Ramón Gutiérrez-Sánchez

In Vitro and in Vivo Trypanocidal Activity of Flavonoids from Delphinium staphisagria against Chagas Disease

The in vitro and in vivo trypanocidal activities of nine flavonoids (1-9) isolated from the aerial parts of Delphinium staphisagria have been studied in both the acute and chronic phases of Chagas disease. The antiproliferative activity of these substances against Trypanosoma cruzi (epimastigote, amastigote, and trypomastigote forms) in some cases exhibited more potent antitrypanosomatid activity and lower toxicity than the reference drug, benznidazole. Studies in vitro using ultrastructural analysis together with metabolism-excretion studies were also performed in order to identify the possible action mechanism of the compounds tested. Alterations mainly at the level of the mitochondria may explain metabolic changes in succinate and acetate production, perhaps due to the disturbance of the enzymes involved in sugar metabolism within the mitochondrion. In vivo studies provided results consistent with those observed in vitro. No signs of toxicity were detected in mice treated with the flavonoids tested, and the parasitic charge was significantly lower than in the control assay with benznidazole. The effects of these compounds were also demonstrated with the change in the anti-T. cruzi antibody levels during the chronic stage.

In vitro anti-leishmania evaluation of nickel complexes with a triazolopyrimidine derivative against Leishmania infantum and Leishmania braziliensis

Studies on the anti-proliferative activity in vitro of seven ternary nickel (II) complexes with a triazolopyrimidine derivative and different aliphatic or aromatic amines as auxiliary ligands against promastigote and amastigote forms of Leishmania infantum and Leishmania braziliensis have been carried out. These compounds are not toxic for the host cells and two of them are effective at lower concentrations than the reference drug used in the present study (Glucantime). In general, the in vitro growth rate of Leishmania spp. was reduced, its capacity to infect cells was negatively affected and the multiplication of the amastigotes decreased. Ultrastructural analysis and metabolism excretion studies were executed in order to propose a possible mechanism for the action of the assayed compounds. Our results show that the potential mechanism is at the level of organelles membranes, either by direct action on the microtubules or by their disorganization, leading to vacuolization, degradation and ultimately cell death.

Leishmanicidal activity of nine novel flavonoids from Delphinium staphisagria.

Objectives. To evaluate the in vitro leishmanicidal activity of nine flavonoid derivatives from Delphinium staphisagria against L. infantum and L. braziliensis. Design and Methods. The in vitro activity of compounds 1–9 was assayed on extracellular promastigote and axenic amastigote forms and on intracellular amastigote forms of the parasites. Infectivity and cytotoxicity tests were carried on J774.2 macrophage cells using Glucantime as the reference drug. The mechanisms of action were analysed performing metabolite excretion and transmission electronic microscope ultrastructural alteration studies. Results. Nine flavonoids showed leishmanicidal activity against promastigote as well as amastigote forms of Leishmania infantum and L. braziliensis. These compounds were nontoxic to mammalian cells and were effective at similar concentrations up to or lower than that of the reference drug (Glucantime). The results showed that 2″-acetylpetiolaroside (compound 8) was clearly the most active. Conclusion. This study has demonstrated that flavonoid derivatives are active against L. infantum and L. braziliensis.

The Stochastic Rayleigh diffusion model : Statistical inference and computational aspects. Applications to modelling of real cases

Abstract In this paper, we consider a Stochastic System modelling by the Stochastic Rayleigh Diffusion Process and we discuss theoretical aspects of the latter and establish a statistical methodology to adjust it to real cases, particulary, in the field of biometry and related areas. The Rayleigh process, according to the definition of [C. Giorno, A. Nobile, L. Ricciardi, L. Sacerdote, Some remarks on the Rayleigh process, Journal of Applied Probability 23 (1986) 398–408], is examined from the perspective of the corresponding nonlinear stochastic differential equation, and from its associated probability density function we obtain the corresponding mean functions (trend function and conditional trend function), which depend of Kummer functions. The drift parameters are estimated by maximum likelihood on the basis of continuous sampling of the process and they are calculated by computational methods. We propose numerical approximations for the diffusion coefficient, from an extension of the [M. Chesney, J. Elliot, Estimating the instantaneous volatility and covariance of risky assets, Applied Stochastic Models and Data Analysis 11 (1995) 51–58] procedure to the case of nonlinear stochastic differential equations and we establish also computational procedures and simulation algorithm, that are applied to obtened simulated paths of the fitted process. The proposed methodology is applied to two studies carried out in Andalusia (Spain) on females and males life expectancy at birth, between 1944 and 2001.

Lanthanide complexes containing 5-methyl-1,2,4-triazolo(1,5-a) pyrimidin-7(4H)-one and their therapeutic potential to fight leishmaniasis and Chagas disease☆

In the last years, numerous and significant advances in lanthanide coordination chemistry have been achieved. The unique chemical nature of these metal ions which is conferred by their f-electrons has led to a wide range of coordination compounds with interesting structural, physical and also biological properties. Consequently, lanthanide complexes have found applications mainly in catalysis, gas adsorption, photochemistry and as diagnostic tools. However, research on their therapeutic potential and the understanding of their mechanism of action is still taking its first steps, and there is a distinct lack of research in the parasitology field. In the present work, we describe the synthesis and physical properties of seven new lanthanide complexes with the anionic form of the bioactive ligand 5-methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one (HmtpO), namely [Ln(mtpO)3(H2O)6]·9H2O (Ln=La(III), Nd(III), Eu(III), Gd(III), Tb(III), Dy(III) and Er(III)). In addition, results on the in vitro antiproliferative activity against Leishmania spp. and Trypanosoma cruzi are described. The high activity of the new compounds against parasite proliferation and their low cytotoxicity against reference host cell lines show a great potential of this type of compounds to become a new generation of highly effective and non-toxic antiparasitic agents to fight the so considered neglected diseases leishmaniasis and Chagas disease.

A new stochastic Gompertz diffusion process with threshold parameter: Computational aspects and applications

Abstract In this paper we propose a new homogeneous stochastic Gompertz diffusion model with a threshold parameter. This can be considered an extension of the homogeneous three parameter Gompertz process with the addition of a fourth parameter. From the corresponding Kolmogorov equations and Ito’s stochastic differential equations, we obtain the transition probability density function and the moments of this process (specifically, the trend functions). The parameters are estimated by considering discrete sampling of the sample path of the model and by using maximum likelihood methodology. Estimation of the threshold parameter requires us to solve a non-linear equation, which is achieved by the Newton–Raphson method. Simulated model data are considered and the methodology in question is applied to estimate the parameters; the values obtained are compared with those used in the simulation. Finally, the model is applied to model the evolution of the trend of the dynamic variable “average monthly salary cost”, for all sectors and broken down (construction, industry, services) in Spain, for the period (1985–2005).

INFERENCE IN GOMPERTZ-TYPE NONHOMOGENEOUS STOCHASTIC SYSTEMS BY MEANS OF DISCRETE SAMPLING

ABSTRACT We consider an extension of the Gompertz homogeneous diffusion process by introducing time functions (exogenous factors) that affect its trend. After obtaining its transition probability density function, the inference on the parameters of the process is obtained by considering discrete sampling of the sample paths. Finally, we apply this stochastic process to model housing price in Spain.

Scorpiand-like azamacrocycles prevent the chronic establishment of Trypanosoma cruzi in a murine model.

Chagas disease is today one of the most important neglected diseases for its upcoming expansion to non-endemic areas and has become a threat to blood recipients in many countries. In this study, the trypanocidal activity of ten derivatives of a family of aza-scorpiand like macrocycles is evaluated against Trypanosoma cruzi in vitro and in vivo murine model in which the acute and chronic phases of Chagas disease were analyzed. The compounds 4, 3 and 1 were found to be more active against the parasite and less toxic against Vero cells than the reference drug benznidazole, 4 being the most active compound, particularly in the chronic phase. While all these compounds showed a remarkable degree of inhibition of the Fe-SOD enzyme of the epimastigote forms of T. cruzi, they produced a negligible inhibition of human CuZn-SOD and Mn-SOD from Escherichia coli. The modifications observed by (1)H NMR and the amounts of excreted catabolites by the parasites after treatment suggested that the mechanism of action could be based on interactions of the side chains of the compounds with enzymes of the parasite metabolism. The ultrastructural alterations observed in treated epimastigote forms confirmed that the compounds having the highest activity are those causing the largest cell damage. A complementary histopathological analysis confirmed that the compounds tested were significantly less toxic to mammals than the reference drug.

In vitro and in vivo studies of the trypanocidal activity of four terpenoid derivatives against Trypanosoma cruzi.

Four terpenoid derivatives were examined for their activity against Trypanosoma cruzi. Our results show that two compounds were very active in vitro against both extra- and intracellular forms. These compounds, non-toxic for the host cells, are more effective than the reference drug benznidazole. The capacity to infect cells was negatively affected and the number of amastigotes and trypomastigotes was reduced. A wide range of ultrastructural alterations was found in the epimastigote forms treated with these compounds. Some metabolic changes occurred presumably at the level of succinate and acetate production, perhaps caused by the disturbance of the enzymes involved in sugar metabolism inside the mitochondria. In vivo results were consistent with those observed in vitro. The parasitic load was significantly lower than in the control assay with benznidazole. The effects of these products showed the reduction of the anti-T. cruzi antibodies level during the chronic stage.

A stochastic Gompertz model highlighting internal and external therapy function for tumour growth

Abstract This paper proposes a model of tumour cell growth based on a Gompertz-type nonhomogeneous stochastic diffusion, whose drift coefficient depends on two functions of time that influence the dynamic behaviour of the model, and which can be interpreted in the context of this type of cell growth. The first of these time functions is an immunologic endogenous therapy factor, and the second is an exogenous therapy factor that models the dynamics of an externally controllable treatment on tumour growth. We establish the basic probabilistic characteristics of the model from the corresponding Ito differential equation, explicitly obtaining the expression of the trend functions. We then study the functional aspects and computational statistics associated with the maximum likelihood estimation of the model parameters. Finally, we provide a detailed discussion of the inter-relationships between the internal parameters of the diffusion process and the overall diffusion coefficient of the model.