Synthesis, in vitro activity and in vivo toxicity of the new 2,3-dinitrobutadiene derivative (1E,3E)-1,4-bis(2-naphthyl)-2,3-dinitro-1,3-butadiene

Abstract Our interesting results on the antiproliferative (in vitro) and antitumour (in vivo) activities of (1E,3E)-1,4-bis(1-naphthyl)-2,3-dinitro-1,3-butadiene (1-Naph-DNB) have more recently induced us to design and synthesize some new 1,4-diaryl-2,3-dinitro-1,3-butadienes characterized by a common arylnitrobutadiene array but with different geometric and/or functional properties. This task was undertaken with the aim to obtain new compounds with an enhanced antiproliferative activity and, possibly, a different specificity with respect to the original (lead) compound. (1E,3E)-1,4-Bis(2-naphthyl)-2,3-dinitro-1,3-butadiene (2-Naph-DNB) is one of the molecules so obtained, a structural isomer of 1-Naph-DNB provided with a different spatial arrangement. When analyzed in vitro for its inhibition of cell proliferation 2-Naph-DNB showed a remarkable activity in the range of micromolar concentrations, with significant differences, with respect to 1-Naph-DNB, against some cell lines. Furthermore, it was able to significantly trigger apoptosis, to up-regulate p53, to block cells in the G2/M phase of the cell cycle and, finally, to slightly bind to DNA forming interstrand cross-links (ISCL). 2-Naph-DNB was then analyzed for its toxic activity in vivo in CD1 mice. This allowed the determination of toxicity parameters such as the lethal doses (LD) and the maximal tolerated dose (MTD) together with the definition of the spectrum of tissue alterations due to its administration i.v. Altogether our data suggest that the idea of modifying the geometry of the lead compound 1-Naph-DNB deserves further investigation aimed at synthesizing new molecules with similar chemical functionalities but with different spatial requirements, hopefully characterized by still enhanced activities in terms of inhibition of cell proliferation and apoptosis

Vacuna tetravalente de influenza en los programas nacionales de inmunización para los países de América Latina

Since 2012-2013 influenza season, World Health Organization (who) recommends the formulation of tetravalent vaccines. Globally, many countries already use tetravalent vaccines in their national immunization programs, while in Latin America only a small number. Two Influenza b lineages co-circulate, their epidemiological behavior is unpredictable. On average they represent 22.6% of influenza cases and more than 50% in predominant seasons. The lack of concordance between recommended and circulating strains was 25 and 32% in the 2010-2017 and 2000-2013 seasons, respectively. There are no clinical differences between influenza A and B. It occurs more frequently from five to 19 years of age. Influenza b has a higher proportion of attributable deaths than influenza a (1.1 vs. 0.4%), or 2.65 (95% ci 1.18-5.94). A greater number of hospitalizations when the strains mismatch (46.3 vs. 28.5%; p <.0001). Different evaluations have demonstrated its cost effectiveness. The compilation of this information supports the use of quadrivalent vaccines in Latin American countries.Revisión por pare

Transplacental passage of Pt after treatment with the new triamine complex cis-diaminechloro-[2-(diethylamino) ethyl 4-amino-benzoate, N4]-chloride platinum (II) monohydrochloride monohydrate

Cis-diaminechloro-[2-(diethylamino) ethyl 4-amino-benzoate, N4]-chloride platinum (II) monohydrochloride monohydrate (DPR) is a monofunctional Pt triamine complex synthesized starting from cisplatin and procaine hydrochloride, characterized by a good antitumor activity coupled with low toxic effects and able to impair prenatal development of mice but at doses outside or just in the upper range of therapeutic doses. In the present paper the transplacental passage of DPRderived Pt was investigated in CD1 mice on days 9, 13, 16 and 18 of pregnancy, 24 h after ip administration of 21 mg/kg DPR. For comparison, groups of mice were treated with an equivalent Pt-containing dose of cisplatin (10.7 mg/kg). Similarly to cisplatin, small amounts of Pt were detected in fetuses on day 9. From day 13 of gestation the concentration of DPR- and cisplatin- derived Pt increased up to the highest fetal concentrations detected on day 16. On day 18 the concentration of Pt decreased. Most importantly, on days 13\u201318 of pregnancy cisplatin-derived Pt was always significantly higher than that assayed after DPR administration. In addition, on day 13 of pregnancy Pt exposure of fetuses was significantly higher when dams were treated with cisplatin (AUC0.5\u201324= 3.40 vs. 4.95 lg\uc6h/g). Finally, it is worth noting that serum decay of Pt after DPR or cisplatin administration in adult female mice was similar with AUC0.13\u20132h s of 7.5 and 6.6 lg\uc6h/ml, respectively. When we determined the concentration of Pt into the main organs of fetuses from dams treated with either DPR or cisplatin on day 18 of gestation, we observed a different organ distribution. In fact, while the concentration of DPR-derived Pt was greater in the heart (1.08\ub10.30 vs. 0.78\ub10.35 lg/g, p &lt;0.10), an opposite situation was found in the kidney (0.51\ub10.20 vs. 0.69\ub10.22 lg/g, p &lt;0.05). In conclusion, our data show that DPR may pass through the placenta with an efficiency significantly lower than that of cisplatin. This finding may represent one of the possible causes of the lower embryotoxic/teratogenic effect of DPR as compared to cisplatin

Study of feasibility of the treatment with procainamide hydrochloride and cisplatin in pregnant mice

Cisplatin is one of the most widely utilized anticancer drugs; nevertheless its use is often hampered by the onset of serious side effects. In spite of its tight binding to DNA, great teratogenic effects do not characterize cisplatin, although its embryolethal and growth retardation activities are quite remarkable. On the basis of our previous observations, demonstrating the usefulness of procainamide hydrochloride for the protection against cisplatin toxic effects in adult mice and rats, we now analyze the feasibility of the combined treatment with cisplatin and the antiarrhythmic drug procainamide hydrochloride in pregnant mice and the possible protective action of procainamide against the embryotoxic activity of cisplatin. Our data, obtained in CD-1 dams after treatment with 8 or 12 mg/kg cisplatin ip, with or without 50 mg/kg procainamide hydrochlo- ride iv, confirm the embryotoxic effects of cisplatin. We also demonstrate that procainamide may be administered with cisplatin without causing an increase in its embryotoxic effects, but slightly improving some embryotoxicity parameters in living embryos such as the fetal weight, the percentage of fetuses with skeletal anomalies, and the number of ossification centres. The mechanism of action of this partially protective activity seems to be linked in part to the lower cisplatin accumulation in fetal tissue, probably due to an interaction of drugs at the level of placenta, in part to the protection of procainamide against maternal toxicity of cisplatin. A relevant result of this research is the suggestion that procainamide hydrochloride might be administered in case of pregnancy to protect against the maternal toxic effects of cisplatin without an increased embryotoxic/teratogenic risk for the offspring

Bladder cell culture on small intestinal submucosa as bioscaffold: Experimental study on engineered urothelial grafts

Objectives: To investigate the feasibility to perform primary urothelial cell culture using porcine small intestinal submucosa as a delivery scaffold both in vitro and after in vivo implantation in a rabbit model. Materials and methods: Bladder mucosa samples were aseptically obtained from a group of eight male rabbits. The mucosa was cut into fragments and placed on small intestinal submucosa matrices for selective urothelial cell culture. After complete in vitro epithelization the matrices were shaped into tubes and placed in the subcutaneous tissue and subdartos of donor rabbits. The pattern of cell growth and delivery was evaluated on retrieved grafts using histology and immunostaining at the end of the in vitro phase; then 5, 10 and 20 days after implantation. Results: Histological and immunohistochemical analysis of the in vitro primary culture showed the acellular matrices covered with a thin uninterrupted monolayer of urothelial cells. The implants examined on the day 5 mantained the epithelial configuration of the cultured grafts in all samples retrieved. On the day 10 the urothelium showed increased thickness taking on a bilayer configuration. On day 20, all grafts presented the transitional cells arranged in a double layer closely resembling the natural urothelium. The immunostaining pattern displayed the mantaining of urothelial cell phenotype. No differences in epithelium growth and delivery were noted between the two sites of implantation. Five days after implantation, the histological analysis of small intestinal submucosa showed a medium degree tissue reaction with the presence of acute inflammatory cells. Angiogenesis was demonstrated by the development of several new vessels inside the matrix. After twenty days, small intestinal submucosa was gradually replaced with host tissue. Conclusion: The small intestinal submucosa proved to function as a means of delivering of autologous urothelial cells cultured in vitro. After ectopic in vivo implantation the bioscaffold maintained viability and growth of the surrounding cells until its degradation