Pharmacokinetic and pharmacodynamic properties of aerosolized ("vaped") THC in adolescent male and female rats.

RATIONALE: Adolescent exposure to ∆9-tetrahydrocannabinol (THC), the psychotropic constituent of cannabis, might affect brain development, and in rodent models leads to long-term behavioral and physiological alterations. Yet, the basic pharmacology of this drug in adolescent rodents, especially when ingested via ecologically relevant routes like aerosol inhalation, commonly referred to as "vaping," is still poorly characterized. Moreover, sex differences exist in THC metabolism, kinetics, and behavioral effects, but these have not been rigorously examined after vapor dosing in adolescents. OBJECTIVES: We investigated the pharmacokinetics and pharmacodynamics of aerosolized THC (30 min inhalation exposure, 25 or 100 mg/ml) in adolescent Wistar rats of both sexes. METHODS: Liquid chromatography/mass spectrometry analysis of THC and its major metabolites was conducted on blood plasma and brain tissue at 5, 30, 60, and 120 min following a 30-min aerosol dosing session. Effects on activity in a novel environment for 120 min after aerosol, and temperature, were measured in separate rats. RESULTS: We found sex-dependent differences in the pharmacokinetics of THC and its active (11-OH-THC) and inactive (11-COOH-THC) metabolites in the blood and brain, along with dose- and sex-dependent effects on anxiety-like and exploratory behaviors; namely, greater 11-OH-THC levels accompanied by greater behavioral effects in females at the low dose but similar hypothermic effects in both sexes at the high dose. CONCLUSIONS: These results provide a benchmark for dosing adolescent rats with aerosolized (or "vaped") THC, which could facilitate adoption by other labs of this potentially human-relevant THC exposure model to understand cannabis effects on the developing brain.

Effect of Brazil's conditional cash transfer programme on tuberculosis incidence.

OBJECTIVE: To evaluate the impact of the Brazilian cash transfer programme (Bolsa Família Programme, BFP) on tuberculosis (TB) incidence in Brazil from 2004 to 2012. DESIGN: We studied tuberculosis surveillance data using a combination of an ecological multiple-group and time-trend design covering 2458 Brazilian municipalities. The main independent variable was BFP coverage and the outcome was the TB incidence rate. All study variables were obtained from national databases. We used fixed-effects negative binomial models for panel data adjusted for selected covariates and a variable representing time. RESULTS: After controlling for covariates, TB incidence rates were significantly reduced in municipalities with high BFP coverage compared with those with low and intermediate coverage (in a model with a time variable incidence rate ratio = 0.96, 95%CI 0.93-0.99). CONCLUSION: This was the first evidence of a statistically significant association between the increase in cash transfer programme coverage and a reduction in TB incidence rate. Our findings provide support for social protection interventions for tackling TB worldwide.

Wastewater reclamation systems in small communities.

The demands established in the rules and regulations by the administration in Catalonia seem to exclude small communities from wastewater reclamation and reuse, due to the comparatively high costs associated with the practice at small scale. In the framework of the DRAC project (Demonstration on Wastewater Reclamation and Reuse in Catalonia) two different pre-treatment systems, one extensive (infiltration-percolation) and another intensive (ring filter), each one followed by chlorine dioxide disinfection, were tested in order to be applied for small communities wastewater reclamation and reuse. The results of this study show that infiltration-percolation systems remove very efficiently physico-chemical contaminants and microorganisms. The ring filter system does not show a significant removal rate of contaminants, The use of infiltration-percolation as a pre-treatment for advanced chemical disinfection allows reducing the dose of disinfectant and the contact time needed to achieve a specific water quality, and diminishes disinfection byproducts (DBPs) generation. Therefore, this reclamation line is suitable for small communities due to its efficiency and low cost. However, further studies are needed in relation to the removal mechanisms of microorganisms, organic compounds in IP systems and the possible DBPs formation using chlorine dioxide.

Wastewater infiltration percolation for water reuse and receiving body protection: thirteen years' experience in Spain.

Infiltration percolation (IP) is an extensive technology to treat primary or secondary effluents of small and middle size communities before reuse or disposal to sensitive receiving bodies. Thirteen years of implementation of IP in Spain has highlighted the necessity to abide by defined design and construction rules and operation conditions in order to achieve consistently the treatment objectives and guarantee a long lasting treatment capacity. From this experience, high care should be taken of (i) the characteristics of the sand constituting the filter, (ii) the drainage conditions, (iii) the influent spreading over the infiltration surface and (iv) the risks related to recurrent overloading. Simple monitoring measures are suggested in order to improve the reliability of IP plants.

Development of a knowledge-based decision support system for identifying adequate wastewater treatment for small communities.

The identification of adequate treatment for small communities is a complex problem since it makes it necessary to combine aspects of the community and landscape, the receiving environment, and the available wastewater treatment technologies. This paper presents the development and implementation of a Knowledge-Based Decision Support System (KB-DSS) to tackle this problem. Different knowledge sources have been consulted in order to make up a comprehensive and accurate knowledge base. The core of the KB-DSS embraces two objectives. The first one is to assist in the selection of the treatment level adequate to fulfil the target quality standards for the receiving environment. The second one is to select the specific type of treatment. The KB-DSS is being applied to each one of the 3,482 different small communities comprised in the Small Communities Wastewater Treatment Plan of Catalonia, grouped according to river catchments. This paper also summarizes the different steps involved in the operation of the knowledge-based DSS when solving a real case study.

El factor de impacto y los cómputos de citasen la evaluación de la actividad científicay las revistas médicas / Impact factor and calculations of the cited references in the evaluation of the scientific activity and medical journals

Objetivo: la moderna normativa científica requiere que los autores que presentan los resultados de sus investigaciones citen a otras publicaciones que les han precedido; el cómputo de citas permite determinar la repercusión o impacto que han tenido las publicaciones y sus autores. En este trabajo se exponen los problemas que conlleva el análisis de citas y se comentan las consecuencias que su uso acrítico está provocando entre los científicos españoles. Material y Métodos: partiendo de un análisis de la literatura y de los resultados obtenidos en diversos trabajos publicados sobre el tema, se realiza una revisión crítica de las características, ventajas e inconvenientes de los análisis de citas, así como del factor de impacto obtenido de repertorios que, como el Science Citation Index, no son representativos de la ciencia que se cultiva en nuestra área geográfica. También se define el factor de impacto ponderado, que permite la comparación entre revistas de diferentes disciplinas. Resultados: el uso del factor de impacto se está generalizando como indicador para la evaluación individual de la actividad investigadora de personas, grupos e instituciones, y como medida para comparar entre sí la calidad o el prestigio de éstos. Sin embargo, estas evaluaciones no tienen en cuenta las numerosas limitaciones que presenta y que cuestionan seriamente su validez. Conclusiones: el impacto no mide la calidad de las publicaciones, sino la repercusión que han tenido en trabajos posteriores. El uso del factor de impacto en la evaluación de la investigación está provocando graves consecuencias, tanto entre los profesionales, que ven frustradas sus expectativas de promoción profesional, como en el periodismo científico español, que acude impotente a la exportación gratuita de la ciencia española a las revistas extranjeras, sobre todo a las angloamericanas del área de cobertura del Science Citation Index, y a la agonía progresiva de nuestras revistas médicas. Se propone la elaboración de índices de citas en los que estén plenamente representadas las revistas españolas más importantes y se formulan algunas propuestas para mejorar su calidad (AU)

Chiral discrimination of the analgesic cizolirtine by using cyclodextrins: A (1)H NMR study on the solution structures of their host-guest complexes.

The use of four cyclodextrins (three native and one beta-CD derivative) as NMR chiral solvating agents to resolve the enantiomers of (+/-)-cizolirtine, 1, and its chemical precursor (the carbinol, (+/-)-2), was investigated. The best enantiodiscrimination occurred when beta-cyclodextrin was used. ROESY experiments were performed to qualitatively ascertain the most probable host-guest structures in D(2)O solution, and the binding features found were explained in terms of spatial fitting of the guest molecules into the macrocyclic cavities. No geometrical differences were noted between the two diastereomeric complexes formed by a cyclodextrin and a racemic substrate, so the magnetic nonequivalence induced on guest protons by the enantioselective binding had to be explained as a result of subtle disparities in the orientation and/or the conformational state of the complexed enantiomers.

7-Azetidinylquinolones as antibacterial agents. 3. Synthesis, properties and structure-activity relationships of the stereoisomers containing a 7-(3-amino-2-methyl-1-azetidinyl) moiety.

A series of stereochemically pure 7-(3-amino-2-methyl-1-azetidinyl)-1,4- dihydro-6-fluoro-4-oxoquinoline- and -1,8-naphthyridine-3-carboxylic acids, with varied substituents at the 1-, 5-, and 8-positions, was prepared to determine the effects of chirality on potency and in vivo efficacy relative to the racemic mixtures (for part 2, see: J. Med. Chem. 1994, 37, 4195-4210). A series of chiral 9-fluoro-2,3-dihydro-3-methyl-7-oxo-10-(substituted-1- azetidinyl)-7H-pyrido[1,2,3- de]-1,4-benzoxazine-6-carboxylic acids was synthesized to study the effect of the azetidine moiety on tricyclic quinolone antibacterial agents. A series of amino acid prodrugs of chiral naphthyridines 24a and 24b and quinolone 33a (cetefloxacin) was prepared and evaluated for antibacterial activity, solubility, and pharmacokinetic behavior. The absolute configuration of the new azetidinylquinolones was established by X-ray analysis of one of the diastereomeric salts of the resolved azetidinols (15) and of compound 25a (E-4767), which showed the best in vitro and in vivo overall profile. Structure-activity relationship studies indicated that the absolute stereochemistry at the asymmetric centers of both the azetidine and the oxazine rings was critical to increase in vitro activity and oral efficacy. The 3S configuration in the pyridobenzoxazine series and the (2S,3R) configuration of the 3-amino-2-methylazetidine moiety for all new compounds conferred the best antibacterial activity.

7-azetidinylquinolones as antibacterial agents. 2. Synthesis and biological activity of 7-(2,3-disubstituted-1-azetidinyl)-4-oxoquinoline- and -1,8-naphthyridine-3-carboxylic acids. Properties and structure-activity relationships of quinolones with an azetidine moiety.

A series of 7-(2,3-disubstituted-1-azetidinyl)-1,4-dihydro-6-fluoro-4- oxoquinoline- and -1,8-naphthyridine-3-carboxylic acids, with varied substituents at the 1-, 5-, and 8-positions, was prepared to study the effects on potency and physicochemical properties of the substituent at position 2 of the azetidine moiety. The activity of the title compounds was determined in vitro against Gram-positive and Gram-negative bacteria, and the in vivo efficacy of selected derivatives was determined using a mouse infection model. The X-ray crystal structures of 6b, 6c, and 6d were found to be in reasonable agreement with the corresponding AM1 calculated geometries. Correlations between antibacterial potency of all the synthesized 7-azetidinylquinolones and naphthyridines and their calculated electronic properties and experimental capacity factors were established. Antibacterial efficacy and pharmacokinetic and physicochemical properties of selected derivatives were compared to the relevant 7-(3-amino-1-azetidinyl) and 7-(3-amino-3-methyl-1-azetidinyl) analogues (for Part 1, see: J. Med. Chem. 1993, 36, 801-810). A combination of a cyclopropyl or a substituted phenyl group at N-1 and a trans-3-amino-2-methyl-1-azetidinyl group at C-7 conferred the best overall antibacterial, pharmacokinetic, and physicochemical properties to the azetidinylquinolones studied.

7-Azetidinylquinolones as antibacterial agents. Synthesis and structure-activity relationships.

A series of novel antibacterial quinolones and naphthyridones has been prepared which contain 7-azetidinyl substituents in place of the usual piperazine or aminopyrrolidine groups. These azetidinyl derivatives were evaluated for in vitro activity by determining minimum inhibitory concentrations against a variety of bacteria. In vivo efficacy in the mouse infection model and blood levels in the mouse were determined for several compounds. The influence on the structure-activity relationships of varying substituents in the azetidine ring and at position 8 (CH, CF, CCl, N) and N-1 (ethyl, fluoroethyl, cyclopropyl, tert-butyl, 4-fluorophenyl, and 2,4-difluorophenyl) was also studied. Compounds with outstandingly broad-spectrum activity, particularly against Gram-positive organisms, improved in vivo efficacy, and high blood levels were identified in this work. 7-Azetidinyl-8-chloroquinolones were considered as warranting further development.