Search

Background‘Digital Mental Health services,’ or mental health care delivered via internet, computers, mobile phones, tablets, or text messaging services, are an increasingly important way to expand care to underserved groups in low-resource settings. In order to continue providing psychiatric, psychotherapeutic and counselling care during COVID-19-related movement restrictions, Médecins Sans Frontières (MSF), a humanitarian medical organization, abruptly transitioned part of its mental health (MH) activities to digitally supported remote services in 2020 across humanitarian and resource-constrained settings. MethodsFrom June-July of 2020, investigators used a mixed method, sequential explanatory study design to assess MSF staff perceptions of digital MH services provided during the COVID-19 crisis. Preliminary quantitative results influenced qualitative question guide design. Eighty-one quantitative online questionnaires were collected and a subset of 13 qualitative follow-up in-depth interviews (IDI) occurred.ResultsRespondents in 44 countries (6 world regions), mostly from Sub-Saharan Africa (39.5%), the Middle East (18.5%) and Asia (13.6%) participated. Most digital MH interventions depended on audio-only platforms (80%). 30% of respondents reported that more than half of their patients were unreachable using digital interventions, usually because of poor network coverage (73.8%), a lack of communication devices (72.1%), or a lack of a private space at home (67.2%). Nearly half (47.5%) of respondents felt their staff had a decreased ability to provide comprehensive MH care using digital platforms. Most respondents thought MH staff had a negative (46%) or mixed (42%) impression of remote care. Nevertheless, almost all respondents (96.7%) thought digital MH services had some degree of utility, most commonly citing improved access to care (37.7%) and greater time efficiency (32.8%) as reasons for its continued use.ConclusionDigital MH activities were seen as an acceptable alternative to in-person therapeutic interventions in humanitarian settings during the COVID-19 pandemic. However, they were not considered suitable for all patients in the humanitarian contexts studied, especially survivors of sexual or interpersonal violence, pediatric and geriatric cases, and patients with severe MH conditions. Audio-only technologies that lacked non-verbal cues were particularly challenging and made risk assessment and emergency care more difficult. Prior to considering digital MH services, communications infrastructure should be assessed, and comprehensive, context-specific protocols should be developed.

'Tele-Mental Health (MH) services,' are an increasingly important way to expand care to underserved groups in low-resource settings. In order to continue providing psychiatric, psychotherapeutic and counselling care during COVID-19-related movement restrictions, Médecins Sans Frontières (MSF), a humanitarian medical organization, abruptly transitioned part of its MH activities across humanitarian and resource-constrained settings to remote format.From June-July of 2020, investigators used a mixed method, sequential explanatory study design to assess MSF staff perceptions of tele-MH services. Preliminary quantitative results influenced qualitative question guide design. Eighty-one quantitative online questionnaires were collected and a subset of 13 qualitative follow-up in-depth interviews occurred.Respondents in 44 countries (6 geographic regions), mostly from Sub-Saharan Africa (39.5%), the Middle East and North Africa (18.5%) and Asia (13.6%) participated. Most tele-MH interventions depended on audio-only platforms (80%). 30% of respondents reported that more than half of their patients were unreachable using these interventions, usually because of poor network coverage (73.8%), a lack of communication devices (72.1%), or a lack of a private space at home (67.2%). Nearly half (47.5%) of respondents felt their staff had a decreased ability to provide comprehensive MH care using telecommunication platforms. Most respondents thought MH staff had a negative (46%) or mixed (42%) impression of remote care. Nevertheless, almost all respondents (96.7%) thought tele-MH services had some degree of usefulness, notably improved access to care (37.7%) and time efficiency (32.8%). Qualitative results outlined a myriad of challenges, notably in establishing therapeutic alliance, providing care for vulnerable populations and those inherent to the communications infrastructure.Tele-MH services were perceived to be a feasible alternative solution to in-person therapeutic interventions in humanitarian settings during the COVID-19 pandemic. However, they were not considered suitable for all patients in the contexts studied, especially survivors of sexual or interpersonal violence, pediatric and geriatric cases, and patients with severe MH conditions. Audio-only technologies that lacked non-verbal cues were particularly challenging and made risk assessment and emergency care more difficult. Prior to considering tele-MH services, communications infrastructure should be assessed, and comprehensive, context-specific protocols should be developed.

Janus kinases (JAKs) have a key role in regulating the expression and function of relevant inflammatory cytokines involved in asthma and chronic obstructive pulmonary disease. Herein are described the design, synthesis, and pharmacological evaluation of a series of novel purinone JAK inhibitors with profiles suitable for inhaled administration. Replacement of the imidazopyridine hinge binding motif present in the initial compounds of this series with a pyridone ring resulted in the mitigation of cell cytotoxicity. Further systematic structure-activity relationship (SAR) efforts driven by structural biology studies led to the discovery of pyridone 34, a potent pan-JAK inhibitor with good selectivity, long lung retention time, low oral bioavailability, and proven efficacy in the lipopolysaccharide-induced rat model of airway inflammation by the inhaled route.

Background Onychomycosis is a difficult-to-treat fungal nail infection whose treatment can involve systemic or topical antifungal approaches. Objectives To assess the efficacy and safety of terbinafine 10% nail lacquer in distal lateral subungual onychomycosis (DLSO). Patients/methods Patients with mild-to-moderate DLSO were randomised (3:3:1) to receive double-blind topical terbinafine 10% (n = 406) or its vehicle (n = 410) administered once daily for 4 weeks and then once weekly for 44 weeks, or open-label topical amorolfine 5% (n = 137) for 48 weeks, with a 12-week follow-up period. The primary efficacy endpoint, complete cure rate at Week 60, was a composite of negative potassium hydroxide (KOH) microscopy, negative culture for dermatophytes and no residual clinical involvement of the target big toenail. Results Complete cure rates at Week 60 in the terbinafine, vehicle and amorolfine groups were 5.67%, 2.20% and 2.92%, respectively (odds ratio (OR) vs vehicle = 2.68; 95% confidence intervals (CI): 1.22-5.86; p = .0138). Statistically significant differences in responder (negative KOH and negative culture and ≤10% residual clinical involvement) and mycological cure rates (negative KOH and negative culture) at Week 60 were obtained between terbinafine and vehicle. Terbinafine was well-tolerated with no systemic adverse reactions identified; the most common topical adverse reactions were erythema and skin irritation. Conclusions Terbinafine 10% nail lacquer was an effective treatment for mild-to-moderate onychomycosis improving both clinical and mycological criteria compared with vehicle. Furthermore, there may be some benefits compared to the currently available topical agent, amorolfine 5%. Treatment was well-tolerated and safe.

Objective We present the results of a cross‐cultural validation of the Mental Health Global State (MHGS) scale for adults and adolescents (

RESUMEN Introducción: Los estudiantes universitarios son particularmente vulnerables a una inadecuada nutrición, con la subsecuente afectación en su estado nutricional y de salud. Objetivo: Investigar la frecuencia de exceso de peso (EP) y algunos de sus factores asociados en estudiantes de la Universidad de Antioquia-Colombia. Métodos: Estudio transversal en 424 estudiantes, ambos sexos, con edades de 21,4±4,0 años. El EP se diagnosticó según índice de masa corporal (IMC) ≥ 25 kg/m2; el riesgo de adiposidad central (RAC) como perímetro de cintura (PC) ≥ 80 cm en mujeres y ≥ 90 cm en hombres. Se midieron variables sociodemográficas y asociadas con el estilo de vida (EV). Se empleó estadística descriptiva, prueba Chi2 y α = 0,05. Resultados: El 17,1% de los estudiantes presentó EP, mayor en hombres que en mujeres (22,6% vs 14,0%); un 8,1% mostró RAC, mayor en mujeres (9,1% vs 6,5%). El IMC se asoció con el sexo (p= 0,001). El RAC no mostró asociación con las características sociodemográficas ni de EV. Conclusión: Un porcentaje considerable de los universitarios presentó exceso de peso establecidos a partir de IMC, lo cual fue asociado al sexo del estudiante. No obstante, es importante promover espacios universitarios que propendan por estilos de vida saludables.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the clinical effects and safety of haloperidol compared to olanzapine for people with schizophrenia and schizophrenia‐like illnesses.

Spleen tyrosine kinase (Syk) is essential for signal transduction of immunoreceptors. Inhibition of Syk abrogates mast cell degranulation and B cell responses. We hypothesized that Syk inhibition in the lung by inhaled route could block airway mast cells degranulation and the early asthmatic response without the need of systemic exposure. We discovered LAS189386, a novel Syk inhibitor with suitable properties for inhaled administration. The aim of this study was to characterize the in vitro and in vivo profile of LAS189386. The compound was profiled in Syk enzymatic assay, against a panel of selected kinases and in Syk-dependent cellular assays in mast cells and B cells. Pharmacokinetics and in vivo efficacy was assessed by intratracheal route. Airway resistance and mast cell degranulation after OVA challenge was evaluated in an ovalbumin-sensitized Brown Norway rat model. LAS189386 potently inhibits Syk enzymatic activity (IC50 7.2 nM), Syk phosphorylation (IC50 41 nM), LAD2 cells degranulation (IC50 56 nM), and B cell activation (IC50 22 nM). LAS189386 inhibits early asthmatic response and airway mast cell degranulation without affecting systemic mast cells. The present results support the hypothesis that topical inhibition of Syk in the lung, without systemic exposure, is sufficient to inhibit EAR in rats. Syk inhibition by inhaled route constitutes a promising therapeutic option for asthma.

Long-acting muscarinic antagonists are widely used to treat chronic obstructive pulmonary disease (COPD). In addition to bronchodilation, muscarinic antagonism may affect pulmonary histopathological changes. The effects of long-acting muscarinic antagonists have not been thoroughly evaluated in experimental models of COPD induced by chronic exposure to cigarette smoke (CS). We investigated the effects of aclidinium bromide on pulmonary function, airway remodeling, and lung inflammation in a CS-exposed model of COPD. A total of 36 guinea pigs were exposed to CS and 22 were sham exposed for 24 weeks. Animals were nebulized daily with vehicle, 10 μg/ml, or 30 μg/ml aclidinium, resulting in six experimental groups. Pulmonary function was assessed weekly by whole-body plethysmography, determining the enhanced pause (Penh) at baseline, after treatment, and after CS/sham exposure. Lung changes were evaluated by morphometry and immunohistochemistry. CS exposure increased Penh in all conditions. CS-exposed animals treated with aclidinium showed lower baseline Penh than untreated animals (P = 0.02). CS induced thickening of all bronchial wall layers, airspace enlargement, and inflammatory cell infiltrate in airways and septa. Treatment with aclidinium abrogated the CS-induced smooth muscle enlargement in small airways (P = 0.001), and tended to reduce airspace enlargement (P = 0.054). Aclidinium also attenuated CS-induced neutrophilia in alveolar septa (P = 0.04). We conclude that, in guinea pigs chronically exposed to CS, aclidinium has an antiremodeling effect on small airways, which is associated with improved respiratory function, and attenuates neutrophilic infiltration in alveolar septa. These results indicate that, in COPD, aclidinium may exert beneficial effects on lung structure in addition to its bronchodilator action.

Background and purpose The Janus Kinase (JAK) family mediates the cytokine receptor-induced signalling pathways involved in inflammatory processes. The activation of the signal transducers and activators of transcription (STATs) by JAK kinases is a key point in these pathways. Four JAK proteins, JAK1, JAK2, JAK3 and tyrosine kinase 2 (Tyk2) associate with the intracellular domains of surface cytokine receptors are phosphorylating STATs and modulating gene expression. The aim of this study was to explore the role of JAK inhibition in an acute model of inhaled lipopolysaccharide (LPS)-induced airway inflammation in rats through evaluating the effects of tofacitinib, a marketed pan-JAK inhibitor. Specifically, some pulmonary inflammation parameters were studied and the lung STAT3 phosphorylation was assessed as a target engagement marker of JAK inhibition in the model. Experimental approach Rats were exposed to an aerosol of LPS (0.1 mg/ml) or phosphate-buffered saline (PBS) during 40 min. Bronchoalveolar lavage fluid (BALF) and lung samples were collected 4 h after PBS or LPS exposure. Neutrophils in BALF were counted and a panel of cytokines were measured in BALF. Phosphorylation of STAT3 was studied in lung homogenates by ELISA and localization of phospho-STAT3 (pSTAT3) in lung tissue was also evaluated by immunohistochemistry. In order to assess the effect of JAK inhibition, tofacitinib was administered 1 h before challenge at doses of 3, 10 and 30 mg/kg p.o. Key results Inhaled LPS challenge induced an augment of neutrophils and cytokines in the BALF as well as an increase in pSTAT3 expression in the lungs. Tofacitinib by oral route inhibited the LPS-induced airway neutrophilia, the levels of some cytokines in the BALF and the phosphorylation of STAT3 in the lung tissue. Conclusions and implications In summary, this study shows that JAK inhibition ameliorates inhaled LPS-induced airway inflammation in rats, suggesting that at least JAK/STAT3 signalling is involved in the establishment of the pulmonary neutrophilia induced by LPS. JAKs inhibitors should be further investigated as a potential therapy for respiratory inflammatory diseases.

A novel class of potent Syk inhibitors has been developed from rational design. Highly potent aminopyridine derivatives bearing a 4-trifluoromethyl-2-pyridyl motif and represented by compound 13b IC50: 0.6 nM were identified. Substitution by a 2-pyrazinyl motif and SAR expansion in position 4 of the central core provided diverse potent non-cytotoxic Syk inhibitors showing nanomolar activity inhibiting human mast cell line LAD2 degranulation.

Data from the Mexican national leprosy control programme 1989-2009 are described and analysed. After initial increases associated with the introduction of MDT and the start of the global elimination initiative in the early 1990 s, both prevalence and incidence declined dramatically throughout most of the country. Reported prevalence fell below 1 per 10000 in 1994 and has remained below that level ever since. There is considerable geographic heterogeneity, with highest case detection rates in western states bordering the Pacific and lowest in the south east. Reasons for these geographic differences are unclear. There is evidence of increases in average age of cases, and in proportions male and MB, as in several other populations with declining leprosy. There is some evidence of increasing leprosy in states bordering on Texas, USA, where M. leprae is known to be harboured in armadillos. The relevance of armadillos for leprosy in Mexico is unclear but a priority question.

A series of aminopyrazines as inhibitors of Syk kinase activity and showing inhibition of LAD2 cells degranulation is described. Optimization of the carboxamide motif with aminomethylpiperidines provided high potency inhibiting Syk but low cellular activity. Amides of cis and trans adamantanol showed good inhibitory activity against Syk as well as remarkable activity in LAD2 cells degranulation assay.

The aim of the following study was to characterize a passive systemic anaphylaxis rat model of dinitrophenyl (DNP)-induced plasma extravasation in the trachea to determine if the model is appropriate for the evaluation of new drugs targeting airway mast cells by oral and intratracheal (i.t.) route. To this purpose we have used fluticasone and a range of anti-allergic drugs including compounds either active on mast cell activation, such as cromoglycate and the Syk inhibitor R406, or active on mast cell mediators, such as cetirizine and montelukast. To further characterize the model, the effect of fluticasone, cromoglycate and R406 on rat tracheal mast cell degranulation was also assessed histologically. DNP-induced tracheal plasma extravasation was inhibited by cromoglycate (i.v. and i.t.) and R406 (p.o.), but not by fluticasone (i.t.), cetirizine or montelukast (p.o.). Cromoglycate and R406 also showed inhibition of tracheal mast cell degranulation, whereas fluticasone was inactive. These results suggest that the DNP-induced tracheal plasma extravasation model constitutes a useful animal model for the evaluation, by oral and i.t. route, of new anti-allergic drugs intended to target airway mast cells.

Some heterocyclic systems, called privileged scaffolds, appear frequently in bioactive products and marketed drugs. The combination of a recognized privileged scaffold (hydantoin) and a functional group with high incidence in bioactive molecules (guanidine) guided the design of a library of amphipatic compounds, which allowed the discovery of novel TRPV1 ion channel blockers. The library was synthesized by parallel solid-phase synthesis from an orthogonally protected resin-bound Lys-Lys skeleton. Key steps of the synthetic procedure were the construction of the hydantoin ring, by reaction of the N-terminal amino group with N,N-disuccinimidyl carbonate (DSC) and subsequent base-induced cyclization, and the guanidinylation of the C-terminal Lys side-chain after removal of the Alloc protecting-group. The preliminary biological studies have allowed the identification of some of the key structural features directing the blockage of capsaicin-induced Ca(2+) influx through TRPV1 channels, particularly, the strong preference showed for highly lipophilic acyl groups and substituted guanidine moieties. Active compounds based on this new pharmacophoric scaffold that display in vitro and in vivo inhibitory activity.

Mexico is a country with sporadic leprosy cases, and the reemergence of drug resistance is a concern. In this study, molecular analysis of Mycobacterium leprae was employed to clarify the spread of drug-resistant leprosy. Thus, drug resistance-determining regions in the folP1, rpoB, and gyrA genes, which are associated with resistance to dapsone, rifampicin, and ofloxacin, respectively, were analyzed by direct sequencing of the PCR product. No mutations in the folP1 gene were observed in any of the 72 slit skin samples obtained from 38 patients, although two samples carrying a mutation at codon 425 in the rpoB gene, which confers resistance to rifampicin, a key component of multidrug therapy, were identified. In addition, a mutation at codon 91 in the gyrA gene, which correlates with ofloxacin resistance, was found in one sample. These results demonstrate the existence of rifampicin- and ofloxacin-resistant leprosy. Interestingly, wild-type and mutant sequences in the gyrA gene were found to coexist in one clinical sample. In addition, all three drug resistance-related mutations were found in only one of the two earlobes of the patients concerned, suggesting a possible pathway for the spread of drug-resistant M. leprae.

Peptides representing the sequence of the immunodominant loop of foot-and-mouth disease virus strain C-S8 (YTASARGDLAHLTTTHARHLP, residues 136-156 of VP1) and of several variant viruses have been prepared by solid phase methods. In addition, five peptides with single-residue replacements at Leu147 (Ile, Nle, Val, Ala, Gly) have been synthesized. Tosyl and dinitrophenyl protections for histidine have been compared, the latter being found to give better synthetic products. The peptides have been tested in an immunodot assay against a panel of monoclonal antibodies directed towards the VP1 loop. Immunochemical results are discussed on the basis of the mobility of the region reproduced by the peptides and the nature of the side chain of residue 147.

The vanilloid receptor subunit 1, or transient receptor potential vanilloid 1 (TRPV1), integrates physical and chemical stimuli in the peripheral nervous system, playing a key role in inflammatory pain. Identification of potent TRPV1 antagonists is thus an important goal of current neuropharmacology. Herein, we describe the solid-phase synthesis of a series of indole-based peptoids (N-alkylglycines) and the biological activity of the peptoids as novel TRPV1 antagonists. The potency and selectivity of the compounds were determined by electrophysiological recordings in Xenopus oocytes. The most potent and selective noncompetitive TRPV1 antagonist of the series, compound 7, represents an interesting pharmacophoric structure for analgesic lead optimization.

Pain is a complex disease that usually remains poorly treated or undertreated, especially the neuropathic pain caused by injury to the peripheral or central nervous system. Antagonists of the NMDA receptor complex have emerged as potential drugs for pain management. A strong case is being raised for non-competitive or uncompetitive antagonists with low-to-moderate affinity and fast on/offset kinetics as drugs with good therapeutic profiles, because of their reduced side effects.

Summary Allatostatins with a typical C-terminal sequence YXFGL-NH2 are insect neuropeptides with inhibitory properties upon Juvenile Hormone production in the corpora allata, vitellogenin release by the fat body, and gut and dorsal vessel motility. All these biological effects are rapidly reversible, suggesting the occurrence of effective mechanisms for inactivation of the peptides. We have studied the degradation of DRLYSFGL-NH2 (BLAST-2), one of the allatostatins of Blattella germanica, in the internal milieu of adult females of this cockroach. The experimental approach combined the use of the radioiodinated derivative [125I-Tyr4]BLAST-2, microdialysis techniques and HPLC analysis with a radioisotope detector. Under these experimental conditions, the half-life of BLAST-2 in the internal milieu of the adult female of B. germanica was between 3 and 6 min. Such a short half-life explains the high doses of allatostatins required to obtain the expected biological effects when tested in vivo, and suggests that circulating allatostatins are subject to rapid rates of synthesis and degradation in order to be operative physiologically.

NK-lysin and granulysin are homologous cationic anti-bacterial peptides produced by pig and human cytolytic lymphocytes, respectively. The solution structure of NK-lysin comprises five amphipathic α-helices. To investigate the properties of a helix-loop-helix region postulated to be a membrane-docking part of NK-lysin, we synthesized 22- and 29-residue peptides reproducing this region for both NK-lysin and granulysin. CD spectroscopy of the synthetic peptides in a liposomal solution showed spectra typical of α-helical peptides. The peptides were active against Gram-positive and Gram-negative bacteria, with the two NK-lysin peptides showing higher anti-bacterial activities than the two from granulysin. One NK-lysin peptide was active against Pseudomonas aeruginosa and Staphylococcus aureus, two organisms against which NK-lysin is inactive. Granulysin peptides were inactive against these bacteria, in contrast with granulysin, which is known to be active against them. Both NK-lysin and all synthetic analogues killed Mycobacterium tuberculosis and K562 tumour cells, but did not display haemolytic activity. These results identify a potent anti-mycobacterial domain in NK-lysin and granulysin consisting of a 22-residue (helix 3) sequence plus a disulphide-constrained loop.

The 2-amino-3-oxohexahydroindolizino[8,7-b]indole-5-carboxylate system (IBTM) has been proposed as a dipeptide surrogate of type II‘ β-turns. To evaluate which of the 11bR and 11bS diastereomers of IBTM best reproduces the conformational properties of type II‘ β-turns, gramicidin S (GS), a cyclic antibiotic peptide that contains two such units, has been chosen as a test compound and the effect of either diastereomer on both conformation and activity of the resulting peptide analogues has been determined. A conventional approach to the cyclic peptide structure based on solution cyclization of a partially protected precursor was only practicable for the (S)-IBTM diastereomer. As an alternative, a solid phase mediated cyclization approach has been devised and applied successfully to both gramicidin S and its Lys2,2‘ analogue, then extended to the (R)-IBTM-containing analogues. NMR conformational analysis has clearly shown that only the (R) diastereomer of IBTM is a suitable mimic of the type II‘ β-turn confo...

RESUMEN: Objetivo: Observar las relaciones entre estatus socioeco-nómico, estatura y problemas nutricionales de sobrepe-so, obesidad, riesgo de complicaciones metabólicas en hombres y mujeres de Medellín. Métodos: estudio transversal, descriptivo con una mues-tra de 5,556 adultos con edades entre 18 y 69 años. Se evaluaron peso, estatura y perímetro de cintura. Como variables socioeconómicas se evaluaron los ingresos fa-miliares, el estrato socioeconómico y el nivel educativo. Resultados: Se encontró que en hombres y mujeres la estatura alcanzada está asociada con las condiciones so-cioeconómicas medidas por estrato e ingresos familiares. En las mujeres la estatura alcanzada, la edad y el estrato están asociados con la obesidad, el sobrepeso y los ries-gos de complicaciones metabólicas. Conclusión: la obesidad, el sobrepeso y el riesgo de com-plicaciones metabólicas en la adultez son el resultado no solo de hábitos individuales no saludables como patrón alimentario basado en alimentos altamente energéticos, sumado a bajo gasto calórico, sino también a una acumu-lación de privaciones alimentarias a lo largo de la vida y deben ser intervenidas antes del nacimiento y durante la infancia y la adultezÁlvarez LS et al / Colombia Médica - Vol. 44 Nº 3, 2013 (Jul-Sep) ABSTRACT: Objective: to observe the relationship between socioeconomic status, height and nutritional problems related to obesity, overweight and risk of metabolic complications in men and women of Medellin (Colombia). Methods: cross-sectional study with a sample of 5,556 adults between 18 and 69 years of age. We assessed weight, height and waist circumference. Socioeconomic variables were evaluated by family income, socioeconomic stratum and academic level achieved. Results: we found that in men and women the height reached in adulthood is associated with socioeconomic conditions as measured by the socioeconomic strata and family income. In women, height, age, and socioeconomic strata are associated with obesity, overweight and risk of obesity, and risk of metabolic complications. Conclusion: These results are not only from individual unhealthy habits, such as eating patterns based on high density foods combined with low energy expenditure, but also from the cumulative effect of food deprivation throughout life. Therefore, policies intended to prevent them should take a preventive approach that begins before birth and continues during childhood and adulthood COL0065608 COL0003249

Small peptides patterned after the N-terminus of the synaptosomal protein of 25 kDa (SNAP-25), a member of the protein complex implicated in Ca 2+ -dependent neuronal exocytosis, inhibit in vitro the release of neuromodulators involved in pain signaling, suggesting an in vivo analgesic activity. Here, we report that compound DD04107, a 6-mer palmitoylated peptide that blocks the inflammatory recruitment the inflammatory recruitment of ion channels to the plasma membrane of nociceptors, and the release of calcitonin gen-related peptide (CGRP) from primary sensory neurons, displays potent and long-lasting in vivo anti-hyperalgesia and anti-allodynia in chronic models of inflammatory and neuropathic pain, such as the complete Freund9s Adjuvant, osteosarcoma, chemotherapy and diabetic neuropathic models. Subcutaneous administration of the peptide produced a dose-dependent anti-hyperalgesic and anti-allodynic activity that lasted ≥24 h. The compound showed a systemic distribution, characterized by a bicompartmental pharmacokinetic profile. Safety pharmacology studies indicated that the peptide is largely devoid of side effects, and substantiated that the in vivo activity is not due to locomotor impairment. Therefore, DD04107 is a potent and long-lasting anti-nociceptive compound that displays a safe pharmacological profile. These findings support the notion that neuronal exocytosis of receptors and neuronal algogens pivotally contribute to chronic inflammatory and neuropathic pain, and imply a central role of peptidergic nociceptor sensitization to the pathogenesis of pain.

to compare the results of nutritional assessment of children and adolescents under 18 years of age using the WHO growth standards and the cut-off points proposed by the resolution 2121 of 2010 of the Social Security Ministry of Colombia. Materials and methods: we evaluated the nutritional status by using the indicators height/age and body max index (BMI) in children and adolescents under 18 years of age and weigh/height in children under five belonging to 2719 rural and urban households in Medellin. They were sampled in the study Food and nutritional profile of Medellin 2010 conducted by the municipal government. Results: we found lower prevalence rates of adequate weight/height and BMI in children less than five years of age using the Colombian standards as compared to the WHO standards. BMI for children over 5 years of age behaved similarly. The difference is explained for using different cut-off points and inclusion of new nutritional risk categories. Conclusions: for population-based studies may not be required to introduce the categories of nutritional risk and to change the cut-off points for overweight and obesity set up by the WHO standards given that they are more rigorous than others parameters for evaluating these two nutritional conditions. Related to individual follow-ups it is important to complement anthropometric measure evaluation with social aspects, family history, and rearing habits in children with BMI between 1 and 2 standard deviations. Key words: anthropometry, nutrition assessment, nutritional status, growth, body weight, body mass index, World Health Organization, children, adolescent, Colombia. RESUMEN: Comparar los resultados de la evaluación nutricional de los menores de 18 años de Medellín usando los estándares de la OMS, su sistema de clasificación y el propuesto por el Ministerio de la Protección Social de Colombia. Materiales y métodos: se evaluó el estado nutricional por los indicadores talla/edad e índice de masa corporal en menores de 18 y peso/talla en menores de cinco pertenecientes a 2.719 hogares urbanos y rurales de la ciudad de Medellín, que participaron en el estudio Perfil alimentario y nutricional de Medellín 2010, realizado por la Alcaldía de Medellín. Resultados: se encontraron menores prevalencias de peso/talla e IMC adecuados y mayores de sobrepeso y obesidad en menores de cinco años usando la clasificación colombiana, en relación con la de la OMS. Situación similar a la descrita para IMC se encontró en los mayores de 5 años. Las diferencias se explican por utilizar distintos puntos de corte e inclusión de nuevas categorías de riego nutricional. Conclusiones: aunque se requieren más estudios para alcanzar conclusiones definitivas, para estudios poblacionales posiblemente no se requiera introducir las categorías de riesgo nutricional, ni cambiar los puntos de corte para establecer sobrepeso y obesidad, pues los nuevos estándares de la OMS son más exigentes que otros patrones para evaluar estas dos condiciones. En el seguimiento individual se recomienda complementar la información antropométrica con aspectos sociales, antecedentes familiares y hábitos de crianza en niños con IMC entre >1 y ≤2 desviaciones estándar. Palabras clave: evaluación nutricional, antropometría, estado nutricional, crecimiento, índice de masa corporal, peso corporal, Organización Mundial de la Salud, niños, adolescentes, Colombia.

To study the conformational requirements of epitopes from a conserved antigenic area (area II) of respiratory syncytial (RS) virus fusion (F) glycoprotein, peptides of increasing length containing amino acids essential for these epitopes were synthesized. The synthetic peptides were tested for binding to a panel of neutralizing monoclonal antibodies (MAbs) for this area as well as to rabbit hyperimmune and human convalescent antisera. Antibody binding was dependent on peptide length; thus, a 61-residue peptide spanning amino acids 215 to 275 of the F1 subunit (peptide F215-275) reacted with more antibodies than a shorter (41-residue) peptide F235-275, and this one with more than the (21-residue) peptide F255-275. Most human convalescent sera contained antibodies that reacted with peptides F215-275 and F235-275 but failed to react with F255-275. The results of antibody binding could be related to the structure adopted by the peptides in solution, as determined by circular dichroism spectroscopy and susceptibility of peptides to trypsin digestion. Pretreatment of peptide F215-275 with SDS abolished reactivity with certain MAbs, supporting the notion that higher order structures were needed for antibody binding. High titre anti-peptide antisera were induced in rabbits inoculated with the peptides; however, these sera failed to react with the native F molecule. In mice, only the largest F215-275 peptide induced an anti-peptide response, but their sera reacted poorly with the native F protein and the animals were not protected against an RS virus challenge. These results illustrate the potential use of synthetic peptides in studies of the F protein physical and antigenic structures as well as the problems in designing synthetic RS virus vaccines.

Aclidinium bromide is a novel potent, long-acting inhaled muscarinic antagonist in development for the treatment of chronic obstructive pulmonary disease. Aclidinium showed subnanomolar affinity for the five human muscarinic receptors (M(1)-M(5)). [(3)H]Aclidinium dissociated slightly faster from M(2) and M(3) receptors than [(3)H]tiotropium but much more slowly than [(3)H]ipratropium. Its association rate for the M(3) receptor was similar to [(3)H]ipratropium and 2.6 times faster than [(3)H]tiotropium. Residence half-life of [(3)H]aclidinium at the M(2) receptor was shorter than at the M(3) receptor, demonstrating kinetic selectivity for the M(3) receptor. In isolated guinea pig trachea, aclidinium showed comparable potency to ipratropium and tiotropium, faster onset of action than tiotropium, and duration of action similar to tiotropium and significantly longer than ipratropium. Nebulized aclidinium inhibited bronchoconstriction induced by acetylcholine in guinea pigs in a concentration-dependent manner with an onset of action faster than tiotropium. Duration of action of aclidinium (t(1/2) = 29 h) was much longer than ipratropium (8 h) but shorter than tiotropium (64 h). In dogs, aclidinium induced a smaller and more transient increase in heart rate than tiotropium at comparable supratherapeutic doses. Therefore, under these conditions, aclidinium showed a greater therapeutic index than tiotropium (4.2 versus 1.6). These results indicate that aclidinium is a potent muscarinic antagonist with a fast onset of action, a long duration of effect, and a favorable cardiovascular safety profile.

The transient receptor potential vanilloid member 1 (TRPV1). an integrator of multiple pain-producing stimuli, is regarded nowadays as an important biological target for the discovery of novel analgesics. Here, we describe the first experimental evidence for the behavior of an old family of analgesic dipeptldes, namely Xaa-Trp(Nps) and Trp(Nps)-Xaa (Xaa=Lys, Arg) derivatives, as potent TRPV1 channel bolckers. We also report the synthesis and biological investigation of a series of new conformatidnally restricted Trp(Nps)-dipeptide derivatives with improved TRPV1/ NMDA selectivity. Compound 15b, Which incorporates an N-terminal 2S-azetidine-derived Arg residue, was the most selective compound in this series. Collectively, a new family of TRPV1 channel blockers emerged from our results, although further modifications are required to fine-tune the potency/selectivity/ toxicity balance.

Vanilloid receptor subunit 1 (TRPV1) is an integrator of physical and chemical stimuli in the peripheral nervous system. This receptor plays a key role in the pathophysiology of inflammatory pain. Thus, the identification of receptor antagonists with analgesic and anti-inflammatory activity in vivo is an important goal of current neuropharmacology. Here, we report that [L-arginyl]-[N-[2,4-dichlorophenethyl]glycyl]-N-(2,4-dichlorophenethyl) glycinamide (H-Arg-15-15C) is a channel blocker that abrogates capsaicin and pH-evoked TRPV1 channel activity with submicromolar activity. Compound H-Arg-15-15C preferentially inhibits TRPV1, showing marginal block of other neuronal receptors. Compound H-Arg-15-15C acts as a noncompetitive capsaicin antagonist with modest voltage-dependent blockade activity. The compound inhibited capsaicin-evoked nerve activity in afferent fibers without affecting mechanically activated activity. Notably, administration of compound H-Arg-15-15C prevented the irritant activity of a local administration of capsaicin and formalin and reversed the thermal hyperalgesia evoked by injection of complete Freund’s adjuvant. Furthermore, it attenuated carrageenan-induced paw inflammation. Compound H-Arg-15-15C specifically decreased inflammatory conditions without affecting normal nociception. Taken together, these findings demonstrate that compound H-Arg-15-15C is a channel blocker of TRPV1 with analgesic and anti-inflammatory activity in vivo at clinically useful doses and substantiate the tenet that TRPV1 plays an important role in the etiology of chronic inflammatory pain., Supported by grants from the Ministerio de Educacion Ciencia y Deporte (SAF 2003/0509), La Fundación Ramón Areces (01/08-500), and Generalitat Valenciana (GV04B-0398) to A.F.M., PROFIT-090000-2001-70 and CDTI-03-006 (Ministerio de Industria) to DiverDrugs, SL.

Excessive activation of glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype is considered a relevant initial step underlying different neurodegenerative diseases. Recently, with the approval of memantine to treat Alzheimer dementia, NMDA receptors have regained clinical interest. Accordingly, the development and validation of NMDA receptor antagonists is being reconsidered. We recently identified a family of trialkylglycines that act as channel blockers of the NMDAreceptor. Their neuroprotective activity against excitotoxic insults remains elusive. To address this issue, we first characterized the contribution of glutamate receptor subtypes to hippocampal death in culture as a function of days in culture in vitro (DIV). Whereas at 7 DIV neither NMDA nor glutamate produced a significant neuronal death, at 14 and 21 DIV, NMDA produced the death of 40% of the neurons exposed to this receptor agonist that was fully protected by MK-801. Similar results were obtained for L-glutamate at 14 DIV. In contrast, when neurons at 21 DIV were used, glutamate killed 51.1 +/- 4.9% of the neuronal population. This neuronal death was only partially prevented by MK-801, and fully abrogated by a combination of MK-801 and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Glucose deprivation injured 37.1 +/- 9.2% of the neurons through a mechanism sensitive to MK-801. The family of recently identified N-alkylglycines tested protected neurons against NMDA and glucosedeprivation toxicity, but not against glutamate toxicity. Noteworthy, N-alkylglicines with a moderate protection against NMDA-induced toxicity strongly protected from beta-amyloid toxicity. Collectively, these findings imply both NMDA and non-NMDA receptors in excitotoxicity of hippocampal neurons, and suggest that blockade of NMDA receptors alone may not suffice to efficiently abrogate neurodegeneration.

28 pages, 5 figures., Inflammatory pain is a condition caused by tissue injury and requires efficient drug treatment. The identification and cloning of the vanilloid receptor TRPV1 represents a significant step in the clarification of the molecular mechanisms underlying transduction of noxious chemical and thermal stimuli by peripheral nociceptors. Because of its central implication in hyperalgesia, the TRPV1 receptor has emerged as a key therapeutic target for inflammatory pain management. Modulators of the TRPV1 receptor complex are considered to be useful and selective painkillers. The challenge, however, is to develop receptor-selective drugs that preserve the physiological activity of TRPV1 receptors while correcting those contributing to pathology. Thus, normal proprioceptive and nociceptive responses that represent a safety mechanism to prevent tissue injury must be preserved., Financial support from grants from MCYT, Fundació La Caixa, Fundació Marató TV3, and FIS.

Metabolic studies on insect allatostatins have suggested that the dipeptide Leu-Tyr may be a target for endopeptidases. In order to increase resistance to degradation, methyleneamino Ψ[CH 2 NH] and ketomethylene Ψ[COCH 2 ] peptide bond surrogates have been introduced at the position Leu 3 -Tyr 4 of the allatostatin Asp-Arg-Leu-Tyr-Ser-Phe-Gly-Leu-amide (BLAST-2), and Leu 3 -Phe 4 of [Phe 4 ]BLAST-2, respectively. Assays of inhibition of juvenile hormone (JH) synthesis in vitro by corpora allata from the cockroach Blattella germanica showed that both analogues were similarly active to the respective model peptides. The methyleneamino analogue was further tested in vivo as an inhibitor of JH synthesis, and in vivo and in vitro as an inhibitor of vitellogenin production by the fat body of B. germanica . The analogue was less active than BLAST-2 when tested in vitro , but more active than it when tested in vivo .

IFSCC Magazine, 11 (2008) (4) 311–315 This paper was presented as a keynote lecture at the IFSCC Congress 2008, Barcelona, Spain. Cutaneous neurogenic inflammation is emerging as an underlying mechanism for several skin conditions. The intimate cross-talk between the cutaneous immune system and the peripheral nervous system is fundamental for skin biology. However, an imbalance or dysfunction results in the onset of an inflammatory state that is reinforced by the synergic and complementary action of both systems. Cumulative evidence indicates that the thermoreceptor TRPV1 is a key player of neurogenic inflammation. This receptor is activated by both physical and chemical stimuli, and its activity is potentiated by pro-inflammatory mediators. An increase in TRPV1 activity results in an increment of neuronal excitability that leads to the release of proalgesic agents that stimulate the immune system. Therefore, the TRPV1 receptor is being considered as a cosmeceutical target, and agents that reduce its activity will be useful cosmeceuticals. Keywords: Algogens, epidermis, immune system, nociceptor, sensitization