Jorge Carlos Santos da Costa

Lidocaine-derivative JMF2-1 prevents ovalbumin-induced airway inflammation by regulating the function and survival of T cells

Cite this as: P. C. Olsen, T. P. T. Ferreira, M. F. Serra, F. A. Farias‐Filho, B. P. Fonseca, J. P. B. Viola, R. S. B. Cordeiro, P. M. R. Silva, J. C. S. Costa and M. A. Martins, Clinical & Experimental Allergy, 2011 (41) 250–259.

In vitro and in vivo activity of meglumine antimoniate produced at Farmanguinhos-Fiocruz, Brazil, against Leishmania (Leishmania) amazonensis, L (L.) chagasi and L (Viannia) braziliensis

The leishmanicidal activity of four batches of meglumine antimoniate, produced in Farmanguinhos-Fiocruz, Brazil (TAMs), was assessed and compared to Glucantime-Aventis Pharma Ltda. Using the amastigote-like in vitro model, the active concentrations of Sb v varied from 10microg/ml to 300microg/ml for L. (L.) chagasi and from 50microg/ml to 300microg/ml for L. (L.) amazonensis, with no statistically significant differences among the four batches of TAMs and Glucantime. The inhibitory concentrations (IC50) determined by the amastigote-infected macrophage model for TAM01/03 and Glucantime were, respectively: 26.3microg/ml and 127.6microg/ml for L. chagasi, 15.4microg /ml and 22.9microg/ml for L. amazonensis, and 12.1 microg/ml and 24.2microg/ml for L. (V.) braziliensis. The activities of the four batches of TAMs were confirmed in an in vivo model by assessing, during eight weeks skin lesions caused by L. braziliensis in hamster that were treated with 20mg Sb v/Kg/day for 30 consecutive days. The meglumine antimoniate produced by Farmanguinhos was as effective as the reference drug, Glucantime-Aventis, against three species of Leishmania that are of medical importance in Brazil.

Simple Reduction of Heteroaromatic Esters to Alcohols Using a Sodium Borohydride–Methanol System

Abstract Some heteroaromatic esters were reduced to the corresponding alcohols by using a sodium borohydride–methanol system. The reduction was completed within 0.15–2.0 h in refluxing THF. The alcohol products were isolated after aqueous workup in moderate to excellent yield (48–97%).

JM25-1, a Lidocaine Analog Combining Airway Relaxant and Antiinflammatory Properties: Implications for New Bronchospasm Therapy.

Background:Inhaled lidocaine antagonized bronchospasm in animal models and patients, but adverse effects limited its efficacy. This study evaluated the antibronchospasm potential of the analog JM25-1, exploring in vitro mechanisms and translation to an animal model. Methods:The effectiveness of JM25-1 was assessed in GH3 cells, rat tracheal rings, mouse lymphocytes, and human eosinophil systems in vitro, assessing changes in Na+ current, contraction, proliferation, and survival, respectively. Lung function and inflammatory changes were studied in ovalbumin-sensitized mice. Results:The efficacy of JM25-1 was higher than lidocaine in inhibiting carbachol-induced and calcium-induced tracheal contractions (maximum effect inhibition at 1 mM [%]: 67 ± 10 [JM25-1] vs. 41 ± 11 [lidocaine] [P < 0.001] for carbachol; 100 ± 3 [JM25-1] vs. 36 ± 26 [lidocaine] [P < 0.001] for Ca2+; mean ± SD; n = 9 each) but lower in Na+ current (50% inhibitory concentration = 151.5, n = 8 vs. 0.2 mM; n = 5; P < 0.001). JM25-1 also inhibited eosinophil survival (dead cells [%]: 65 ± 6; n = 4; P < 0.001 at 1 mM) and lymphocyte proliferation (cells in phase S + G2 [%]: 94 ± 10; n = 6; P < 0.001) at 0.6 mM. Aerosolized JM25-1 (1%) decreased lung eosinophil numbers from 13.2 ± 2.4 to 1.7 ± 0.7 × 104/&mgr;m2 (n = 6; P < 0.001) and neutrophils from 1.9 ± 0.4 to 0.2 ± 0.1 × 104/&mgr;m2 (n = 7; P < 0.001). Other parameters, including airway hyperreactivity, cytokines, mucus, and extracellular matrix deposition, were also sensitive to aerosolized JM25-1. Conclusion:These findings highlight the potential of JM25-1, emphasizing its putative value in drug development for clinical conditions where there is bronchospasm.

Local anaesthetic medication for the treatment of asthma

It is presumed that drugs able to prevent bronchial spasm and/or inflammation may have therapeutic potential to control asthma symptoms. The local anaesthetic lidocaine has recently received increased attention as an alternative form of treatment for asthmatic patients. This paper reviews the major findings on the topic and summarizes the putative mechanisms underlying the airway effects of local anaesthetic agents. We think that lidocaine extends the spectrum of options in asthma therapy, probably by counteracting both spasmogenic and inflammatory stimuli in the bronchial airways. The possibility of development of new anti-asthma compounds based on the synthesis of lidocaine derivatives is also on the horizon.

Two for one: Cyclic AMP mediates the anti-inflammatory and anti-spasmodic properties of the non-anesthetic lidocaine analog JMF2-1

Inhalation of JMF2-1, an analog of lidocaine with reduced anesthetic activity, prevents airway contraction and lung inflammation in experimental asthma models. We sought to test if the JMF2-1 effects are a consequence of increased intracellular cAMP levels in asthma cell targets, such as smooth muscle cells and T cells. Functional effect of JMF2-1 on carbachol-induced contraction of intact or epithelial-denuded rat trachea was assessed in conventional organ baths. cAMP was quantified by radioimmunoassay in cultured guinea pig tracheal smooth muscle cells, as well as lymph node cells from BALB/c mice, exposed to JMF2-1. We found that JMF2-1 (0.1-1mM) concentration-dependently inhibited epithelium-intact tracheal ring contraction induced by carbachol challenge. The antispasmodic effect remained unaltered following epithelium removal or pretreatment with NG-nitro-L-arginine methyl ester (100μM), but it was clearly sensitive to 9-(tetrahydro-2-furyl) adenine (SQ22,536, 100μM), an adenylate cyclase inhibitor. JMF2-1 (300 and 600μM) also dose-dependently increased cAMP intracellular levels of both cultured airway smooth muscle cells and T lymphocytes. This effect was consistently abrogated by SQ22,536 and reproduced by forskolin in both systems. JMF2-1 induced apoptosis of anti-CD3 activated T cells in a mechanism sensitive to zIETD, indicating that JMF2-1 mediates caspase-8-dependent apoptosis. Furthermore, forskolin also inhibited anti-CD3 induced T cell proliferation and survival. Our results suggest that JMF2-1 inhibits respiratory smooth muscle contraction as well as T cell proliferation and survival through enhancement of intracellular cAMP levels. These findings may help to explain the anti-inflammatory and antispasmodic effects of JMF2-1 observed in previous studies.

Synthesis of 6, 7-Methylenedioxylapachol

Abstract Compound 1c, a synthetic derivative of lapachol (1a), was synthesized in 37% overall yield from safrole (2).

AB0230 Symptoms of Depression, Anxiety and Poor Sleep Quality in Patients Followed in a Rheumatology Day-Care Unit: Associated Sociodemographic and Disease-Related Factors

Background The presence of depression, anxiety and sleep disorders are common among patients with inflammatory rheumatic diseases. Frequently are underdiagnosed in clinical practice and can negatively influence the perception of pain by the patient, the disease activity and the individuals quality of life. Objectives To determine the levels of depression, anxiety and sleep quality in patients with inflammatory rheumatic diseases followed in a rheumatology day-care unit, with current or past history of biological treatment, and to identify associated demographic and disease-related factors. Methods The Beck depression and anxiety inventory (BDI and BAI) and Pittsburgh sleep quality index (PSQI) were applied as instruments for measuring the severity of depression, anxiety and sleep quality, respectively. Disease activity was ascertained using validated clinical index: ASDAS-PCR for spondylarthritis with predominant axial involvement and DAS28-ESR for spondylarthritis with predominant peripheral involvement or rheumatoid arthritis. Health Assessment Questionnaire (HAQ) was used to assess impairment in daily activities due to illness and Short Form-36 (SF-36) to assess health related quality of life. A p value of <0.05 was considered as significant. Results A total of 84 patients were consecutively included, of which 50 (59.5%) were female, with a mean age of 46.25±13.25 years (19 to 85) and a mean disease duration of 14.62±8.07 years (1 to 38). Thirty six (42.9%) patients had rheumatoid arthritis and 48 (57.1%) had spondylarthritis. Symptoms of anxiety and depression were found in 46 (54.8%) and 30 (35.7%) patients, with moderate or severe score in 23 (27.3%) and 14 (16.7%) patients respectively. Thirteen (15.5%) patients were taking antidepressant treatment. Poor sleep quality was found in 53 (63.1%) patients but only 14 (16.7%) took sleeping pills. Strong correlation (p<0.01) was found between high scores of anxiety, depression and sleep index. These scores correlated too with high HAQ and pain on a VAS, low SF36 and both on their mental and emotional components (p<0.01). High ASDAS-PCR scores were positively correlated with anxiety, depression and sleep index (p<0.01). Similarly high DAS-28 positively correlated with depression (p<0.01) and poor sleep quality (p<0.05), but not with anxiety. The female gender and other than single civil status were associated with higher anxiety and history of hypertension with more depressive symptoms (p<0.05). Active employees and current corticosteroid treatment were associated both with higher anxiety and depression scores (p<0.05). Older age and longer disease duration associated with poorer sleep quality (p<0.05). The scores were not statistically different between bDMARDS or cDMARDS, the kind of disease, habits or other associated diseases. Conclusions Anxiety, depression and sleep disorders were very prevalent in this patient group. Higher disease activity, worse quality of life and higher pain were noted in the presence of these disturbances. The female gender, civil status, employment, corticoid therapy and history of hypertension were also associated. Recognize and treat both conditions is important to best manage these patients. Disclosure of Interest None declared

AB1104 Influence of Sociodemographic and Clinical Factors in Health Related Quality of Life in Patients Followed in a Rheumatology Day-Care Unit

Background The health-related quality of life (HRQL) is an important indicator of the burden of inflammatory rheumatic diseases (IRD). Their outcomes may also be affected by coexisting chronic conditions that can cause functional impairment and activity limitation with significant reductions in HRQL. Objectives To determine the health status and quality of life in patients with IRD followed in a rheumatology day-care unit and to identify associated demographic and disease-related parameters influencing it. Methods The Health Assessment Questionnaire (HAQ) to assess impairment in daily activities due to illness and Short Form-36 (SF-36) to assess HRQL were applied to patients on day-care routine visits. Disease activity clinical measures (DAS28-ESR, ASDAS-PCR, mean pain on VAS) were collected according to the disease and the predominant involvement. A p value of <0.05 was considered as significant. Results A total of 84 patients were consecutively included, predominantly female (59.5%), with a mean age of 46.25±13.25 years (range 19-85) and a mean disease duration of 14.62±8.07 years (1-38). Thirty six (42.9%) patients had rheumatoid arthritis and 48 (57.1%) had spondylarthritis. Seventy seven (91.7%) patients with current bDMARDS, 51 (60.7%) also with cDMARDS and 19 (22.6%) with low doses corticosteroid treatment. Twenty four (28.6%) had associated hypertension, 4 (4.8%) diabetes and 10 (11.9%) dyslipidemia. The mean DAS28-ERS was 2.59±1.06 (0.53 to 6.94), median ASDAS-PCR 1.40±1.15 (0.20 to 5.50), mean pain on a VAS 3.77±2.58 (0 to 10), mean HAQ 0.76±0.71 (0 to 2.88) and mean SF-36 418.71±162.31 (103.50 to 707). Strong correlation (p<0.01) was found between high scores of HAQ and low SF-36. These scores correlated also with older age, high pain on a VAS and high disease activity measured by ASDAS-PCR and DAS28-ESR. Longer disease duration correlated as well with lower level of SF-36 (p<0.05), but not with HAQ. Rheumatoid arthritis showed significant higher levels of HAQ than spondylarthritis. The female gender, current corticosteroid treatment and history of hypertension were associated both with higher HAQ and lower SF-36 (p<0.05). The scores were not statistically different between bDMARDS or cDMARDS, smoking and alcohol consumption, civil or employment status, level of education or other associated diseases. Conclusions Our findings suggest that not only the activity or duration of the disease, but also the gender, concomitant comorbidities and therapies can influence the HRQL and daily activities. The disease activity could be a determinant of disability but is important to incorporate coexisting conditions and demographic data in the evaluation of HRQL. Disclosure of Interest None declared