospholipase A(2) with high potency in whole human plasma. 5-(Pyrazolylmethyl) derivative 16 and 5-(methoxypyrimidinylmethyl) derivative 27 demonstrated excellent pharmacodynamic profiles which correlated well with their pharmacokinetic effects.

The lipophilic 1-substituent in a series of 1-((amidolinked)-alkyl)-pyrimidones, inhibitors of recombinant lipoprotein-associated phospholipase A(2), has been modified to give inhibitors of high potency in human plasma and enhanced physicochemical properties. Phenylpiperazineacetamide derivative 23 shows very promising oral activity.

Modification of the pyrimidone 5-substituent in a series of 1-((amidolinked)-alkyl)-pyrimidones, lipophilic inhibitors of lipoprotein-associated phospholipase A2, has given inhibitors of nanomolar potency and improved physicochemical properties. Compound 23 was identified as a potent, highly water soluble. CNS penetrant inhibitor suitable for intravenous administration.

From two related series of 2-(alkylthio)-pyrimidones, a novel series of 1-((amidolinked)-alkyl)-pyrimidones has been designed as nanomolar inhibitors of human lipoprotein-associated phospholipase A2. These compounds show greatly enhanced activity in isolated plasma. Selected derivatives such as compounds 51 and 52 are orally active with a good duration of action.

The synthesis of analogues of SB-253514, a novel natural product derived inhibitor of lipoprotein associated phospholipase A2 (Lp-PLA2), is described together with their ability to inhibit Lp-PLA2.

Rhizopus delemar lipase catalysed ester hydrolysis of the alpha-methoxy-beta-phenylpropanoate 1 affords the (R)-(+) and (S)-(-) isomers in > 84% enantiomeric excess. Absolute stereochemistry was determined by a single crystal X-ray analysis of a related synthetic analogue. The activity of these two enantiomers on glucose transport in vitro and as anti-diabetic agents in vivo is reported and their unexpected equivalence attributed to an enzyme-mediated stereospecific isomerisation of the (R)-(+) isomer. Binding studies using recombinant human PPARgamma (peroxisomal proliferator activated receptor gamma), now established as a molecular target for this compound class, indicate a 20-fold higher binding affinity for the (S) antipode relative to the (R) antipode.

Cinnamyl derivatives of thieno[2,3-d]oxazinones are mechanism-based inhibitors of the HSV-2, VZV and CMV herpes proteases which demonstrate nanomolar potency. Compounds 5 and 28 inhibit protease processing in HSV-2 infected cells with a selectivity index of at least 30.

Enedione derivatives of thieno[2,3-d]oxazinones are nanomolar inhibitors of CMV protease which act through a novel dual acylation of the catalytic serine and alkylation of the protease cysteine 161 via a Michael addition to the enedione moiety of the inhibitor.

998 children aged 6, 8 and 10, from low income families living in the Federal District, Brazil and attending public, first grade, schools, received bi-annual topical APF Gel-Tray applications. The mass methodology proposed by the National Dental Caries Preventive Program of the Brazilian Ministry of Health, without previous prophylaxis, was adopted. After one year, in fluoridated communities the reduction in the incidence of CPOS was of 31.6%, 24.9% and 39.5%, respectively, for the groups aged 6, 8 and 10. In non fluoridated communities the reductions were, respectively, of 24.3%, 26.6% and 27.7%, in every case with statistic significance at the 95% confidence level. Considering the positive results in a developing area, it is recommended that oral health institutions at all levels could adopt a comprehensive and continuous preventive program for children under their responsibility.

Structural modifications of the potassium channel activator cromakalim (1) are described in which the amide moiety at C-4 has been replaced by carboxamide and thiocarboxamide functions. Analogues in which the hydroxyl group at C-3 has been oxidized or removed are also disclosed. Such analogues display an interesting profile of smooth muscle relaxant activity in the guinea pig isolated trachea, not all of which appears to result from the opening of potassium channels, but few compounds retain useful in vivo activity. However, one compound in particular, 6-cyano-2,2-dimethyl-N-methyl-2H-1-benzopyran-4-thiocarboxamide (13) was shown to be a potent potassium channel activator in vitro and to provide prolonged protection to guinea pigs from the respiratory effects of inhaled histamine.

The synthesis of a novel series of smooth muscle relaxants which have been shown to act via the opening or activation of potassium channels is described. Compounds have been evaluated for their ability to inhibit spontaneous tone in guinea pig isolated trachealis and structure-activity relationships are discussed. One compound in particular, 1,1-dimethyl-5-nitro-3-(2-pyridon-1-yl)indan-2-ol, (16) was identified as a potent relaxant of airways smooth muscle in vitro with IC50 = 0.15 microM and was found to significantly inhibit histamine-induced dyspnoea in conscious guinea pigs when given orally 30-45 min prior to challenge.

A series of 4-amido-3,4-dihydro-2H-1-benzopyran-3-ols and 4-amido-2H-1-benzopyrans related to the potassium channel activator cromakalim have been prepared and evaluated for their relaxant activity in guinea pig isolated tracheal spirals. Several analogues show enhanced relaxant activity relative to cromakalim in this preparation and the rank order of potency for those substituents investigated at C-6 was CF3 greater than CN greater than C2H5 greater than aza greater than or equal to CH3. One compound, trans-3,4-dihydro-2,2-dimethyl-4-(2-oxopiperidin-1-yl)-7-(trifluor omethyl)-2H- 1-benzopyran-3-ol (24), was resolved into its two enantiomers and the activity was shown to reside essentially in the (+)-isomer, adding further support to the suggestion that the smooth muscle receptor for these potassium channel activators is stereoselective.