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Arroyo Cabral, Argentina

Giglio J.,Catedra de Radioquimica | Fernandez S.,Catedra de Radioquimica | Pietzsch H.-J.,Helmholtz Center Dresden | Dematteis S.,Catedra de Inmunologia | And 3 more authors.
Nuclear Medicine and Biology

The evaluation of oxygenation status of solid tumors is an important field of radiopharmaceutical research. With the aim to develop new potential 99mTc-radiopharmaceuticals for imaging hypoxia, we have synthesized two novel isocyanide derivatives of metronidazole, which has demonstrated high affinity for hypoxic tumors in vitro and in vivo. Methods: Metronidazole derivatives 4-isocyano-N-[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl]butanamide (M1) and 1-(4-isocyanobutanoyl)-4-[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl]piperazine (M2) were synthesized, and labeling was performed through preparation of their corresponding 99mTc-(4+1) complexes, 99mTc-NS3M1 and 99mTc-NS3M2. The structure of the technetium complexes was corroborated by preparation and characterization of the corresponding rhenium complexes. We have studied the main physicochemical properties (stability, lipophilicity and plasma protein binding). Biological behavior in HCT-15 cells both in oxia and in hypoxia was assessed. Biodistribution in normal mice and in animals bearing induced 3LL Lewis murine lung carcinoma was also studied. Results: Metronidazole derivatives were successfully synthesized. Labeling with high radiochemical purity was achieved for both ligands. 99mTc complexes were stable in labeling milieu and human plasma. However, presence of the piperazine linker in M2 resulted in higher lipophilicity and protein binding. Although cell uptake in hypoxic conditions was observed for both radiotracers, 99mTc-NS3M2 biodistribution was considered unsuitable for a potential radiopharmaceutical due to high liver uptake and poor blood clearance. However, 99mTc-NS3M1 demonstrated a very favorable in vivo profile both in normal mice and in mice bearing induced tumors. Conclusion: Selective uptake and retention in tumor together with favorable tumor/muscle ratio make 99mTc-NS3M1 a promising candidate for further evaluation as potential hypoxia imaging agent in tumors. © 2012 Elsevier Inc.. Source

The aim of this work consisted to study the clinical and hematological effects that included blood coagulation and antibody production of a group of three horses immunized for the production of monovalent serum against Bothrops alternatus venom, in order to correlate the results with the humoral immune response of the animals. The results showed that immunization of horses with the essayed protocol induce slight clinic alterations and discrete changes in some parameters of the hemogram. Results also showed variations in the neutralizing capacity of the serum on different venom components, particularly toxins that affect blood coagulation. Also, it was verified a direct relationship between the rate of white blood cells and serum immunoglobulin production. Furthermore, they also indicate that the three-month rest period may be considered as too long as it causes a marked decrease in antibody titles, losing the serum its neutralizing capacity to venom compounds. Nevertheless, after re-administration of venom horses provided a rapid reposition of anti-toxins against B. alternatus venom, tolerating high venom doses during this second period of immunization. Source

Saiz C.,University of the Republic of Uruguay | Castillo V.,University of the Republic of Uruguay | Fontan P.,University of the Republic of Uruguay | Bonilla M.,Catedra de Inmunologia | And 3 more authors.
Molecular Diversity

In this study, we report a strategy using dynamic combinatorial chemistry for targeting the thioredoxin (Trx)-reductase catalytic site on Trx glutathione reductase (TGR), a pyridine nucleotide thiol-disulfide oxido-reductase. We chose Echinococcus granulosus TGR since it is a bottleneck enzyme of platyhelminth parasites and a validated pharmacological target. A dynamic combinatorial library (DCL) was constructed based on thiol-disulfide reversible exchange. We demonstrate the use of 5-thio-2-nitrobenzoic acid (TNB) as a non-covalent anchor fragment in a DCL templated by E. granulosus TGR. The heterodimer of TNB and bisthiazolidine (2af) was identified, upon library analysis by HPLC (IC -{50} 50 = 24 \upmu μ M). Furthermore, 14 analogs were synthetically prepared and evaluated against TGR. This allowed the study of a structure-activity relationship and the identification of a disulfide TNB-tricyclic bisthiazolidine (2aj) as the best enzyme inhibitor in these series, with an IC -{50} 50 = 14 \upmu μ M. Thus, our results validate the use of DCL for targeting thiol-disulfide oxido-reductases. © 2013 Springer Science+Business Media Dordrecht. Source

Marunak S.,Catedra de Farmacologia | Nunez S.,Catedra de Inmunologia | Fernandez C.,Catedra de Farmacologia | Leiva L.,Northeast National University | Acosta de Perez O.,Catedra de Farmacologia
Revista Veterinaria

Snake venoms induce a wide variety of disorders, some of them on blood coagulation, since they contain both coagulant and anticoagulant components. In this assay we present the effects of venom of Bothrops diporus from Argentina on the hemostatic system of different mammal species, in order to estimate blood-clotting, fibrinolytic, and lethal activities. From our results, it can be stated that this venom has trombin-like enzymes that produced coagulation of plasma, being ovine and human the most sensitive species. Minimum coagulant dose for this venom was compared to those from Central America (Bothrops asper, Costa Rica), suggesting that venom of snakes from warmer areas have less coagulant activity. Source

Kim H.-J.,University of California at Davis | McCoy M.R.,University of California at Davis | Majkova Z.,University of California at Davis | Dechant J.E.,University of California at Davis | And 4 more authors.
Analytical Chemistry

Some unique subclasses of Camelidae antibodies are devoid of the light chain, and the antigen binding site is comprised exclusively of the variable domain of the heavy chain (VHH). Although conventional antibodies dominate current assay development, recombinant VHHs have a high potential as alternative reagents for the next generation of immunoassay. We expressed VHHs from an immunized alpaca and developed a VHH-based immunoassay using 3-phenoxybenzoic acid (3-PBA), a major metabolite of pyrethroid insecticides as a model system. A phage VHH library was constructed, and seven VHH clones were selected by competitive binding with 3-PBA. The best immunoassay developed with one of these VHHs showed an IC 50 of 1.4 ng/mL (limit of detection (LOD) = 0.1 ng/mL). These parameters were further improved by using the phage borne VHH, IC 50 = 0.1 ng/mL and LOD = 0.01 ng/mL. Both assays showed a similar tolerance to methanol and dimethylsulfoxide up to 50% in assay buffer. The assay was highly specific to 3-PBA and its 4-hydroxylated derivative, 4-hydroxy 3-PBA, (150% cross reactivity) with negligible cross reactivity with other tested structural analogues, and the recovery from spiked urine sample ranged from 80 to 112%. In conclusion, a highly specific and sensitive VHH for 3-PBA was developed using sequences from immunized alpaca and phage display technology for antibody selection. © 2011 American Chemical Society. Source

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