Treatment of hemangiomas in children using a Nd:YAG laser in conjunction with ice cooling of the epidermis: techniques and results

BACKGROUND: Hemangiomas are the most common type of congenital anomaly in childhood. Although many resolve spontaneously, intervention is required when their growth could damage vital adjacent structures. Various therapeutic approaches to childhood hemangiomas with different types of laser have been described previously. The objective of this study was to determine whether the cooling of the epidermis during irradiation of hemangiomas with a Nd:YAG laser prevents thermal damage and decreases the number of sessions required to treat these lesions. METHODS: Between 1993 and 2001, 110 patients aged 3 months to 4 years, with cutaneous hemangiomas were treated with a Nd:YAG laser. The lesion was cooled with ice prior to, during, and after the irradiation. During each session the laser beam passed through the pieces of ice. The laser power was between 35–45 W with a pulse length of 2–10 seconds. RESULTS: After 6 months of follow-up, from the first session of laser treatment, total resolution was obtained in 72 (65.5%) patients. A second or third session followed in 30 out of 38 patients in which, the initial results were good, moderate, or poor. The parents of the remaining eight children refused this second session and these patients excluded from the study Complications were seen in nine (8.8%) patients. One patient had postoperative bleeding which stopped spontaneously, while atrophic scars occurred in six (5.8%) patients, and hypertrophic scars in two (1.9%) patients. CONCLUSIONS: Nd:YAG laser irradiation in conjunction with ice protection of the epidermis produces good cosmetic results for the treatment of cutaneous hemangiomas in children, and decreases the number of sessions for treatment of these lesions

Prediction of High-Grade Vesicoureteral Reflux after Pediatric Urinary Tract Infection: External Validation Study of Procalcitonin-Based Decision Rule

BACKGROUND: Predicting vesico-ureteral reflux (VUR) 653 at the time of the first urinary tract infection (UTI) would make it possible to restrict cystography to high-risk children. We previously derived the following clinical decision rule for that purpose: cystography should be performed in cases with ureteral dilation and a serum procalcitonin level 650.17 ng/mL, or without ureteral dilatation when the serum procalcitonin level 650.63 ng/mL. The rule yielded a 86% sensitivity with a 46% specificity. We aimed to test its reproducibility. STUDY DESIGN: A secondary analysis of prospective series of children with a first UTI. The rule was applied, and predictive ability was calculated. RESULTS: The study included 413 patients (157 boys, VUR 653 in 11%) from eight centers in five countries. The rule offered a 46% specificity (95% CI, 41-52), not different from the one in the derivation study. However, the sensitivity significantly decreased to 64% (95%CI, 50-76), leading to a difference of 20% (95%CI, 17-36). In all, 16 (34%) patients among the 47 with VUR 653 were misdiagnosed by the rule. This lack of reproducibility might result primarily from a difference between derivation and validation populations regarding inflammatory parameters (CRP, PCT); the validation set samples may have been collected earlier than for the derivation one. CONCLUSIONS: The rule built to predict VUR 653 had a stable specificity (ie. 46%), but a decreased sensitivity (ie. 64%) because of the time variability of PCT measurement. Some refinement may be warranted

Endocytic uptake, transport and macromolecular interactions of anionic PAMAM dendrimers within lung tissue

Purpose: Polyamidoamine (PAMAM) dendrimers are a promising class of nanocarrier with applications in both small and large molecule drug delivery. Here we report a comprehensive evaluation of the uptake and transport pathways that contribute to the lung disposition of dendrimers. Methods: Anionic PAMAM dendrimers and control dextran probes were applied to an isolated perfused rat lung (IPRL) model and lung epithelial monolayers. Endocytosis pathways were examined in primary alveolar epithelial cultures by confocal microscopy. Molecular interactions of dendrimers with protein and lipid lung fluid components were studied using small angle neutron scattering (SANS). Results: Dendrimers were absorbed across the intact lung via a passive, size-dependent transport pathway at rates slower than dextrans of similar molecular sizes. SANS investigations of concentration-dependent PAMAM transport in the IPRL confirmed no aggregation of PAMAMs with either albumin or dipalmitoylphosphatidylcholine lung lining fluid components. Distinct endocytic compartments were identified within primary alveolar epithelial cells and their functionality in the rapid uptake of fluorescent dendrimers and model macromolecular probes was confirmed by co-localisation studies. Conclusions: PAMAM dendrimers display favourable lung biocompatibility but modest lung to blood absorption kinetics. These data support the investigation of dendrimer-based carriers for controlled-release drug delivery to the deep lung

Effect of a bioactive curcumin derivative on DPPC membrane: A DSC and Raman spectroscopy study

Interactions of dimethoxycurcumin (1) a lipophilic bioactive curcumin derivative with dipalmitoyl phosphatidylcholine (DPPC) were investigated. The thermodynamic changes caused by (1) and its location into DPPC lipid bilayers were monitored by differential scanning calorimetry and Raman spectroscopy. The results reveal that (1) influences the thermotropic properties of DPPC lipid membrane causing abolition of the pretransition and broadening of the phase-transition profile and slightly decreases the Tm at increasing concentrations. The Raman height intensity ratios of the peaks I2935/2880, I2844/2880 and I1090/1130 are representative of the interaction of (1) with the alkyl chains and furnish information about the ratio between disorder and order that exists in the conformation of the alkyl chain. The intensity changes of the peak at 715 cm-1 indicates interaction between the choline head group and (1). The Raman spectroscopy results are in agreement with the thermal analysis results. Biologically active lipophilic molecules such as (1) should be studied in terms of their interaction with lipid bilayers prior to the development of advanced lipid carrier systems such as liposomes. The results of these studies provide information on the membrane integrity and physicochemical properties that are essential for the rational design lipidic drug delivery systems. © 2006 Elsevier B.V. All rights reserved

The physicochemical/thermodynamic balance of advanced drug liposomal delivery systems

The aim of this work is to study the morphological characteristics via fractal analysis and the alterations of the thermotropic behavior of dipalmitoylphosphatidylcholine (DPPC) liposomes, caused by the incorporation of cholesterol, poly(amidoamine) (PAMAM) dendrimer, and MPOx (poly(2-methyl-2- oxazoline)-grad-poly(2-phenyl-2-oxazoline)) gradient block copolymer (9:1 molar ratio). A gamut of light scattering techniques and differential scanning calorimetry were used in order to extract information on the morphological (in different dispersion media) and thermodynamic characteristics of liposomal drug nanocarriers, respectively. The vesicles' structure of liposomes has a different thermodynamic content, which corresponds to a different thermotropic behavior, in comparison to pure lipid bilayers. The observed metastable phase only for DPPC liposomes has been considered as a "physical impurity", which leads to "physical incompatibility" and consequently promotes the aggregation of DPPC liposomes in aqueous media. The incorporation of biomaterials such as PAMAM G4 and MPOx, caused alterations in the thermotropic behavior of DPPC liposomes affecting only the main transition specific enthalpy ΔH. All the other calorimetric parameters remained unaltered. These findings supported the hypothesis that the exceptional stability and transition cooperativity of the chimeric liposomal membrane might be due to the reduction of the vesicle size with the smaller membrane curvature that is indicated by the fractal dimensionality of the system. In conclusion, the results from the thermal analysis of the liposomal systems were in line with the picture of their structural characteristics, as indicated by the interplay between physicochemical and thermodynamical parameters, which determines their fractal morphology. © 2013 Akadémiai Kiadó, Budapest, Hungary

A DSC and Raman spectroscopy study on the effect of PAMAM dendrimer on DPPC model lipid membranes

The interaction between PAMAM (polyamidoamine) dendrimer generation 4 (G4) and 3,5 (G3,5) with model lipid membranes composed of dipalmytoylphosphatidylcholine (DPPC) has been investigated. Differential scanning calorimetry (DSC) and Raman spectroscopy were applied to assess the thermodynamic changes caused by PAMAM G4 and G3,5 and to specify the exact location of these dendrimers into the DPPC lipid bilayer. DSC thermograms indicated that the maximum percentages of PAMAM G4 and of G3,5 that can be incorporated in the DPPC membrane without deranging its integrity were 5% and 3%, respectively. The Raman intensity ratios I2935/2880, I2844/2880 and I1090/1130 cm-1 showed the degree of the fluidity of the lipid bilayer, while the absorption at 715 cm-1 showed a strong interaction of PAMAM G4 and G3,5 with the polar head group of phospholipid. The results showed that the incorporation of the PAMAM G4 and G3,5 dendrimers in DPPC bilayers causes a concentration dependent increase of the membrane fluidity and that the bilayers interact strongly with both the lipophilic part and the polar head group of the phospholipids. Due to the current weak knowledge relating to the mechanism(s) under which dendrimers interact with lipidic membranes and transport through cells, these results may justify the tendency of dendrimers to disrupt biological membranes. The findings from this study could also prove helpful to rationally design new liposomal drug carriers for bioactive molecules by combining dendrimeric and liposomal technologies. © 2006 Elsevier B.V. All rights reserved

Dendrimers and the development of new complex nanomaterials for biomedical applications

New nano-scale drug carriers offer the possibility of increasing the therapeutic index of drug molecules by increasing their effectiveness, diminishing their toxicity against physiological tissues and achieving controlled therapeutic levels for a prolonged time. This review gives an overview of approaches to the development of these novel complex nanocarriers with emphasis on those involving dendrimers and related systems. The combination of two of more nano-sized units for producing an overall system with unique properties could be advantageous compared to more simple nanotechnology-based carriers. Recent advances in medicinal chemistry offer the possibility of exact tailoring of the properties of such complex systems which, in conjunction with full physicochemical characterization, may lead to novel and highly effective drug products. An assessment is given of the potential of systems such as chimeric advanced Drug Delivery nano Systems (chi-aDDnSs) for the delivery of drugs compared with conventional carriers. Rational synthesis of molecules that can act as modulators of the properties of chi-aDDnSs and may be the future in the design and development of nanocarriers, not only for the delivery of drug molecules but also for genetic material and imaging agents is sought. © 2012 Bentham Science Publishers

New chimeric advanced Drug Delivery nano Systems (chi-aDDnSs) as doxorubicin carriers

Since the late 1960s, the field of drug delivery has focused on the creation of new formulations with improved properties, taking much attention to drug release from the carrier. Liposomes and dendrimers represent two of the most studied drug carriers. A Modulatory Liposomal Controlled Release System (MLCRS) combining liposomal and dendrimeric technology has been recently published as well as Liposomal locked-in Dendrimers (LLDs) technology which was considered to be a class of MLCRSs. Chimeric advanced Drug Delivery nano Systems (chi-aDDnSs) can be defined as mixed nanosystems due to the combination of the bionanomaterials used and can offer advantages as drug carriers. This work deals with the production of two new chi-aDDnSs incorporating the newly synthesized dendrimer PG1. One of the two formulations bears the exact lipidic composition as the commercial liposomal drug " Myocet" Doxorubicin (Dox) was incorporated into conventional (free of dendrimer) liposomal formulations and into the corresponding chi-aDDnSs, and the physicochemical characteristics, the in vitro drug release and the in vitro cytotoxicity against human cancer cell lines were assessed. The results revealed a different modulation release effect of doxorubicin from the chi-aDDnS, compared to the Myocet replica. Pharmacological cytotoxicity concerning all the chi-aDDnSs was very close to that of the conventional liposomal systems. © 2010

β-lactam functionalized poly(isoprene-b-ethylene oxide) amphiphilic block copolymer micelles as a new nanocarrier system for curcumin

Curcumin is a natural compound with biological activities and potent anticancer effects that has the drawback of poor water solubility which leads to low bioavailability. In this work curcumin was formulated in new physicochemically characterized micellar carriers composed of new synthetic block copolymers. The study of the in vitro release rate of curcumin from the formulas, as well as the in vitro activity of free curcumin and of curcumin-loaded into micelles, against a panel of colorectal cancer cell lines was also part of this study. New β -lactam functionalized poly(isoprene-b-ethylene oxide) amphiphilic block copolymers, were synthesized by the combination of anionic polymerization and selective postpolymerization functionalization of the polyisoprene block with chlorosulfonylisocyanate. Micelles composed of the synthetic copolymers were formulated in order to incorporate curcumin. As the results revealed, increase in the percentage of the lipophilic block of micelles, led to higher encapsulation efficiency and loading capacity while the size was found to be smaller and the in vitro release rate slower. In vitro cytotoxicity results showed similar or slightly higher activity for curcuminloaded into micelles than free curcumin, a fact that could be attributed to the similar in vitro cellular uptake profiles of curcumin and of curcumin-loaded into micelles. © 2010 Bentham Science Publishers Ltd