Small molecules, big targets: drug discovery faces the protein-protein interaction challenge.

Protein-protein interactions (PPIs) are of pivotal importance in the regulation of biological systems and are consequently implicated in the development of disease states. Recent work has begun to show that, with the right tools, certain classes of PPI can yield to the efforts of medicinal chemists to develop inhibitors, and the first PPI inhibitors have reached clinical development. In this Review, we describe the research leading to these breakthroughs and highlight the existence of groups of structurally related PPIs within the PPI target class. For each of these groups, we use examples of successful discovery efforts to illustrate the research strategies that have proved most useful.JS, DES and ARB thank the Wellcome Trust for funding.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nrd.2016.2

Pharmacokinetics of midazolam in resuscitated patients treated with moderate hypothermia

Item does not contain fulltextBackground Patients who remain comatose after resuscitation are treated with moderate hypothermia. Little is known about the pharmacokinetics of drugs in patients who are treated with moderate hypothermia. Objective We investigated the pharmacokinetics of midazolam in resuscitated patients treated with moderate hypothermia in comparison to normothermic and non-resuscitated patients. Setting This study was performed on the ICU of a Dutch non-academic hospital. The study population consisted of nine patients in the hypothermic group and eight patients in the control group. Method The resuscitated patients were cooled to a target temperature of 33 degrees C and rewarmed 24 h after start of cooling. Midazolam was given as continuous infusion. The control group consisted of non-resuscitated ICU-patients who were treated with midazolam as sedative. Plasma concentration-time data were collected for midazolam and its metabolites. Main outcome measure Non-linear mixed effect modelling was used to analyze midazolam population pharmacokinetics and identify possible covariates. Results A two-compartment pharmacokinetic model best describes the data. The pharmacokinetic models of the investigated groups are not significantly different. Pharmacokinetic parameter estimates for midazolam for the hypothermic group are a body clearance (CL) of 12.6 l/h, an apparent volume of the central compartment (V1) of 19.1 l, an apparent volume of the peripheral compartment (V2) of 108 l and an intercompartmental clearance (Q) of 18.4 l/h. Estimated parameters for the control group are CL of 14.2 l/h, a V1 of 15.7 l, a V2 of 171 l and Q of 25.6 l/h. In the covariate analysis, body temperature did not significantly improve the model. Conclusion We found no significant difference in the pharmacokinetics of midazolam between resuscitated patients treated with hypothermia during 24 h and the control group

Caracterização da função mastigatória em crianças com dentição decídua e dentição mista Characteristics of masticatory function in children with deciduous and mixed dentition

OBJETIVO: caracterizar a mastigação de crianças com dentição decídua e com dentição mista, buscando verificar se há variações inerentes ao processo de desenvolvimento desta função. MÉTODOS: participaram 78 crianças, 4 a 11 anos, ambos os gêneros, divididas em dois grupos: GI - dentição decídua completa e GII - dentição mista. Foi realizada inspeção visual das estruturas do sistema estomatognático seguida da avaliação da mastigação, utilizando-se pão francês. A coleta dos dados foi realizada por meio da observação visual direta e registro em vídeo, visando confirmação dos dados observados, analisando-se os seguintes dados durante a mastigação: tipo de mordida, postura de lábios, amassamento com a língua, quantidade ingerida, padrão mastigatório, ciclos mastigatórios, movimentos mandibulares, uso dos dedos para juntar o alimento e verificação de movimentação exagerada da musculatura perioral. RESULTADOS: pode-se considerar que crianças de G1 e G2 apresentam as seguintes características: mordida frontal, porção média de alimento, presença de vedamento labial, média de 27 ciclos mastigatórios por porção, movimentos mandibulares rotatórios, ausência de amassamento do alimento com a língua, ausência da utilização dos dedos para juntar o alimento e ausência de uso exagerado da musculatura perioral. Não foram encontradas diferenças estatisticamente significantes entre as características mastigatórias dos dois grupos, sendo que apenas a presença de amassamento do alimento com a língua é predominante na dentição decídua. CONCLUSÃO: parece não existir diferenciação das características quanto ao padrão mastigatório em relação às fases de dentição estudadas, sendo apenas o amassamento do alimento mais frequente na decídua.<br>PURPOSE: to raise and to characterize the chewing pattern in children with deciduous and mixed dentition. METHODS: 78 children, from 4 to 11-year old, both genders, divided in two groups: GI: children with complete deciduous dentition and GII: with mixed dentition. Visual inspection of the stomatognathic system was followed by the evaluation of chewing, using three portions of French bread, with the first portion ignored. Data analysis was carried through visual observation and video recording, in order to review and confirm the observed characteristics. The following items were analyzed: type of bite, lips' position, kneading with the tongue, ingested amount, chewing pattern, number of chewing cycles, mandibular movements, the use of fingers to join food and verification of overstated movement of the perioral muscles. RESULTS: we can consider that children of GI and GII have the following characteristics: frontal bite, regular amount of food, presence of lips closed, average of 27 chewing cycles for portion, rotatory mandible movements, absence of food tongue kneading, no use of fingers to join the food and no overstated movements of the perioral muscles. Significant statistical differences were not found between the two groups. Only the presence of kneading food with the tongue is more common in deciduous dentition. CONCLUSION: it seems that there are no differences of the chewing pattern characteristics in relation to the dentition phase, considering deciduous or mixed dentition, excepting food kneading with the tongue that is more frequent in deciduous dentition