Estrés y ansiedad perioperatorios en padres de niños intervenidos de cardiopatías congénitas / Perioperative stress and anxiety in parents of children operated on for congenital heart disease

Introducción: Los niveles de estrés y la ansiedad que sufren los padres y madres de niños con cardiopatía congénita (PMNCC) durante el ingreso para cirugía cardíaca de sus hijos pueden ser más elevados que los que sufren otros padres y madres que pasan por la misma experiencia. Objetivo: El objetivo general de este estudio fue medir el estrés y la ansiedad que sufren los PMNCC y los padres de niños tratados mediante cirugía renal (PMNCR) en relación con la intervención de sus hijos. El objetivo específico del estudio cuantitativo fue comparar el estrés y ansiedad global con relación al sexo, el momento del periodo perioperatorio y la cohorte. El objetivo general del apartado cualitativo es explorar la vivencia que tienen los PMNCC y PMNCR durante su estancia hospitalaria e identificar los factores específicos que influyen en la génesis del estrés y la ansiedad. Método: Se realizó un estudio de cohortes en el que se incluyeron los PMNCC y los PMNCR. La parte cuantitativa se realizó comparando las puntuaciones de 3cuestionarios que miden los niveles de estrés (PSS-14), ansiedad estado (STAIE) y ansiedad rasgo (STAIR) a lo largo de 3momentos perioperatorios. Paralelamente se hizo un estudio cualitativo con entrevistas semiestructuradas y recogida de diarios sobre los que se realizó un análisis fenomenológico descriptivo, según Munhall. El análisis del texto se realizó según la propuesta de Colaizzi. Resultados: Los niveles de estrés y ansiedad fueron significativamente más altos en los PMNCC respecto a los PMNCR. Las madres de la cohorte cardíaca fueron las que presentaron las puntuaciones más altas en todas las escalas. En el estudio cualitativo emergieron 4temas: «estrés y ansiedad desde el momento del diagnóstico», «intervención quirúrgica como momento crítico», «dureza del postoperatorio en la Unidad de Cuidados Intensivos» y «alegría y agradecimiento versus dependencia y temor ante el futuro»...(AU)

Introduction: Levels of stress and anxiety suffered by parents of children with congenital heart disease (PCUCS) during their children's admission for cardiac surgery may be higher than those suffered by other parents who go through the same experience. Objective: General objective of this study was to measure the stress and anxiety suffered by PCUCS and parents of children undergoing renal surgery (PCURS) in relation to the intervention of their children. The specific objective of the quantitative study was to compare global stress and anxiety according to sex, time of the perioperative period, and cohort. The general objective of the qualitative section is to explore the experience that PCUCS and PCURS have during their hospital stay and to identify the specific factors that influence the genesis of stress and anxiety. Method: A cohort study was carried out in which PCURS and PCUCS were included. The quantitative part was performed by comparing the scores of 3questionnaires that measure stress levels (PSS-14), state anxiety (STAIE) and trait anxiety (STAIR) throughout 3perioperative moments. At the same time, a qualitative study was carried out with semi-structured interviews and collection of diaries on which a descriptive phenomenological analysis was carried out, according to Munhall. The analysis of the text was carried out according to Colaizzi. Results: Stress and anxiety levels were significantly higher in PCUCS compared to PCURS. Mothers in the cardiac cohort were those with the highest scores on all scales. In the qualitative study, 4themes emerged: “stress and anxiety from the moment of diagnosis”, “surgical intervention as a critical moment”, “harshness of the postoperative period in the Intensive Care Unit” and “joy and gratitude versus dependence and fear for the future”...(AU)

Perioperative stress and anxiety in parents of children operated on for congenital heart disease.

INTRODUCTION: Levels of stress and anxiety suffered by parents of children with congenital heart disease (PCUCS) during their children's admission for cardiac surgery may be higher than those suffered by other parents who go through the same experience. OBJECTIVE: General objective of this study was to measure the stress and anxiety suffered by PCUCS and parents of children undergoing renal surgery (PCURS) in relation to the intervention of their children. The specific objective of the quantitative study was to compare global stress and anxiety according to sex, time of the perioperative period, and cohort. The general objective of the qualitative section is to explore the experience that PCUCS and PCURS have during their hospital stay and to identify the specific factors that influence the genesis of stress and anxiety. METHOD: A cohort study was carried out in which PCURS and PCUCS were included. The quantitative part was performed by comparing the scores of three questionnaires that measure stress levels (PSS-14), state anxiety (STAIE) and trait anxiety (STAIR) throughout three perioperative moments. At the same time, a qualitative study was carried out with semi-structured interviews and collection of diaries on which a descriptive phenomenological analysis was carried out, according to Munhall. The analysis of the text was carried out according to Colaizzi. RESULTS: Stress and anxiety levels were significantly higher in PCUCS compared to PCURS. Mothers in the cardiac cohort were those with the highest scores on all scales. In the qualitative study, four themes emerged: "stress and anxiety from the moment of diagnosis", "surgical intervention as a critical moment", "harshness of the postoperative period in the Intensive Care Unit" and "joy and gratitude versus dependence and fear for the future". CONCLUSIONS: PCUCS suffer higher levels of stress and anxiety than PCURS, being the mothers of the cardiac cohort those who suffer these disorders with greater intensity. This study can constitute a starting point to develop strategies that cover these parental needs.

Role of Endothelial Kinin B1 Receptor on the Membrane Potential of Transgenic Rat Aorta.

The kinin receptors are classically involved in inflammation, pain and sepsis. The effects of the kinin B1 receptor agonist des-Arg9-bradykinin (DBK) and lipopolysaccharide (LPS) were investigated by comparing the membrane potential responses of aortic rings from transgenic rats overexpressing the kinin B1 receptor (B1R) in the endothelium (TGR(Tie2B1)) and Sprague Dawley (SD) rats. No difference in the resting membrane potential in the aorta's smooth muscle from the transgenic and SD rats was observed. The aorta rings from SD rats hyperpolarized only to LPS but not to DBK, whereas the aorta rings from TGR(Tie2B1) responded by the administration of both drugs. DBK and LPS responses were inhibited by the B1 receptor antagonist R715 and by iberiotoxin in both cases. Thapsigargin induced a hyperpolarization in the smooth muscle of SD rats that was not reversed by R715, but was reversed by iberiotoxin and this hyperpolarization was further augmented by DBK administration. These results show that the model of overexpression of vascular B1 receptors in the TGR(Tie2B1) rats represent a good model to study the role of functional B1 receptors in the absence of any pathological stimulus. The data also show that KCa channels are the final mediators of the hyperpolarizing responses to DBK and LPS. In addition, we suggest an interaction between the B1R and TLR4, since the hyperpolarization induced by LPS could be abolished in the presence of R715.

Cardiac morphofunctional characteristics of transgenic rats with overexpression of the bradykinin B1 receptor in the endothelium.

Our aim was to evaluate whether endothelial overexpressing of the bradykinin B1 receptor could be associated with altered left ventricular and myocardial performance. Echocardiography and hemodynamic were employed to assess left ventricular morphology and function in Sprague Dawley transgenic rats overexpressing the endothelial bradykinin B1 receptor (Tie2B1 rats). The myocardial inotropism was evaluated on papillary muscles contracting in vitro. In Tie2B1 animals, an enlarged left ventricular cavity and lower fractional shortening coupled with a lower rate of pressure change values indicated depressed left ventricular performance. Papillary muscle mechanics revealed that both Tie2B1 and wild-type rat groups had the same contractile capacities under basal conditions; however, in transgenic animals, there was accentuated inotropism due to post-pause potentiation. Following treatment with the Arg(9)-BK agonist, Tie2B1 papillary muscles displayed a reduction in myocardial inotropism. Endothelial B1 receptor overexpression has expanded the LV cavity and worsened its function. There was an exacerbated response of papillary muscle in vitro to a prolonged resting pause, and the use of a B1 receptor agonist impairs myocardial inotropism.

Bioactivity of Ceftazidime and Fluconazole Included in Polymethyl Methacrylate Bone Cement for Use in Arthroplasty.

BACKGROUND: The microorganisms that most frequently cause prosthetic joint infection are methicillin-resistant Staphylococcus aureus and gram-negative aerobic bacillus. Studies have documented the efficacy of mixing antibiotics with polymethyl methacrylate, but that of antifungal drugs has not received much attention. The objective of this in vitro study was to characterize the elution profile and bioactivity of ceftazidime and fluconazole when incorporated into bone cement in proportions intended for prophylaxis and treatment of bone infections. METHODS: Antibiotic-loaded bone cement cylinders in a proportion of 1:40 and 4:40 (ratio of grams of antibiotic to grams of cement) were assayed. Drug delivery was investigated in a flow-through dissolution apparatus (SotaxCE7). To assess bioactivity, antibiotic concentrations were simulated in the joint space of 1000 patients. Antibacterial properties were evaluated by counting colony forming units and the inhibition-halo test. RESULTS: The ratio of released ceftazidime and fluconazole was 453% and 648%, respectively, higher when used for treatment proportions than prophylaxis proportions. A bioactivity simulation exercise showed that the efficacy of ceftazidime/fluconazole determined as the amount of drug is released at the active site in the first 3 days after surgery would depend on the sensitivity of the microorganism and would increase substantially after drain removal. The microbiology study showed that biofilm formation by Pseudomonas aeruginosa could be a problem when ceftazidime was used in treatment or prophylaxis proportions. CONCLUSION: Our in vitro findings suggest that ceftazidime and fluconazole can be added into polymethyl methacrylate for the prevention/treatment of infections associated to joint surgery. Their efficacy depends on the sensitivity of the microorganism causing the infection.

Activation of tumor suppressor LKB1 by honokiol abrogates cancer stem-like phenotype in breast cancer via inhibition of oncogenic Stat3.

Tumor suppressor and upstream master kinase Liver kinase B1 (LKB1) plays a significant role in suppressing cancer growth and metastatic progression. We show that low-LKB1 expression significantly correlates with poor survival outcome in breast cancer. In line with this observation, loss-of-LKB1 rendered breast cancer cells highly migratory and invasive, attaining cancer stem cell-like phenotype. Accordingly, LKB1-null breast cancer cells exhibited an increased ability to form mammospheres and elevated expression of pluripotency-factors (Oct4, Nanog and Sox2), properties also observed in spontaneous tumors in Lkb1-/- mice. Conversely, LKB1-overexpression in LKB1-null cells abrogated invasion, migration and mammosphere-formation. Honokiol (HNK), a bioactive molecule from Magnolia grandiflora increased LKB1 expression, inhibited individual cell-motility and abrogated the stem-like phenotype of breast cancer cells by reducing the formation of mammosphere, expression of pluripotency-factors and aldehyde dehydrogenase activity. LKB1, and its substrate, AMP-dependent protein kinase (AMPK) are important for HNK-mediated inhibition of pluripotency factors since LKB1-silencing and AMPK-inhibition abrogated, while LKB1-overexpression and AMPK-activation potentiated HNK's effects. Mechanistic studies showed that HNK inhibited Stat3-phosphorylation/activation in an LKB1-dependent manner, preventing its recruitment to canonical binding-sites in the promoters of Nanog, Oct4 and Sox2. Thus, inhibition of the coactivation-function of Stat3 resulted in suppression of expression of pluripotency factors. Further, we showed that HNK inhibited breast tumorigenesis in mice in an LKB1-dependent manner. Molecular analyses of HNK-treated xenografts corroborated our in vitro mechanistic findings. Collectively, these results present the first in vitro and in vivo evidence to support crosstalk between LKB1, Stat3 and pluripotency factors in breast cancer and effective anticancer modulation of this axis with HNK treatment.

Effectiveness and Safety of CT-P13 (Biosimilar Infliximab) in Patients with Inflammatory Bowel Disease in Real Life at 6 Months.

BACKGROUND: CT-P13 is a biosimilar of Remicade®, an agent approved in some countries for use in inflammatory bowel disease (IBD). Controlled clinical trials have demonstrated the efficacy and safety of CT-P13 in rheumatic diseases, but not in IBD. AIMS: To assess the effectiveness and safety of CT-P13 in IBD patients in real clinical practice. METHODS: This is a prospective observational study in patients with moderate to severe Crohn's disease or ulcerative colitis treated with CT-P13. The study was performed in one single center. Patients included were naive or switched to anti-TNF treatment from the reference infliximab (Remicade®) to CT-P13. Efficacy and safety were assessed in naive and switched patients who were in remission at the time of the switch at months 3 and 6 of therapy. RESULTS: 87.5 and 83.9% of switched CD patients who were in remission at the time of the switch continued in remission, and 66.7 and 50% of naive CD patients reached remission, at months 3 and 6. In UC switched cases, 92 and 91.3% of patients in remission at the time of the switch continued in remission, at 3 and 6 months. In naive UC patients, the remission rates were 44.4 and 66.7%, at months 3 and 6. Adverse events occurred in 7.5% of patients during 6 months of study. CONCLUSIONS: CT-P13 was efficacious and well tolerated in patients with CD or UC.

Transdermal therapeutic systems for memantine delivery. Comparison of passive and iontophoretic transport.

Memantine is a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist used in the treatment of moderate to severe dementia including the symptoms of Alzheimer's disease (AD). It is administered orally but compliance, swallowing problems and the routine use of multiple medications in elderly AD patients means that an alternative route of administration would be of interest. The aim of the present study was to develop memantine hydrochloride occlusive transdermal therapeutic systems (TTS) for passive and iontophoretic delivery across the skin. Polyvinyl pyrrolidone (PVP) and a mixture with polyvinyl alcohol (PVA) were employed as polymeric matrices. The study involved the TTS characterization in addition to quantification of the memantine transport across porcine skin in vitro. The evaluation of the TTS physical properties suggested that systems were made more mechanically resistant by including PVA (6%) or high concentrations of PVP (24%). Moreover, a linear correlation was observed between the concentration of PVP and the bioadhesion of the systems. Drug delivery experiments showed that the highest transdermal flux provided by a passive TTS (PVP 24% w/w limonene) was 8.89±0.81µgcm-2h-1 whereas the highest iontophoretic transport was 46.4±3.6µgcm-2h-1. These innovative TTS would enable two dosage regimens that could lead to therapeutic plasma concentrations.

HOXA5 determines cell fate transition and impedes tumor initiation and progression in breast cancer through regulation of E-cadherin and CD24.

Loss of HOXA5 expression occurs frequently in breast cancer and correlates with higher pathological grade and poorer disease outcome. However, how HOX proteins drive differentiation in mammalian cells is poorly understood. In this paper, we investigated cellular and molecular consequences of loss of HOXA5 in breast cancer, and the role played by retinoic acid in HOXA5 function. Analysis of global gene expression data from HOXA5-depleted MCF10A breast epithelial cells, followed by validation, pointed to a role for HOXA5 in maintaining several molecular traits typical of the epithelial lineage such as cell-cell adhesion, tight junctions and markers of differentiation. Depleting HOXA5 in immortalized MCF10A or transformed MCF10A-Kras cells reduced their CD24+/CD44lo population, enhanced self-renewal capacity and reduced expression of E-cadherin (CDH1) and CD24. In the case of MCF10A-Kras, HOXA5 loss increased branching and protrusive morphology in Matrigel, all features suggestive of epithelial to basal transition. Further, orthotopically implanted xenografts of MCF10A-Kras-scr grew as well-differentiated pseudo-luminal carcinomas, while MCF10A-Kras-shHOXA5 cells formed aggressive, poorly differentiated carcinomas. Conversely, ectopic expression of HOXA5 in aggressive SUM149 or SUM159 breast cancer cells reversed the cellular and molecular alterations observed in the HOXA5-depleted cells. Retinoic acid is a known upstream regulator of HOXA5 expression. HOXA5 depletion in MCF10A cells engineered to express doxycycline-induced shHOXA5 slowed transition of cells from a less differentiated CD24-/CD44+ to the more differentiated CD24+/CD44+ state. This transition was promoted by retinal treatment, which upregulated endogenous HOXA5 expression and caused re-expression of occludin and claudin-7 (CLDN7). Expression of CDH1 and CD24 was transcriptionally upregulated by direct binding of HOXA5 to their promoter sequences as demonstrated by luciferase and ChIP analyses. Thus, loss of HOXA5 in mammary cells leads to loss of epithelial traits, an increase in stemness and cell plasticity, and the acquisition of more aggressive phenotypes.

Detection of Broadly Neutralizing Activity within the First Months of HIV-1 Infection.

UNLABELLED: A fraction of HIV-1 patients are able to generate broadly neutralizing antibodies (bNAbs) after 2 to 4 years of infection. In rare occasions such antibodies are observed close to the first year of HIV-1 infection but never within the first 6 months. In this study, we analyzed the neutralization breadth of sera from 157 antiretroviral-naive individuals who were infected for less than 1 year. A range of neutralizing activities was observed with a previously described panel of six recombinant viruses from five different subtypes (M. Medina-Ramirez et al., J Virol 85:5804-5813, 2011, http://dx.doi.org/10.1128/JVI.02482-10). Some sera were broadly reactive, predominantly targeting envelope epitopes within the V2 glycan-dependent region. The neutralization breadth was positively associated with time postinfection (P = 0.0001), but contrary to what has been reported for chronic infections, no association with the viral load was observed. Notably, five individuals within the first 6 months of infection (two as early as 77 and 96 days postinfection) showed substantial cross-neutralization. This was confirmed with an extended panel of 20 Env pseudoviruses from four different subtypes (two in tier 3, 14 in tier 2, and four in tier 1). Sera from these individuals were capable of neutralizing viruses from four different subtypes with a geometric mean 50% infective dose (ID50) between 100 and 800. These results indicate that induction of cross-neutralizing responses, albeit rare, is achievable even within 6 months of HIV-1 infection. These observations encourage the search for immunogens able to elicit this kind of response in preventive HIV-1 vaccine approaches. IMPORTANCE: There are very few individuals able to mount broadly neutralizing activity (bNA) close to the first year postinfection. It is not known how early in the infection cross-neutralizing responses can be induced. In the present study, we show that bNAbs, despite being rare, can be induced much earlier than previously thought. The identification of HIV-1-infected patients with these activities within the first months of infection and characterization of these responses will help in defining new immunogen designs and neutralization targets for vaccine-mediated induction of bNAbs.

Definition of an 18-mer Synthetic Peptide Derived from the GB virus C E1 Protein as a New HIV-1 Entry Inhibitor.

BACKGROUND: A slower progression of AIDS and increased survival in GBV-C positive individuals, compared with GBV-C negative individuals has been demonstrated; while the loss of GBV-C viremia was closely associated with a rise in mortality and increased progression of AIDS. Following on from the previous reported studies that support the thesis that GBV-C E2 interferes with HIV-1 entry, in this work we try to determine the role of the GBV-C E1 protein in HIV-1 inhibition. METHODS: The present work involves the construction of several overlapping peptide libraries scanning the GBV-C E1 protein and the evaluation of their anti-HIV activity. RESULTS: Specifically, an 18-mer synthetic peptide from the GBV-C E1 protein, E1(139-156), showed similar antiviral activity against HIVs from viruses from clades A, B, C, D and AE. Competitive ELISA using specific gp41-targeting mAbs, fluorescence resonance energy transfer as well as haemolysis assays demonstrated that this E1 peptide sequence interacts with the highly conserved N-terminal region of the HIV-1 gp41 (the fusion peptide) which is essential for viral entry. CONCLUSIONS: We have defined a novel peptide lead compound and described the inhibitory role of a highly conserved fragment of the E1 protein. GENERAL SIGNIFICANCE: The results together allow us to consider the non-pathogenic E1 GBV-C protein as an attractive source of peptides for the development of novel anti-HIV therapies.

Development of antimigraine transdermal delivery systems of pizotifen malate.

The aim of this study was to develop and evaluate a transdermal delivery system of pizotifen malate. Pizotifen is frequently used in the preventive treatment of migraine, but is also indicated in eating disorders. In the course of the project, the effects of chemical enhancers such as ethanol, 1,8-cineole, limonene, azone and different fatty acids (decanoic, decenoic, dodecanoic, linoleic and oleic acids) were determined, first using a pizotifen solution. Steady state flux, diffusion and partition parameters were estimated by fitting the Scheuplein equation to the data obtained. Among the chemical enhancers studied, decenoic acid showed the highest enhancement activity, which seemed to be due to the length of its alkyl chain and unsaturation at the 9th carbon. The influence of iontophoresis and the involvement of electrotransport in said process was determined. The absorption profile obtained with iontophoresis was similar to that obtained with fatty acids and terpenes, though skin deposition of the drug was lower with the former. Transdermal delivery systems (TDS) of pizotifen were manufactured by including chemical enhancers, decenoic acid or oleic acid, and were subsequently characterized. When the results obtained with solutions were compared with those obtained with the TDS, a positive enhancement effect was observed with the latter with respect to the partitioning and diffusion of the drug across the skin. Our findings endorse the suitability of our TDS for delivering therapeutic amounts of pizotifen malate.

Impact of nutritional status on the pharmacokinetics of erlotinib in rats.

Malnourishment is a complex condition in which physiopathological changes take place in multiple systems as a result of energy, protein and nutrient deficiency. The purpose of this study was to evaluate, using an experimental animal model, the impact of nutritional status on the pharmacokinetic profile of erlotinib, a reversible, highly selective, human epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor. Two groups of rats -WN (well-nourished) and UN (undernourished) - were fed with different diets for 23-26 days. Rats were assigned randomly to one of three erlotinib treatments (n = 42) consisting of a single dose administered intravenously (i.v.), via oral solution or via oral suspension. Blood samples were assayed for erlotinib concentration. A population pharmacokinetic model was developed and pharmacokinetic parameters obtained in UN rats were compared with those in WN rats. Erlotinib clearance suffered a 5% decrease in the mild-undernutrition status. Moreover, when the drug was administered orally as a suspension, the extent and rate of absorption underwent a 20% increase in UN rats. The results of this study might help to explain, at least in part, the variability of erlotinib treatment and could represent the first step towards establishing new dosage guidelines for the treatment of undernourished cancer patients. Copyright © 2015 John Wiley & Sons, Ltd.

Diferencias de protección frente al riesgo biológico laboral en relación al sistema preventivo elegido por la empresa / Differences of occupational biohazard protection in relation to preventive system chosen by the company

El objetivo de este trabajo ha sido obtener información sobre el nivel de exposición y protección de los trabajadores a los agentes biológicos laborales en diferentes sectores de actividad valorando sus diferencias en relación al sistema preventivo elegido por las empresas. Se realizó un estudio en el que participaron 590 trabajadores de 59 empresas españolas en las que se pasaron 2 cuestionarios, uno para la empresa y otro para los trabajadores, obteniéndose una muestra definitiva de 518 trabajadores pertenecientes a 51 empresas en las que existía exposición a agentes biológicos. Se encontraron diferencias significativas en la gestión del riesgo biológico laboral en función del sistema preventivo elegido por la empresa concluyendo que la protección a la exposición laboral a agentes biológicos no está desarrollada por completo porque no se dispone de herramientas que permitan su fácil realización y por lo tanto la gestión de los riesgos biológicos general no es adecuada (AU)

The aim of this study was to obtain information on the level of exposure and protection of workers to biological agents at work in relation to the preventive system choosen for the companies. An study in which 590 workers from 59 Spanish companies in which 2 questionnaires were given, one for the company and other for the workers, yielding a final sample of 518 workers from 51 companies in which there is exposure to biological agents. Our results provide significant differences in the management of occupational exposure to biological agents depending on the preventive system chosen by the company concluding that the protection is not fully developed because there are not enough tools available that allow easy implementation and the overall management of biological risks is inadequate (AU)

Transdermal absorption of memantin--effect of chemical enhancers, iontophoresis, and role of enhancer lipophilicity.

The transdermal administration of memantine may have advantages with respect to oral therapy when treating advanced stages of Alzheimer's disease. With the ultimate objective of administrating memantine through a transdermal patch, the absorption of the drug across skin was evaluated by means of in vitro permeation studies. The effect of several chemical enhancers was studied in order to enhance percutaneous absorption of the memantine. The iontophoretic transdermal transport of memantine hydrochloride using a current density of 0.5 mA/cm(2) was also investigated. Results demonstrated that pre-treatment of the skin with R-(+)-limonene, laurocapram, decenoic acid, or oleic acid produced a statistically significant increment in the transdermal flux of memantine hydrochloride with respect to the control. Iontophoresis exhibited the greatest ability to enhance the flux of drug with respect to the control; nevertheless, the results obtained with R-(+)-limonene indicate that this compound could be of great use as a percutaneous enhancer in a memantine transdermal delivery system. In this study, the relationship between enhancement activity and lipophilicity was also studied. Satisfactory correlations have been obtained between the optimum lipophilicity of the enhancer and n-octanol/water partition coefficients of drugs. This relationship is a very useful tool that could allow to reduce time and to optimize the selection of appropriate enhancers for transdermal formulations.

Design, characterization and in vitro evaluation of 5-aminosalicylic acid loaded N-succinyl-chitosan microparticles for colon specific delivery.

The objective of this study was to prepare NS-chitosan microparticles for the delivery of 5-aminosalicylic acid (5-ASA) to the colon. Microparticles can spread out over a large area of colon allowing a more effective local efficacy of 5-ASA. N-Succinyl-chitosan was chosen as carrier system because of its excellent pharmaceutical properties in colon drug targeting such as poor solubility in acid environment, biocompatibility, mucoadhesive properties, and low toxicity. It was prepared by introducing succinic group into chitosan N-terminals of the glucosamine units. 5-ASA loaded NS-chitosan microparticles were prepared using spray-drying. As a control, a matrix obtained by freeze-drying technique was also prepared and tested. Fourier transform infrared (FT-IR), differential scanning calorimetry (DSC) and X-ray diffraction studies show the 5-ASA/NS-chitosan electrostatic interactions in both the systems. Mean size of the microparticles was around 5 µm, zeta potential value of both systems was always negative. Scanning electron microscopy (SEM) images show an acceptable spherical non porous structure of microparticles. In vitro swelling and drug release studies were in accordance with the polymer properties, showing the highest swelling ratio and drug release at pH=7.4 (colonic pH) where microparticles were able to deliver more than 90% of 5-ASA during 24h experiments. Rheological studies are in accordance with the swelling and release studies.

HPLC-UV analytical method for determination of pizotifen after in vitro transdermal diffusion studies.

Pizotifen malate is an antihistamine and serotonin inhibitor used in the preventive treatment of migraine and eating disorders. A simple, rapid, accurate and precise high-performance liquid chromatography (HPLC) method involving ultraviolet detection was validated for the quantitative analysis of pizotifen malate in samples from in vitro transdermal diffusion studies. The method was validated for specificity, linearity, accuracy, precision, limit of detection, limit of quantification and robustness. Drug stability in the solution was also determined under different conditions. Separation was carried out using a 250 × 4.0 mm Kromasil(®) C(18) column at room temperature. The detector response, fitted at 254 nm, was found to be linear in a concentration range between 0.24 and 24.0 µg/mL. The limit of detection was 0.02 µg/mL and the limit of quantification was 0.07 µg/mL. Finally, in vitro transdermal diffusion of pizotifen malate was characterized using the validated HPLC method.

N-Succinyl-chitosan systems for 5-aminosalicylic acid colon delivery: in vivo study with TNBS-induced colitis model in rats.

5-Aminosalicylic acid (5-ASA) loaded N-Succinyl-chitosan (SucCH) microparticle and freeze-dried system were prepared as potential delivery systems to the colon. Physicochemical characterization and in vitro release and swelling studies were previously assessed and showed that the two formulations appeared to be good candidates to deliver the drug to the colon. In this work the effectiveness of these two systems in the treatment of inflammatory bowel disease was evaluated. In vitro mucoadhesive studies showed excellent mucoadhesive properties of both the systems to the inflamed colonic mucosa. Experimental colitis was induced by rectal instillation of 2,4,6-trinitrobenzene sulfonic acid (TNBS) into male Wistar rats. Colon/body weight ratio, clinical activity score system, myeloperoxidase activity and histological evaluation were determined as inflammatory indices. The two formulations were compared with drug suspension and SucCH suspension. The results showed that the loading of 5-ASA into SucCH polymer markedly improved efficacy in the healing of induced colitis in rats.

Effect of iontophoresis on in vitro transdermal absorption of almotriptan.

The aim of the present work was to characterize the in vitro transdermal absorption of almotriptan through pig ear skin. The passive diffusion of almotriptan malate and its iontophoretic transport were investigated using current densities of 0.25 and 0.50mA/cm(2). In vitro iontophoresis experiments were conducted on diffusion cells with an agar bridge without background electrolytes in the donor compartment. Although both current densities applied produced a statistically significant increment with respect to passive permeation of almotriptan (p<0.01), that of 0.50mA/cm(2) proved to be the best experimental condition for increasing the transport of almotriptan across the skin. Under these experimental conditions, the transdermal flux of the drug increased 411-fold with respect to passive diffusion, reaching 264±24µg/cm(2)h (mean±SD). Based on these results, and taking into account the pharmacokinetics of almotriptan, therapeutic drug plasma levels for the management of migraine could be achieved via transdermal iontophoresis using a reasonably sized (around 7.2cm(2)) patch.