Development and pharmacological evaluation of ropivacaine-2-hydroxypropyl-beta-cyclodextrin inclusion complex

Ropivacaine (RVC) is an enantiomerically pure local anesthetic (LA) largely used in surgical procedures, which presents physico-chemical and therapeutic properties similar to those of bupivacaine (BPV), but associated to less systemic toxicity This study focuses on the development and pharmacological evaluation of a RVC in 2-hydroxypropyl-beta-cyclodextrin (HP-P-CD) inclusion complex. Phase-solubility diagrams allowed the determination of the association constant between RVC and HP-beta-CD (9.46 M-1) and showed an increase on RVC solubility upon complexation. Release kinetics revealed a decrease on RVC release rate and reduced hemolytic effects after complexation. (onset at 3.7 mM and 11.2 mM for RVC and RVCHP-beta-CD, respectively) were observed. Differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and X-ray analysis (X-ray) showed the formation and the morphology of the complex. Nuclear magnetic resonance (NMR) and job-plot experiments afforded data regarding inclusion complex stoichiometry (1:1) and topology. Sciatic nerve blockade studies showed that RVCHP-beta-CD was able to reduce the latency without increasing the duration of motor blockade, but prolonging the duration and intensity of the sensory blockade (p < 0.001) induced by the LA in mice. These results identify the RVCHP-beta-CD complex as an effective novel approach to enhance the pharmacological effects of RVC, presenting it as a promising new anesthetic formulation. (c) 2007 Elsevier B.V All rights reserved.

Non-inclusion complexes between riboflavin and cyclodextrins

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Computational analysis and physico-chemical characterization of an inclusion compound between praziquantel and methyl-beta-cyclodextrin for use as an alternative in the treatment of schistosomiasis

Schistosomiasis is still an endemic disease in many regions, with 250 million people infected with Schistosoma and about 500,000 deaths per year. Praziquantel (PZQ) is the drug of choice for schistosomiasis treatment, however it is classified as Class II in the Biopharmaceutics Classification System, as its low solubility hinders its performance in biological systems. The use of cyclodextrins is a useful tool to increase the solubility and bioavailability of drugs. The aim of this work was to prepare an inclusion compound of PZQ and methyl-beta-cyclodextrin (MeCD), perform its physico-chemical characterization, and explore its in vitro cytotoxicity. SEM showed a change of the morphological characteristics of PZQ:MeCD crystals, and IR data supported this finding, with changes after interaction with MeCD including effects on the C-H of the aromatic ring, observed at 758 cm(-1). Differential scanning calorimetry measurements revealed that complexation occurred in a 1:1 molar ratio, as evidenced by the lack of a PZQ transition temperature after inclusion into the MeCD cavity. In solution, the PZQ UV spectrum profile in the presence of MeCD was comparable to the PZQ spectrum in a hydrophobic solvent. Phase solubility diagrams showed that there was a 5.5-fold increase in PZQ solubility, and were indicative of a type A(L) isotherm, that was used to determine an association constant (K(a)) of 140.8 M(-1). No cytotoxicity of the PZQ:MeCD inclusion compound was observed in tests using 3T3 cells. The results suggest that the association of PZQ with MeCD could be a good alternative for the treatment of schistosomiasis.

Stability of neutral functional differential equations in terms of measures

In this paper we investigate the relationships between different concepts of stability in measure for the solutions of an autonomous or periodic neutral functional differential equation.

On retarded differential equations with impulses

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Stability of differential equations with piecewise constant argument via discrete equations

Lyapunov stability for a class of differential equation with piecewise constant argument (EPCA) is considered by means of the stability of a discrete equation. Applications to some nonlinear autonomous equations are given improving some linear known cases.

The relationship between differential equations with piecewise constant argument and the associated discrete equations, via dichotomic maps

Dichotomic maps are considered by means of the stability and asymptotic stability of the null solution of a class of differential equations with argument [t] via associated discrete equations, where [.] designates the greatest integer function.

Sufentanil-2-hydroxypropyl-beta-cyclodextrin inclusion complex for pain treatment: Physicochemical, cytotoxicity, and pharmacological evaluation

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Lyapounov stability for impulsive dynamical systems

This article addresses the problem of stability of impulsive control systems whose dynamics are given by measure driven differential inclusions. One important feature concerns the adopted solution which allows the consideration of systems whose singular dynamics do not satisfy the so-called Frobenius condition. After extending the conventional notion of control Lyapounov pair for impulsive systems, some stability conditions of the Lyapounov type are given. Some conclusions follow the outline of the proof of the main result.

Invariance for Impulsive Control Systems

In this article, we provide invariance conditions for control systems whose dynamics are given by measure driven differential inclusions. The solution concept plays a critical role in the extension of the conventional conditions for the impulsive control context. A couple of examples illustrating the specific features of impulsive control systems are included.

Inclusion complex of S(-) bupivacaine and 2-hydroxypropyl- β-cyclodextrin: Study of morphology and cytotoxicity

Local anesthetics (LA) belong to a class of pharmacological compounds that attenuate or eliminate pain by binding to the sodium channel of excitable membranes, blocking the influx of sodium ions and the propagation of the nerve impulse. S (-) bupivacaine (S(-) bvc) is a local anesthetic of amino-amide type, widely used in surgery and obstetrics for sustained peripheral and central nerve blockade. This article focuses on the characterization of an inclusion complex of S(-) bvc in 2-hydroxypropyl-β-cyclodextrin (HP-β-CD). Differential scanning calorimetry, scanning electron microscopy and X-Ray diffraction analysis showed structural changes in the complex. In preliminary toxicity studies, the cell viability tests revealed that the inclusion complex decreased the toxic effect (p<0.001) produced by S(-) bvc. These results suggest that the S(-) bvc:HP-β-CD inclusion complex represents a promising agent for the treatment of regional pain.

On stability of differential equations with piecewise constant argument and the associated discrete equations using dichotomic map

Dichotomic maps are considered by means of the stability of the null solution of a class of differential equations with piecewise constant argument via associated discrete equations. Copyright © 2008 Watam Press.

On stability of differential equations with piecewise constant argument using dichotomic maps

This paper deals with the study of the basic theory of existence, uniqueness and continuation of solutions of di®erential equations with piecewise constant argument. Results about asymptotic stability of the equation x(t) =-bx(t) + f(x([t])) with argu- ment [t], where [t] designates the greatest integer function, are established by means of dichotomic maps. Other example is given to illustrate the application of the method. Copyright © 2011 Watam Press.

Inclusion complex of S(-) bupivacaine and 2-hydroxypropyl-β-cyclodextrin: study of morphology and cytotoxicity

Local anesthetics (LA) belong to a class of pharmacological compounds that attenuate or eliminate pain by binding to the sodium channel of excitable membranes, blocking the influx of sodium ions and the propagation of the nerve impulse. S (-) bupivacaine (S(-) bvc) is a local anesthetic of amino-amide type, widely used in surgery and obstetrics for sustained peripheral and central nerve blockade. This article focuses on the characterization of an inclusion complex of S(-) bvc in 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD). Differential scanning calorimetry, scanning electron microscopy and X-Ray diffraction analysis showed structural changes in the complex. In preliminary toxicity studies, the cell viability tests revealed that the inclusion complex decreased the toxic effect (p<0.001) produced by S(-) bvc. These results suggest that the S(-) bvc:HP-ß-CD inclusion complex represents a promising agent for the treatment of regional pain. Keywords: S(-) bupivacaine; cyclodextrin; inclusion complex.

On exponential stability of functional differential equations with variable impulse perturbations

We consider a class of functional differential equations subject to perturbations, which vary in time, and we study the exponential stability of solutions of these equations using the theory of generalized ordinary differential equations and Lyapunov functionals. We introduce the concept of variational exponential stability for generalized ordinary differential equations and we develop the theory in this direction by establishing conditions for the trivial solutions of generalized ordinary differential equations to be exponentially stable. Then, we apply the results to get corresponding ones for impulsive functional differential equations. We also present an example of a delay differential equation with Perron integrable right-hand side where we apply our result.