Mary Yale Neves

Synthesis, characterization and biodistribution of bisphosphonates Sm-153 complexes: correlation with molecular modeling interaction studies

Bisphosphonates (BPs) are characterized by a P-C-P backbone structure and two phosphonic acid groups bonded to the same carbon, and are established as osteoclast-mediated bone resorption inhibitors. The nature of the groups attached to the central carbon atom are responsible in determining the potency of bisphosphonates as anti-resorption drugs. However, it is not yet clear the exact relationship between their molecular structure and pharmacologic activities. In this study, molecular geometries of pamidronate, alendronate and neridronate, differing only in the length of the aliphatic chains, were predicted by molecular mechanics and their interactions with hydroxyapatite, the main bone mineral component, were examined. We report the synthesis and radiochemical characterization of 153Sm complexes with pamidronate, alendronate and neridronate. Hydroxyapatite binding and biodistribution studies of these complexes have shown a good correlation with the theoretical molecular modeling interaction studies. So, it is possible to conclude that computational chemistry techniques are a good approach to evaluate specific interactions and may play a relevant role in determining the relative ability of BPs to mineral bone, and open new perspectives to the design of new BPs with increased pharmacological activity. These techniques could be extended to BPs as ligands to carrier radioactive metals, aiming for new bone therapeutic radiopharmaceuticals.

Lymphatic uptake of lipid nanoparticles following endotracheal administration.

A previous publication reported the uptake into the lymphatics of pulmonary administered lipid nanoparticles (LN), after aerosolization and inhalation. In the present study LN clearance from the lungs and lymphatic uptake were further evaluated after endotracheal administration. Nanoparticles prepared with gliceryl behenate were radiolabelled by association to the lipophilic tracer D,L-hexamethylpropylene amine oxime (HMPAO) coupled with 99mTc. Labelling efficiency was 97% and stability in body fluids was demonstrated in vitro. Wistar rats were treated by endotracheal administration and lymphatic uptake was determined upon organ sampling. Endotracheally delivered LN are rapidly eliminated from rat lungs and accumulation in para-aortic, axillary and inguinal lymph nodes starts almost immediately after administration. Translocation of LN across the lung mucosa and their uptake into the lymphatics demonstrate their usefulness as potential drug carriers for lung cancer therapy, as well as for immunization purposes.

153Sm3+ and 111In3+ DTPA derivatives with high hepatic specificity: in vivo and in vitro studies

Abstract Two DTPA derivatives, a mono-amide derivative containing an iodinated synthon, DTPA-IOPsp (L 1 ) and the ligand DTPA(BOM) 3 (BOM=benzyloxymethyl) (L 2 ), radiolabelled with 153 Sm 3+ and 111 In 3+ , were studied as potential hepatospecific gamma scintigraphic agents. In vivo studies with Wistar rats show that the main excretory pathway for all the chelates studied is the hepatobiliary system. The complexes of L 2 show even greater hepatobiliary specificity than L 1 , perhaps as a consequence of longer blood circulation times due to their strong affinity towards HSA. The 153 Sm 3+ chelates are also more hepatospecific than the corresponding 111 In 3+ chelates. The La 3+ and In 3+ chelates of L 1 and L 2 show some structural and dynamic differences in aqueous solution, as studied by 1 H NMR spectroscopy. While only two nona-coordinated isomers were observed for the La 3+ complexes with both ligands, its number is much larger in the In 3+ complexes, with both octa- and hepta-coordinated species (with unbound side arms), as well as structural isomers for each coordination number.

Synthesis, characterization, and biodistribution of oxo complexes of technetium-99m with biguanide and N1-Substituted ligands

We report the synthesis, characterization, and biodistribution of 99mTc-complexes with the bidentate-N,N chelate biguanide (Big) and the N1-substituted ligands dimethyl (DMBig), phenyl (PBig), and phenethyl (PEBig). Dynamic gamma-camera studies with 99mTc-Big and 99mTc-DMSA in rabbits indicated distinct renal and urinary excretion profiles. 99mTc-Big was cleared more quickly than 99mTc-DMSA, and for the same acquisition times, the contrast in whole-body images favored 99mTc-Big. Also, the estimated radiation absorbed doses by kidneys and blood for 99mTc-DMSA were significantly higher than for 99mTc-Big. These preliminary studies show that 99mTc-Big has favourable practical and dosimetric features for renal imaging as an alternative to 99mTc-DMSA.

Evaluation in the baboon model of 99mTc-biguanide as a tracer for renal imaging

Studies in various animal species have recently shown that (99m)Tc-BIG has practical and dosimetric benefits for renal imaging that could probably make it a good alternative to (99m)Tc-2, 3-dimercaptosuccinic acid ((99m)Tc-DMSA). In this study, using the baboon experimental model, the biodistribution of (99m)Tc-BIG and (99m)Tc-DMSA are compared. It is demonstrated that early good contrast imaging and more favourable dosimetry is possible with (99m)Tc-BIG compared to (99m)Tc-DMSA, confirming the quoted previous findings with small animals. Time-activity curves for kidneys and other organs support these findings, and MIRDOSE software provided the dosimetry.

Saúde, gênero e reconhecimento no trabalho das professoras: convergências e diferenças no Brasil e na França

O presente artigo trata do reconhecimento do trabalho das professoras e suas implicacoes sobre a saude em dois diferentes contextos economicos e sociais: de um pais da America Latina (Brasil) e de um pais europeu (Franca). Baseia-se, principalmente, nas contribuicoes teoricas da psicodinâmica do trabalho e das ciencias sociais, apresentando exemplos oriundos de diversas pesquisas. Observa-se que, apesar das diferencas em relacao as condicoes laborais das professoras nos dois paises, o nao reconhecimento de seu trabalho esta presente em ambos os contextos. Os baixos salarios (mesmo considerando-se as especificidades de cada um desses contextos) e a falta de valorizacao dos esforcos feitos no cotidiano profissional sao a prova disso. No entanto, na Franca, o mal-estar das professoras advem, sobretudo, de duvidas sobre a utilidade social do trabalho docente, frente as inumeras reformas e as defasagens no nivel de escolaridade dos alunos. No caso do Brasil, o malestar decorre especialmente da precariedade das condicoes de trabalho, que sinalizam a desvalorizacao da profissional, destacando-se o numero excessivo de alunos por turma e a necessidade de complementacao salarial. Nos dois casos registra-se a importância do reconhecimento pelos alunos e do trabalho em equipe na preservacao da saude.

Saúde, subjetividade e trabalho: o enfoque clínico e de gênero

Abstract In this article, we address the theme “health, subjectivity, and work” using two approaches. The first one follows close to Canguilhem’s vitalist concept to understand the relationship between health and work, discussing the theoretical view of Work Clinics – the Ergonomics of Activity, the Work Clinic, the Psychodynamics of Work – and the Ergological perspective. The other approach focuses on gender analyzed from the perspective of the appropriation of working time. To accomplish this purpose, we searched the state of art on the theme and presented results of empirical studies related to services (education, health, and telemarketing), including analyses produced by our investigations, integrating them with these theoretical contributions. The analyses revealed the importance of the social recognition of work, which nature comprises a strong symbolic component that allows subjects to construct a meaning of work. Everyday negotiations of life, and consequently of health, are permeated by class and gender social relations. Time constraints differ according to gender, resulting in different levels of tolerance to the environment. The contributions showed that the movement, the dynamics and the constant changes inherent to life (and work) are aspects to be included in analyses of work-health relationships.

Thermolabile Liposomes: A Controlled Release Delivery Tool in Diagnosis/ Therapy in Experimental Pulmonary Oedema

Liposomes, usually assembled from organic/synthetic lipidic compounds, are biocompatible, biodegradable, non-toxic, and do not induce immune response. Due to their structural versatility in terms of size, composition, surface charge, bilayer fluidity and ability to encapsulate drugs regardless of their solubility, liposomes enable the production of a vast number and type of formulations with potential clinical use. They can be administered through several routes of administration (e.g. i.v., i.m., oral, nasal, etc.). The use of liposomes enables the variation and control retention of drugs in biologic fluids, enhancing blood circulation and specific compartments residence. They can be tailored to target specific tissues and cells. They can play a very important role for imaging diagnosis and/or therapy. After an extensive literature review of the subject, we selected a particular area of potential clinical application: pulmonary ɶdema. This clinical entity has a variety of possible etiologies, conducing to two main types of edema: cardiogenic and non-cardiogenic. At the moment a dedicated technique for the early diagnosis/therapy of this pathology is lacking. We propose a new methodology using a specially designed GUV formulation, encapsulating chosen radiotracers labeled with 99mTc. The aim of the work has been successfully achieved in an experimental animal model of cardiogenic pulmonary oedema. Experiments using an animal model of non-cardiogenic pulmonary oedema are in course (simultaneous study with two different drugs), using the same GUV methodology. Preliminary results are very promising.

THU0033 Overactive Bladder Symptom Bother is Increased in Patients with Systemic Lupus Erythematosus and SjÖGren's Syndrome

Background Interstitial Cystitis (IC) has been suggested to have an underlying autoimmune mechanism and to be associated with Systemic Lupus Erythematosus (SLE) and Sjögrens syndrome (SS). In these conditions, lower urinary tract symptoms (LUTS) associated with overactive bladder (OAB) may be present since early stages of disease and be interpreted by patients as normal. Objectives To compare OAB symptom bother (SB) and health-related quality of life (HRQL) between healthy controls and patients with SLE and SS. Methods In a cross-sectional cohort study, we applied a validated questionnaire assessing LUTS and HRQL, the OAB questionnaire short form (OABq-SF, range 0-100), to SLE/SS patients followed in a hospital outpatient clinic and to patients from a primary health care centre that had none of the diseases. We further collected information on possible confounding variables. Group comparisons by Mann-Whitney and chi-square test and multiple regression analyses were conducted. Based on literature findings, we defined a SB score greater than 20/100 and a HRQL score lower than 90/100, as clinically meaningful. Results We included 203 controls and 93 rheumatic patients (64 SLE, 29 SS). Both groups had similar characteristics except for gender distribution, anti-depressant and corticosteroid consumption (Table 1). OABq-SF SB scores were greater and HRQL scores were lower in the SLE/SS group, compared to controls (p<0.0001 and p=0.0002, respectively). SLE/SS patients had higher proportions of SB score ≥20 (OR 3.1, 1.9-5.2) and HQRL≤90 (OR 2.4, 1.4-4.2). The same differences were seen for the SLE/SS subgroups separately. Multivariate logistic regression revealed that SLE/SS patients were more likely to have a SB score greater than 20/100 (OR 2.72, 1.55-4.79) and a HRQL score lower than 90/100 (OR 1.90, 1.01-3.56), adjusting for age, sex, diuretics, recent urinary infection (≤3 months) and antidepressants. Table 1. Proportion of patients in remission according to different criteria and biologic class Controls (n=203) SLE/Sjögren (n=93) p-value Age 44.7±16.7 47.6±17.5 0.17 Female 129 (63.6) 86 (92.5) <0.0001 Urinary tumor 3 (1.5) 4 (4.3) 0.14 Urinary Infection ≤3 mo 15 (7.4) 5 (5.4) 0.52 Diuretics 21 (10.3) 8 (8.6) 0.64 Anti-cholinergics 4 (2.0) 4 (4.3) 0.25 Anti-depressants 8 (3.9) 20 (21.5) <0.0001 Corticosteroids 3 (1.5) 64 (68.8) <0.0001 SB score 12.97±15.87 22.97±21.11 <0.0001 HRQL score 94.35±10.77 89.26±15.63 0.0002 SB score ≥20 50 (24.6) 47 (50.5) <0.0001 HQRL score ≤90 35 (17.2) 31 (33.3) 0.002 Conclusions Patients with SLE/SS had higher OAB symptom scores and lower HRQL scores compared to controls, using a validated questionnaire. They were also more likely to have a clinically meaningful score, suggesting that OAB and IC might be, indeed, more frequent in these patients. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.4745