Assessing the reaction to and efficacy of the Screener drug discovery and development board game as a pedagogical tool in postgraduate courses.

Screener, a board game supplemented with online resources, was introduced and distributed by the Brazilian Society of Pharmacology and Experimental Therapeutics to postgraduate programs as an instructional tool for the process of drug discovery and development (DDD). In this study, we provided a comprehensive analysis of five critical aspects for evaluating the quality of educational games, namely: 1) description of the intervention; 2) underlying pedagogical theory; 3) identification of local educational gaps; 4) impact on diverse stakeholders; and 5) elucidation of iterative quality enhancement processes. We also present qualitative and quantitative assessments of the effectiveness of this game in 11 postgraduate courses. We employed the MEEGA+ online survey, comprising thirty-three close-ended unipolar items with 5-point Likert-type response scales, to assess student perceptions of the quality and utility of Screener. Based on 115 responses, the results indicated a highly positive outlook among students. In addition, we performed a preliminary evaluation of learning outcomes in two courses involving 28 students. Pre- and post-quizzes were applied, each consisting of 20 True/False questions directly aligned with the game's content. The analysis revealed significant improvement in students' performance following engagement with the game, with scores rising from 8.4 to 13.3 (P<0.0001, paired t-test) and 9.7 to 12.7 (P<0.0001, paired t-test). These findings underscore the utility of Screener as an enjoyable and effective tool for facilitating a positive learning experience in the DDD process. Notably, the game can also reduce the educational disparities across different regions of our continental country.

Antifungal activity of poly(ε-caprolactone) nanoparticles incorporated with Eucalyptus essential oils against Hemileia vastatrix.

Coffee (Coffea L.) is one of the main crops produced globally. Its contamination by the fungus Hemileia vastatrix Berkeley and Broome has been economically detrimental for producers. The objective of this work was to extract and characterize the essential oils from Eucalyptus citriodora Hook, Eucalyptus camaldulensis Dehn and Eucalyptus grandis Hill ex Maiden, produce and characterize nanoparticles containing these essential oils and evaluate the in vivo and in vitro antifungal activity of free and nanoencapsulated essential oils. The principal constituent of the essential oil from E. citriodora was citronellal; that from E. grandis was α-pinene; and that from E. camaldulensis was 1,8-cineol. The in vitro antifungal activity against the fungus H. vastatrix was 100% at a concentration of 1000 µl l-1 for all the oils and nanoparticles containing these natural products. The sizes of the nanoparticles produced with the essential oils from E. citriodora, E. camaldulensis and E. grandis were 402·13 nm, 275·33 nm and 328·5 nm, respectively, with surface charges of -11·8 mV, -9·24 mV and - 6·76 mV, respectively. Fourier transform infrared analyses proved that the encapsulation of essential oils occurred in the polymeric matrix of poly(ε-caprolactone). The incorporation of essential oils into biodegradable poly(ε-caprolactone) nanoparticles increased their efficiency as biofungicides in the fight against coffee rust, decreasing the severity of the disease by up to 90·75% after treatment with the nanoparticles containing the essential oil from E. grandis.

MDGC-MS analysis of essential oils from Protium heptaphyllum (Aubl. ) and their antifungal activity against Candida specie / Análise MDGC-MS de óleos essenciais de Protium heptaphyllum (Aubl. ) e sua atividade antifúngica contra espécies de Candida

ABSTRACT Protium heptaphyllum is found in the Amazon region, and in various Brazilian states and South American countries. Also Known as almecega, it produces an oil resin used in traditional medicine as analgesic, anti-inflammatory, cicatrizant and expectorant, it is rich in pentacyclic triterpenes and essential oil. The main objective of this study was to analyze the chemical composition of P. heptaphyllumresin (OEPh) over different extraction times and to evaluate their antifungal activity against Candida species, obtained from gardeners with onychomycosis, using the disk diffusion method. The OEPh was obtained by hydrodistillation and analyzed by Multidimensional Gas Chromatography coupled with Mass Spectrometry (MDGC / MS). Candida species were obtained from lesions on the nails of horticulturist from a community garden in the city of Teresina, Piauí, Brazil. The antifungal activity in concentrations of 1000 µg/L, 500 µg/L and 250 µg/L, PROTOCOL M44-A2 (CLSI 2009) OEPh was tested. The main constituents identified were: l-limonene, α-terpineol, p-cineol, o-cymene and α-phellandrene, however, its composition varies significantly with extraction time. All species, except C. rugosa, were inhibited with halo (≥ 14 mm) at 1000 μg / L. C. krusei is naturally resistant to the drug fluconazole, but when tested with OEPh the clinical species (case 9) demonstrated sensitivity in three dilutions (halo ≤ 10 ≥ 14) and the standard strain was inhibited at concentration of 1000 μg/Lg / L (halo 14mm). A similar situation also occurred with the standard strain of C. parapsilosis (halo ≥ 11mm). OEPh has considerable antifungal activity, which merits further investigation for alternative clinical applications, since this species is widely distributed in our community, and it presents good yields, and also has important therapeutic applications.

RESUMO Protium heptaphyllum é encontrada na região amazônica, em vários estados do Brasil e países da América do Sul. Conhecida como almecega produz uma resina oleosa usada na medicina popular como analgésica, antiinflamatória, cicatrizante e expectorante, é rica em triterpenos pentaciclicos e óleo essencial. O objetivo principal do presente trabalho foi analisar a composição química do óleo essencial da resina P. heptaphyllum (OEPh) em diferentes tempo de extração e avaliarsuaatividade antifúngica contra espécies de Candida, isoladas de horticultores com onicomicoses, por método de disco-difusão. O OEPh foi obtido por hidrodestilação, analisado por Cromatografia Gasosa Multidimensinal Acoplada a Espectrometria de Massas (MDGC/MS). As espécies de Candida foram obtidas de lesões nas unhas de horticultores de uma horta comunitária na cidade de Teresina, Piauí, Brasil. Testou-se a atividade antifúngica do OEPhnas concentrações de 1000 μg/L, 500 μg/L e 250 μg/L, protocolo M44-A2 (CLSI 2009). Os principais constituintes identificados foram l- limoneno, α-terpineol, p-cineol, o-cimeno e α-felandreno, entretanto, sua composição varia significativamente em decorrência do tempo de extração. Todas as espécies, exceto a C. rugosa, foram inibidas com halo ( Χ ≥ 14 mm) na concentração de 1000 μg/L. C. krusei é naturalmente resistente ao fármaco fluconazol, mas quando testado com OEPh,a espécie clínico (caso 9) demonstrou sensibilidade nas três diluições (halo Χ ≤ 10 ≥ 14) e a cepa padrão foi inibida na concentração de 1000 μg/L (halo Χ 14mm). Fato semelhante também ocorreu com a cepa padrão de C. parapsilosis (halo Χ ≥ 11mm). O OEPh possui atividade antifúngica considerável, merecendo uma investigação mais aprofundada para aplicações clínicas alternativas, uma vez que esta espécie é amplamente distribuída em nossa comunidade, apresenta bom rendimento e, ainda, aplicações terapêuticas importantes.

Efeito de fungos micorrízicos arbusculares na bioprodução de fenóis totais e no crescimento de Passiflora alata Curtis / Total phenols in Passiflora alata Curtis inoculated with mycorrhizal fungi

Os compostos fenólicos encontrados no extrato das folhas de maracujazeiro doce (Passiflora alata Curtis) são os principais responsáveis pelos efeitos terapêuticos, incluindo a atividade ansiolítica. O presente trabalho avaliou o efeito de diferentes espécies de fungo micorrízicos arbusculares (FMAs) e doses de fósforo sobre a bioprodução de fenóis totais, bem como, o crescimento vegetal e os conteúdos de nitrogênio, fósforo e potássio na massa da matéria seca da parte aérea do maracujazeiro doce. O experimento, fatorial 4x2, foi conduzido em um telado com quatro tratamentos microbiológicos: Glomus etunicatum, Glomus intraradices, inóculo misto (Glomus clarum e Gigaspora margarita) e o controle sem fungo, e duas doses de fósforo: 0 e 50 mg kg-1 de solo. O delineamento experimental foi de blocos casualizados com quatro repetições. As plantas foram colhidas 90 dias após a semeadura. Na ausência da adubação fosfatada, o conteúdo de fenóis totais, a massa da matéria seca da parte aérea e o número de folhas foram maiores nos tratamentos inoculados com FMAs, quando comparados ao tratamento sem fungo. Plantas com inóculo misto apresentaram maior altura com ou sem adubação fosfatada. Os tratamentos inoculados com FMAs, tanto na dose 0 quanto na dose 50 mg kg-1 de P incrementaram os conteúdos de N, P e K na parte aérea do maracujazeiro doce, evidenciando a capacidade dos FMAs em promover o melhor estado nutricional das plantas.

The phenolic compounds found in extracts from leaves of sweet passion fruit (Passiflora alata) are mainly responsible for its therapeutic effects, such as the anxiolytic activity. This study evaluated the effects of different species of mycorrhizal fungi (AMF) and phosphorus levels on the bioproduction of total phenols, as well as plant growth and the contents of nitrogen, phosphorus and potassium in the dry mass of shoots of sweet passion fruit. The experiment was conducted in a greenhouse. The factors were arranged in a :[(microbiological treatments: Glomus etunicatum, Glomus intraradices, mixed inoculum (Glomus clarum and Gigaspora margarita) and without fungus] x 2 (doses of phosphorus: 0 and 50 mg kg-1 soil) factorial arrangement, in a randomized block experimental design with four replications. The plants were harvested 90 days after seeding. In the absence of phosphate fertilization, the total phenol content, dry mass of shoot and leaf number were greater in treatments inoculated with AMF compared to the treatments without fungus. Mixed inoculum plants had higher plant height with or without phosphate fertilization. Treatments inoculated with AMF in both the 0 and 50 mg kg-1 doses of P increased the content of N, P and K in the shoots of sweet passion fruit, demonstrating the ability of AMF to promote better nutritional statusfin plants.

Cryptococcus neoformans-Cryptococcus gattii species complex: an international study of wild-type susceptibility endpoint distributions and epidemiological cutoff values for fluconazole, itraconazole, posaconazole, and voriconazole.

Epidemiological cutoff values (ECVs) for the Cryptococcus neoformans-Cryptococcus gattii species complex versus fluconazole, itraconazole, posaconazole, and voriconazole are not available. We established ECVs for these species and agents based on wild-type (WT) MIC distributions. A total of 2,985 to 5,733 CLSI MICs for C. neoformans (including isolates of molecular type VNI [MICs for 759 to 1,137 isolates] and VNII, VNIII, and VNIV [MICs for 24 to 57 isolates]) and 705 to 975 MICs for C. gattii (including 42 to 260 for VGI, VGII, VGIII, and VGIV isolates) were gathered in 15 to 24 laboratories (Europe, United States, Argentina, Australia, Brazil, Canada, Cuba, India, Mexico, and South Africa) and were aggregated for analysis. Additionally, 220 to 359 MICs measured using CLSI yeast nitrogen base (YNB) medium instead of CLSI RPMI medium for C. neoformans were evaluated. CLSI RPMI medium ECVs for distributions originating from at least three laboratories, which included ≥95% of the modeled WT population, were as follows: fluconazole, 8 µg/ml (VNI, C. gattii nontyped, VGI, VGIIa, and VGIII), 16 µg/ml (C. neoformans nontyped, VNIII, and VGIV), and 32 µg/ml (VGII); itraconazole, 0.25 µg/ml (VNI), 0.5 µg/ml (C. neoformans and C. gattii nontyped and VGI to VGIII), and 1 µg/ml (VGIV); posaconazole, 0.25 µg/ml (C. neoformans nontyped and VNI) and 0.5 µg/ml (C. gattii nontyped and VGI); and voriconazole, 0.12 µg/ml (VNIV), 0.25 µg/ml (C. neoformans and C. gattii nontyped, VNI, VNIII, VGII, and VGIIa,), and 0.5 µg/ml (VGI). The number of laboratories contributing data for other molecular types was too low to ascertain that the differences were due to factors other than assay variation. In the absence of clinical breakpoints, our ECVs may aid in the detection of isolates with acquired resistance mechanisms and should be listed in the revised CLSI M27-A3 and CLSI M27-S3 documents.

High fat diets modulate nitric oxide biosynthesis and antioxidant defence in red blood cells from C57BL/6 mice.

The consumption of a high fat (HF) diet is considered a risk factor for the development of obesity. On the other hand, a monounsaturated HF diet has beneficial cardiometabolic effects. Since nitric oxide (NO) modulates vascular homeostasis, we investigate whether HF diets that vary in fatty acid composition have a different effect on theL-arginine-NO pathway and oxidative stress in C57BL/6 mice red blood cells (RBC). The olive oil diet induced an activation of L-arginine transport compared to other diets. NO synthase (NOS) activity was increased in all unsaturated HF diets (olive, sunflower and canola oils). Moreover, the expression of endothelial NOS (eNOS) and inducible NOS (iNOS) was increased in the olive oil group. In contrast, NOS activity from the lard group was decreased associated with diminished l-arginine transport. Olive oil also induced superoxide dismutase activation. Inhibition of the L-arginine-NO pathway in the lard group could contribute to cardiovascular diseases, while unsaturated HF diets may have a protector effect via enhanced NO bioavailability.

Efeito de um programa de condicionamento físico aeróbio nos aspectos psicossociais, na qualidade de vida, nos sintomas e no óxido nítrico exalado de portadores de asma persistente moderada ou grave / Effects of an aerobic physical training program on psychosocial characteristics, quality-of-life, symptoms and exhaled nitric oxide in individuals with moderate or severe persistent asthma

OBJETIVO: Avaliar o papel de um programa de condicionamento físico aeróbio nos aspectos psicossociais, qualidade de vida, sintomas e óxido nítrico exalado (NOe) de adultos com asma persistente moderada ou grave. MATERIAIS E MÉTODOS: Vinte pacientes foram divididos aleatoriamente em Grupo Controle (GC, n= 10; programa de educação e exercícios respiratórios) e Grupo Treinado (GT, n= 10; programa de educação e exercícios respiratórios mais condicionamento aeróbio, 70 por cento potência máxima obtida). A intervenção aconteceu duas vezes por semana durante três meses. Antes e após, foram avaliados a capacidade aeróbia máxima, a função pulmonar, a dispnéia ao esforço, os níveis de ansiedade e depressão e a qualidade de vida. Mensalmente, eram avaliados o NOe em repouso e o número de dias livres de sintomas. RESULTADOS: Apenas o GT apresentou redução dos sintomas (GT 24,8 [IC95 por cento= 23-27] versus GC 15,7 [IC95 por cento= 9-21] dias livres de sintomas, p< 0,05), dos níveis de NOe (GT 25,8 [IC95 por cento= 15,3-44] versus GC 44,3 [IC95 por cento= 24-60] ppb, p< 0,05), da ansiedade (GT 39,3 [IC95 por cento= 37-50] versus GC 40,9 [IC95 por cento= 37-50] escore, p< 0,001) e da depressão (GT 6,6 [IC95 por cento= 1-21] versus GC 9 [IC95 por cento= 1-20] escore, p< 0,001), melhora da qualidade de vida (GT 42,8 [IC95 por cento= 34,3-71,7] versus GC 69,7 [IC95 por cento= 45,1-87,9] por cento, p< 0,001), e incremento da aptidão aeróbia (GT 25,7 [IC95 por cento= 16,2-31,3] versus GC 20,5 [IC95 por cento= 17,3-24,1] mL/kg/min, p< 0,001). CONCLUSÕES: Os resultados sugerem que o treinamento físico reduz o NOe, os sintomas e melhora a qualidade de vida e os aspectos psicossociais de adultos com asma persistente moderada ou grave.

OBJECTIVE: To evaluate the role of an aerobic physical training program on psychosocial characteristics, quality of life, symptoms and exhaled nitric oxide of adults with moderate or severe persistent asthma. METHODS: Twenty patients were randomly assigned to a Control Group (CG, n= 10, education program and respiratory exercises) and a Trained Group (TG, n= 10, education program and respiratory exercises plus aerobic training at 70 percent of the maximum power obtained). The intervention took place twice a week for three months. Maximum aerobic capacity, pulmonary function, effort dyspnea, anxiety levels, depression levels and quality of life were assessed before and after the treatment. Exhaled nitric oxide at rest and the number of days without asthma symptoms were evaluated every month. RESULTS: The TG presented increased numbers of symptom-free days (TG 24.8 days [95 percentCI= 23-27] versus CG 15.7 days [95 percentCI= 9-21]; p< 0.05), decreased exhaled nitric oxide levels (TG 25.8 ppb [95 percentCI= 15.3-44.0] versus CG 44.3 ppb [95 percentCI= 24-60]; p< 0.05), decreased anxiety scores (TG 39.3 [95 percentCI= 37-50] versus CG 40.9 [95 percentCI= 37-50]; p< 0.001), decreased depression scores (TG 6.6 [95 percentCI= 1-21] versus CG 9 [95 percentCI= 1-20]; p< 0.001), improved quality of life (TG 42.8 percent [95 percentCI= 34.3-71.7] versus CG 69.6 percent [95 percentCI= 45.1-87.9]; p< 0.001) and improved aerobic aptitude (TG 25.7 mL/kg/min [95 percentCI= 6.2-31.3] versus CG 20.5 mL/kg/min [95 percentCI= 17.3-24.1]; p< 0.001). CONCLUSIONS: Our results suggest that physical training reduces exhaled nitric oxide and symptoms and improves the quality of life and psychosocial characteristics of adults with moderate or severe persistent asthma.

Warifteine, a bisbenzylisoquinoline alkaloid, decreases immediate allergic and thermal hyperalgesic reactions in sensitized animals.

Warifteine is a bisbenzylisoquinoline alkaloid isolated from the Cissampelos sympodialis Eichl (Menispermaceae). This plant is used in the folk medicine for the treatment of airway respiratory diseases. A murine model of immediate allergic reaction was used to evaluate warifteine treatment in the IgE production, leukocyte activation, thermal hyperalgesia, mast cell degranulation and scratching behavior. BALB/c mice treated with warifteine (0.4-10 mg/Kg) 1 h before OVA sensitization reduced OVA induced paw edema as well as the OVA-specific IgE serum titers as compared with non-treated and OVA-sensitized animals. Warifteine also reduced the mice death evoked by IgE-dependent anaphylactic shock reaction at 30 min after intravenous OVA challenge. To assess the effect of warifteine treatment on T cell proliferative response, spleen cells from warifteine treated or non-treated and OVA-sensitized animals were evaluated. Spleen cells from warifteine treated animals (2.0 mg/kg) did not proliferate following OVA stimulation as compared with spleen cell cultures from non-treated animals. This response may be related with the increase of NO production as observed in peritoneal macrophage cultures treated with warifteine. Thermal hyperalgesia evoked by IgE or histamine/5-hydroxytryptamine challenge was inhibited on rats at dose of 4.0 mg/kg. Warifteine treatment (0.6 or 6.0 microg/ml) also decreased the IgEalphaDNP-BSA sensitized mast degranulation after DNP-BSA challenge measured by histamine release. In addition, compound 48/80-induced scratching behavior was also sensitive to warifteine treatment. These results demonstrate for the first time that warifteine treatment reduced the allergy-associated responses.

Chelating effect of novel pyrimidines in a model of aluminum intoxication.

Long time ago aluminum (Al) was considered as a non-toxic element and its use had no restrictions. However, over the last two decades, scientific publications have indicated that Al is a toxic element. In line with this, aluminum accumulation in the organism is associated with a variety of human pathologies. Efficient therapeutics approach to treat Al intoxication are still not available, but there is a consensus that chelation therapy is the procedure to be used. However, the development of new chelating agents are highly desirable to improve the efficacy of the treatment of Al intoxication. The present study evaluates the chelating effect of two novel pyrimidines: 4-tricloromethyl-1-H-pyrimidin-2-one (THP) and (4-methyl-6-trifluoromethyl-6-pyrimidin-2-il)-hydrazine (MTPH) in a mice model of aluminum intoxication and compares their efficacy with those of desferrioxamine (DFO), a classical agent used for treat Al accumulation. The animals were exposed to aluminum by gavage (0.1 mmol aluminum/kg/day) 5 days/week for 4 weeks. At the end of this period, DFO was injected i.p. and the novel pyrimidines were given by gavage at 0.2 mmol/kg/day for five consecutive days. Aluminum concentration in tissues (brain, liver, kidney and blood) was determined by graphite furnace atomic absorption spectroscopy (GFAAS). The results showed that when administered by gavage, aluminum accumulated in the brain, kidney and liver of mice. MTPH was able to decrease aluminum levels in aluminum plus citrate animal groups, whereas THP was inefficient for this purpose. However, the novel pyrimidines used in this study were unable to surpass the aluminum chelating property of DFO. Thus, new studies must be performed utilizing other chelating agents which can decrease aluminum toxicity.

Anti-allergic properties of the natural PAF antagonist yangambin.

In this study we examined the ability of the furofuran lignan yangambin to influence the local and systemic responses induced by antigen or PAF in actively sensitized or normal rats. Given intraperitoneally 1 h before stimulation, yangambin inhibited the pleural neutrophil and eosinophil infiltration evoked by the i.pl. injection of PAF or antigen into normal or 14 daysensitized rats whereas plasma exudation evoked by both stimuli was unaffected. The pleural neutrophil influx (6 h) after LTB4 stimulation was also significantly inhibited by yangambin. We also evidenced that the hemoconcentration, thrombocytopenia, and leucocytosis noted after i.v. PAF were all attenuated by yangambin. In actively sensitized rats, pretreatment with yangambin failed to modify the antigen-induced hemoconcentration and leucocytosis, but dose-dependently abrogated the thrombocytopenia noted 1 h post-stimulation. In vitro, the anaphylactic contraction of longitudinal jejunal segments to antigen challenge was significantly inhibited by yangambin (10(-5)-10(-4) M). Likewise, the contraction of jejunal segments from normal rats to PAF was markedly blocked by yangambin under conditions where the response to 5-hydroxytryptamine (5-HT) was not altered. In conclusion, our results show that antigen- and PAF-induced pleural neutrophil and eosinophil accumulation, but not exudation, is sensitive to treatment with yangambin. In addition, yangambin also suppressed the pleural neutrophil infiltration triggered by LTB4 as well as the blood thrombocytopenia and intestinal anaphylaxis elicited by antigen in rats. Thus, our findings indicate that yangambin shows an antagonistic action on receptors other than those of PAF, i.e., LTB4, and strongly suggest that it may be a useful drug in the treatment of some allergic inflammatory responses.

Yangambin: a new naturally-occurring platelet-activating factor receptor antagonist: binding and in vitro functional studies.

The effects of the furofuran lignan yangambin on rabbit platelet aggregation and binding of [3H]-PAF to rabbit platelet plasma membranes were studied. Log concentration-response curves to PAF were obtained in the presence or absence of increasing concentrations of yangambin. This lignan dose-dependently inhibited PAF-induced platelet aggregation in platelet-rich plasma (PRP) and shifted PAF curves to the right without decreasing the maximal response. The Schild plot constructed from these data showed a slope of 1.17 and a pA2 of 6.45. Moreover, yangambin at 10(-5) M did not inhibit the platelet aggregation induced by ADP (5 x 10(-7) M), collagen (0.1 microgram ml-1), or thrombin (0.05 U ml-1). Biochemical studies showed that [3H]-PAF labelled in a saturable manner a single class of binding sites on platelet membranes with a Kd of 1.25 +/- 0.24 nM and a maximal binding capacity (Bmax) of 14.9 +/- 2.4 pmol mg protein-1. Both unlabelled PAF and yangambin competitively displaced [3H]-PAF binding with an IC50 of 1.54 +/- 0.37 nM and 1.93 +/- 0.53 microM, respectively. The incubation of rabbit blood neutrophils with yangambin at 10(-5) M did not prevent PAF-induced in vitro chemotaxis in conditions where the PAF antagonist SR 27417 at 10(-5) M abolished the phenomenon. These results indicate that yangambin is an antagonist that selectively blocks PAF receptors on platelets.

Analgesic and anti-ulcerogenic effects of a polar extract from leaves of Vernonia condensata.

An aqueous crude extract and a polar fraction derived from this extract were prepared from leaves of Vernonia condensata Baker and assessed in standard rodent models of algesia and ulcerogenesis. Oral pretreatment with the lyophilized crude extract (200 mg/kg) significantly reduced mouse writhing counts caused by the i.p. injection of increasing concentrations (0.6-1.2%) of acetic acid (0.1 ml/10 g). In doses ranging from 50 to 400 mg/kg, the crude extract inhibited dose-dependently mouse writhing induced by acetic acid (0.6%) (ED50 = 241 mg/kg) and also markedly increased the sleeping time induced by thiopental. The polar fraction, prepared by washing out the crude extract with chloroform, did not alter sleeping time but kept the analgesic activity (ED50 = 154 mg/kg), indicating that these effects are indeed dissociated. In contrast, the tail flick response in the immersion test was not modified by the crude extract or the polar fraction. The relative potency with which polar fraction and non-steroidal anti-inflammatory drugs inhibited mouse writhing caused by acetic acid in mice was indomethacin >> dypirone > polar fraction > aspirin. Furthermore, the combined polar fraction/aspirin or polar fraction/indomethacin treatments presented a marked synergistic effect, in contrast to what was observed when submaximal doses of indomethacin and aspirin were coadministered, suggesting that polar fraction and aspirin like drugs may have complementary analgesic actions. Finally, despite being able to potentiate the analgesic effect of indomethacin in mouse writhing caused by acetic acid, the pretreatment with the polar fraction (200 mg/kg, oral) significantly prevented indomethacin-induced ulcers in rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Neonatal capsaicin treatment decreases airway and pulmonary tissue responsiveness to methacholine.

We studied the effects of selective depletion of neurokinins in sensory nerve fibers by capsaicin treatment on the airway and pulmonary tissue responses to methacholine. Dose-response curves to aerosolized methacholine were performed on anesthetized and mechanically ventilated Wistar rats. Capsaicin (50 mg/kg sc) was administered to 2-day-old rats, and the animals were studied after 12 wk. The response to each dose of methacholine was determined by measuring changes in airway resistance (R(aw)), dynamic pulmonary elastance (Edyn), and pulmonary tissue resistance (Rtis). We calculated sensitivity (Kx) as the concentration of methacholine required for a one-half maximal response and reactivity as the relationship between the maximum response and Kx. Capsaicin treatment resulted in significantly greater values of Kx and lower values of reactivity for R(aw), Edyn, and Rtis compared with control rats. Morphometric analysis of airways showed similar values of the area occupied by smooth muscle but a significantly lower (P < 0.02) area of airway epithelium in capsaicin-treated rats. Our results suggest that methacholine requires capsaicin-sensitive nerves for part of its airway and lung tissue effects.

Homologous tachyphylaxis to bradykinin and its interference with allergic pleurisy in actively sensitized rats.

After recovery from a first intraplantar or intrathoracic stimulation with bradykinin, repeated daily provocation with this peptide resulted in a progressive loss of its ability to cause paw or pleural oedema, reaching 0-20% of the control within seven and four consecutive provocations, respectively. The phenomenon was shown to be time reversible, since the unresponsiveness ceased when stimulations were discontinued, and localized, since paw oedema evoked by the peptide was not modified after desensitization of either the contralateral paw or the pleural cavity. Furthermore desensitization to bradykinin did not influence the pleurisy elicited by either histamine (200 micrograms/cavity), 5-hydroxytryptamine (5-HT) (100 microgram/cavity) or platelet-activating factor (PAF) (1 microgram/cavity), suggesting that the desensitization was selective. In contrast, when actively sensitized animals were submitted to bradykinin-induced tachyphylaxis, pleural exudation and leukocyte influx induced by antigen were drastically reduced, strongly implying bradykinin in this process. We demonstrated that repeated daily stimulation with bradykinin cause selective, local and reversible auto-refractoriness, which may be useful as a tool in attempting to evaluate the role of this peptide in inflammation.