Local Delivery (local + delivery)

Distribution by Scientific Domains

Selected Abstracts

National Service Framework for Children, Young People and Maternity Services: Supporting Local Delivery

Joav Merrick MD

A Novel Technique for Loading of Paclitaxel-PLGA Nanoparticles onto ePTFE Vascular Grafts

Hyun Jung Lim
The major cause of hemodialysis vascular access dysfunction (HVAD) is the occurrence of stenosis followed by thrombosis at venous anastomosis sites due to the aggressive development of venous neointimal hyperplasia. Local delivery of antiproliferative drugs may be effective in inhibiting hyperplasia without causing systemic side effects. We have previously demonstrated that paclitaxel-coated expanded poly(tetrafluoroethylene) (ePTFE) grafts, by a dipping method, could prevent neointimal hyperplasia and stenosis of arteriovenous (AV) hemodialysis grafts, especially at the graft-venous anastomoses; however, large quntities of initial burst release have remained a problem. To achieve controlled drug release, paclitaxel (Ptx)-loaded poly(lactic- co -glycolic acid) (PLGA) nanoparticles (Ptx-PLGA-NPs) were prepared by the emulsion-solvent evaporation method and then transferred to the luminal surface and inner part of ePTFE vascular grafts through our micro tube pumping and spin penetration techniques. Scanning electron microscope (SEM) images of various stages of Ptx-PLGA-NPs unequivocally showed that micro tube pumping followed by spin penetration effectively transferred Ptx-PLGA-NPs to the inner part, as well as the luminal surface, of an ePTFE graft. In addition, the in vitro release profiles of paclitaxel demonstrated that this new system achieved controlled drug delivery with a reduced initial burst release. These results suggest that loading of Ptx-PLGA-NPs to the luminal surface and the inner part of an ePTFE graft is a promising strategy to ultimately inhibit the development of venous neointimal hyperplasia. [source]

MR imaging in assessing cardiovascular interventions and myocardial injury

Alexis Jacquier
Abstract Performing an MR-guided endovascular intervention requires (1) real-time tracking and guidance of catheters/guide wires to the target, (2) high-resolution images of the target and its surroundings in order to define the extent of the target, (3) performing a therapeutic procedure (delivery of stent or injection of gene or cells) and (4) evaluating the outcome of the therapeutic procedure. The combination of X-ray and MR imaging (XMR) in a single suite was designed for new interventional procedures. MR contrast media can be used to delineate myocardial infarcts and microvascular obstruction, thereby defining the target for local delivery of therapeutic agents under MR-guidance. Iron particles, or gadolinium- or dysprosium-chelates are mixed with the soluble injectates or stem cells in order to track intramyocardial delivery and distribution. Preliminary results show that genes encoded for vascular endothelial and fibroblast growth factor and cells are effective in promoting angiogenesis, arteriogenesis, perfusion and LV function. Angiogenic growth factors, genes and cells administered under MR-guided minimally invasive catheter-based procedures will open up new avenues in treating end-stage ischemic heart disease. The optimum dose of the therapeutic agents, delivery devices and real-time imaging techniques to guide the delivery are currently the subject of ongoing research. The aim of this review is to (1) provide an updated review of experiences using MR imaging to guide transcatheter therapy, (2) address the potential of cardiovascular magnetic resonance (MR) imaging and MR contrast media in assessing myocardial injury at a molecular level and labeling cells and (3) illustrate the applicability of the non-invasive MR imaging in the field of angiogenic therapies through recent clinical and experimental publications. Copyright © 2007 John Wiley & Sons, Ltd. [source]

Continuous local intrahippocampal delivery of adenosine reduces seizure frequency in rats with spontaneous seizures

EPILEPSIA, Issue 9 2010
Annelies Van Dycke
Summary Purpose:, Despite different treatment options for patients with refractory epilepsy such as epilepsy surgery and neurostimulation, many patients still have seizures and/or drug-related cerebral and systemic side effects. Local intracerebral delivery of antiepileptic compounds may represent a novel strategy with specific advantages such as the option of higher local doses and reduced side effects. In this study we evaluate the antiepileptic effect of local delivery of adenosine in the kainic acid rat model, a validated model for temporal lobe epilepsy. Methods:, Fifteen rats, in which intraperitoneal kainic acid injection had induced spontaneous seizures, were implanted with a combination of depth electrodes and a cannula in both hippocampi. Cannulas were connected to osmotic minipumps to allow continuous hippocampal delivery. Rats were freely moving and permanently monitored by video-EEG (electroencephalography). Seizures were scored during 2 weeks of local hippocampal delivery of saline (baseline), followed by 2 weeks of local adenosine (6 mg/ml) (n = 10) or saline (n = 5) delivery (0.23 ,l/h) (treatment). In 7 of 10 adenosine-treated rats, saline was also delivered during a washout period. Results:, During the treatment period a mean daily seizure frequency reduction of 33% compared to the baseline rate was found in adenosine-treated rats (p < 0.01). Four rats had a seizure frequency reduction of at least 50%. Both nonconvulsive and convulsive seizures significantly decreased during the treatment period. In the saline-control group, mean daily seizure frequency increased with 35% during the treatment period. Conclusions:, This study demonstrates the antiseizure effect of continuous adenosine delivery in the hippocampi in rats with spontaneous seizures. [source]

Seizure Suppression by Adenosine A1 Receptor Activation in a Mouse Model of Pharmacoresistant Epilepsy

EPILEPSIA, Issue 7 2003
Nicolette Gouder
Summary: Purpose: Because of the high incidence of pharmacoresistance in the treatment of epilepsy (20,30%), alternative treatment strategies are needed. Recently a proof-of-principle for a new therapeutic approach was established by the intraventricular delivery of adenosine released from implants of engineered cells. Adenosine-releasing implants were found to be effective in seizure suppression in a rat model of temporal lobe epilepsy. In the present study, activation of the adenosine system was applied as a possible treatment for pharmacoresistant epilepsy. Methods: A mouse model for drug-resistant mesial temporal lobe epilepsy was used, in which recurrent spontaneous seizure activity was induced by a single intrahippocampal injection of kainic acid (KA; 200 ng in 50 nl). Results: After injection of the selective adenosine A1 -receptor agonist, 2-chloro- N6 -cyclopentyladenosine (CCPA; either 1.5 or 3 mg/kg, i.p.), epileptic discharges determined in EEG recordings were completely suppressed for a period of ,3.5 h after the injections. Seizure suppression was maintained when 8-sulfophenyltheophylline (8-SPT), a non,brain-permeable adenosine-receptor antagonist, was coinjected systemically with CCPA. In contrast, systemic injection of carbamazepine or vehicle alone did not alter the seizure pattern. Conclusions: This study demonstrates that activation of central adenosine A1 receptors leads to the suppression of seizure activity in a mouse model of drug-resistant epilepsy. We conclude that the local delivery of adenosine into the brain is likely to be effective in the control of intractable seizures. [source]

Seizure Suppression by Adenosine-releasing Cells Is Independent of Seizure Frequency

EPILEPSIA, Issue 8 2002
Detlev Boison
Summary: ,Purpose: Intraventricular cellular delivery of adenosine was recently shown to be transiently efficient in the suppression of seizure activity in the rat kindling model of epilepsy. We tested whether the suppression of seizures by adenosine-releasing grafts was independent of seizure frequency. Methods: Adenosine-releasing cells were encapsulated and grafted into the lateral brain ventricle of rats kindled in the hippocampus. During 4 weeks after grafting, electric test stimulations were delivered at a frequency of either once a week or 3 times per week. Seizure activity was evaluated by visual scoring of seizure severity and by the recording of EEGs. Results: Adenosine released from encapsulated cells exerted potent antiepileptic activity for ,2 weeks. One week after grafting, treated rats displayed a complete protection from clonic seizures, and a protection from focal seizures was observed in the majority of animals. Seizure suppression was accompanied by a reduction of afterdischarges in EEG recordings. The protective efficacy of the grafted cells was the same irrespective of whether electrical test stimulations were delivered 1 or 3 times per week. Rats receiving control grafts continued to display full clonic convulsions. Conclusions: This study demonstrated that the frequency of test stimulations did not influence the seizure-suppressive potential of adenosine-releasing grafts. Thus the local delivery of adenosine is likely to be effective in seizure control over a threefold range of seizure-discharge frequency. [source]

The effects of subgingival calculus on the clinical outcomes of locally-delivered controlled-release doxycycline compared to scaling and root planing

Lonnie R. Johnson
Abstract Background, aim: The effect of subgingival calculus on the clinical outcomes of the local delivery of antimicrobials is unknown. This study examines the clinical outcomes of treatment with locally delivered controlled-release doxycycline (DH) or scaling and root planing (SRP) in subsets of adult periodontitis patients with known baseline levels of subgingival calculus. Methods: The data examined were obtained from 393 patients who participated in 2 multi-center trials. All patients had baseline subgingival calculus levels assessed and were then treated at baseline and month 4 with either DH or SRP. Clinical attachment levels (CAL), pocket depth (PD) and bleeding on probing (BOP) were assessed at baseline and months 1, 2, 4, 5, 6, 8 and 9. Results: Treatment with either DH or SRP resulted in significant statistical and clinical improvements in CAL, PD and BOP. These clinical outcomes were equivalent regardless of the extent of subgingival calculus present at baseline. Conclusions: The results indicate that the primary clinical effects of these therapies are the result of a disruption and reduction of the subgingival plaque and not the effect of the removal of subgingival calculus and contaminated cementum. Zusammenfassung Hintergrund, Ziel: Der Effekt von subginvalem Zahnstein auf die klinischen Ergebnisse von lokal freigesetzten antimikrobiellen Mitteln ist unbekannt. Die Studie überprüfte die klinische Ergebnisse der Behandlung mit kontrolliert lokal freigesetztem Doxycyclin (DH) oder mit Wurzelreinigung und -glättung (SRP) bei einer Gruppe von Patienten mit Erwachsenen-Parodontitis mit bekanntem Ausmaß von subgingivalen Zahnstein zu Beginn der Studie. Methoden: Die zu überprüfenden Daten kamen von 393 Patienten, die an 2 multizentrischen Studien teilnahmen. Alle Patienten hatten zur Basis gemessene subgingivale Zahnsteinlevel, und sie wurden dann zur Basis und zum 4. Monat entweder mit DH oder SRP behandelt. Die klinischen Stützgewebeniveaus (CAL), die Sondierungstiefe (PD) und die Provokationsblutung (BOP) wurden zur Basis und zu den Monaten 1, 2, 4, 5, 6, 8 und 9 aufgezeichnet. Ergebnisse: Die Behandlung entweder mit DH oder SRP ergab statistisch signifikante und klinische Verbesserungen beim CAL, bei der PD und bei der BOP. Diese klinischen Ergebnisse waren unabhängig vom Ausmaß des subgingivalen Zahnsteins, der zur Basis vorhanden war, gleich. Schlussfolgerung: Die Ergebnisse zeigen, dass die primären klinischen Effekte von diesen Therapieformen das Resultat der Zerstörung und Reduktion der subgingivalen Plaque sind und nicht den Effekt von der Entfernung des subgingivalen Zahnsteins und kontaminierten Zementes darstellen. Résumé Origine, but: Les effets du tartre sous-gingival sur les comportements cliniques de l'application locale d'antimicrobiens sont inconnus. Cette étude examine le comportement clinique de traitement consistant en l'application locale de doxycycline à libération lente (DH) ou en un détartrage/surfaçage radiculaire seul (SRP) dans des groupes de patients atteints de parodontite de l'adulte avec des niveaux initiaux de tartre sous-gingival connus. Méthodes: Les données examinées sont obtenus chez 393 patients qui participèrent à 2 essais multi-centriques. Chez tous les patients, les niveaux de tartre sousgingivaux initiaux furent évalués et ils furent traités à 0 et à 4 mois avec soit DH, soit SRP. Les niveaux d'attache clinique (CAL), les profondeurs de poche (PD) et le saignement au sondage (BOP) furent évalués initialement et à 1, 2, 4, 5, 6, 8 et 9 mois. Résultats: Le traitement avec les 2 méthodes apportait des améliorations statistiquement significatives pour CAL, PD et BOP. Ces comportements cliniques étaient équivalents quel que fut l'importance du tartre sous-gingival initialement. Conclusions: Les résultats indiquent que les effets cliniques primaires de ces traitements sont le résultat de la réduction et de la désorganisation de la plaque sous-gingivale et non pas l'effet de l'élimination du tartre sous-gingival et du cément contaminé. [source]

"Spontaneous," delayed colon and rectal anastomotic complications associated with bevacizumab therapy

David A. August MD
Abstract Bevacizumab, a humanized monoclonal antibody used to treat recurrent and metastatic colorectal cancer, targets the vascular endothelial growth factor (VEGF) molecule. It is hypothesized that bevacizumab works by both depriving tumors of the neovascularity they require to grow, and by improving local delivery of chemotherapy through alterations of tumor vasculature permeability and Starling forces. Complications of bevacizumab treatment include bowel ischemia and perforation, but to date, these complications have only rarely been described as occurring at the site of presumably healed anastomoses following surgery. We report two cases of delayed, "spontaneous" low anterior colorectal anastomotic dehiscence and one right colon anastomotic colocutaneous fistula associated with bevacizumab therapy. After seeing three patients with complications arising from apparently healed low anterior colorectal or right colon anastomoses following initiation of bevacizumab therapy for treatment of metastatic colorectal cancer, we reviewed the experience of The Cancer Institute of New Jersey (CINJ) with use of bevacizumab in approximately 50 patients between April 2004 and December 2006. The three index cases had been treated surgically at CINJ but received chemotherapy elsewhere. None of the 50 patients receiving bevacizumab at CINJ who had previous colon or rectal anastomoses were identified as having this complication. The medical records of the three index cases were reviewed and analyzed. Additionally, a Medline search was performed to identify other reports documenting similar cases. Two reports of related cases were found in the literature. In two of our index cases who underwent low anterior anastomoses, the patients had received preoperative pelvic irradiation before their initial low anterior resection. In one of the two cases, the initial resection was complicated by an anastomotic leak requiring proximal diversion and then subsequent stoma takedown. In both cases, the dehiscence occurred more than 1 year after anastomosis, and became evident 1,10 months following initiation of bevacizumab treatment. In the third index case, a colocutaneous fistula arising from the anastomotic site presented 5 months following right colon resection and 3 months after starting adjuvant systemic therapy with FOLFOX (5-fluorouracil (5-FU), leucovorin, and oxaliplatin) and bevacizumab. Delayed colorectal anastomotic complications may occur in association with bevacizumab therapy. Contributing factors may include anastomotic leak at the time of the original operation and history of anastomotic irradiation. Clinicians treating patients who receive bevacizumab following colectomy for colorectal cancer should be aware of this possible life-threatening complication. These findings may also be relevant to the design of trials of the use of bevacizumab for the postoperative adjuvant treatment of patients with colorectal cancer. J. Surg. Oncol. 2008;97:180,185. © 2007 Wiley-Liss, Inc. [source]

Spatiotemporal control of vascular endothelial growth factor delivery from injectable hydrogels enhances angiogenesis

Summary. Therapeutic angiogenesis with vascular endothelial growth factor (VEGF) delivery may provide a new approach for the treatment of ischemic diseases, but current strategies to deliver VEGF rely on either bolus delivery or systemic administration, resulting in limited clinical utility, because of the short half-life of VEGF in vivo and its resultant low and transient levels at sites of ischemia. We hypothesize that an injectable hydrogel system can be utilized to provide temporal control and appropriate spatial biodistribution of VEGF in ischemic hindlimbs. A sustained local delivery of relatively low amounts of bioactive VEGF (3 ,g) with this system led to physiologic levels of bioactive VEGF in ischemic murine (ApoE,/,) hindlimbs for 15 days after injection of the gel, as contrasted with complete VEGF deprivation after 72 h with bolus injection. The gel delivery system resulted in significantly greater angiogenesis in these limbs as compared to bolus (266 vs. 161 blood vessels mm,2). Laser Doppler perfusion imaging showed return of tissue perfusion to normal levels by day 28 with the gel system, whereas normal levels of perfusion were never achieved with saline delivery of VEGF or in control mice. The system described in this article could represent an attractive new generation of therapeutic delivery vehicle for treatment of cardiovascular diseases, as it combines long-term in vivo therapeutic benefit (localized bioactive VEGF for 1,2 weeks) with minimally invasive delivery. [source]

Gelatin microspheres crosslinked with genipin for local delivery of growth factors

Luis Solorio
Abstract A main challenge in tissue engineering and regenerative medicine is achieving local and efficient growth factor release to guide cell function. Gelatin is a denatured form of collagen that cells can bind to and degrade through enzymatic action. In this study, gelatin microspheres were used to release bone morphogenetic protein 2 (BMP2). Spherical microparticles with diameters in the range of 2,6 µm were created by an emulsification process and were stabilized by crosslinking with the small molecule genipin. The degree of crosslinking was varied by controlling the incubation time in genipin solution. Loading rate studies, using soy bean trypsin inhibitor as a model protein, showed rapid protein uptake over the first 24 h, followed by a levelling off and then a further increase after approximately 3 days, as the microspheres swelled. Growth factor release studies using microspheres crosslinked to 20%, 50% and 80% of saturation and then loaded with BMP2 showed that higher degrees of crosslinking resulted in higher loading efficiency and slower protein release. After 24 h, the concentration profiles produced by all microsphere formulations were steady and approximately equal. Microspheres incubated with adult human mesenchymal stem cells accumulated preferentially on the cell surface, and degraded over time in culture. BMP2-loaded microspheres caused a three- to eight-fold increase in expression of the bone sialoprotein gene after 14 days in culture, with more crosslinked beads producing a greater effect. These results demonstrate that genipin-crosslinked gelatin microspheres can be used to deliver growth factors locally to cells in order to direct their function. Copyright © 2010 John Wiley & Sons, Ltd. [source]

Local matrix metalloproteinase 2 gene knockdown in balloon-injured rabbit carotid arteries using nonviral-small interfering RNA transfection

Hanna Hlawaty
Abstract Background Small interfering RNA (siRNA) delivery is a promising approach for the treatment of cardiovascular diseases. Matrix metalloproteinase (MMP) 2 over-expression in the arterial wall has been implicated in restenosis after percutaneous coronary intervention, as well as in spontaneous atherosclerotic plaque rupture. We hypothesized that in vivo local delivery of siRNA targeted at MMP2 (MMP2-siRNA) in the balloon-injured carotid artery of hypercholesterolemic rabbits may lead to inhibition of MMP2 expression. Methods Two weeks after balloon injury, 5 µmol/l of Tamra-tagged MMP2-siRNA, scramble siRNA or saline was locally injected in the carotid artery and incubated for 1 h. Results Fluorescent microscopy studies showed the circumferential uptake of siRNA in the superficial layers of neointimal cells. MMP2 mRNA levels, measured by the real-time reverse transcriptase-polymerase chain reaction, was decreased by 79 ± 25% in MMP2-siRNA- versus scramble siRNA-transfected arteries (p < 0.05). MMP2 activity, measured by gelatin zymography performed on the conditioned media of MMP2-siRNA versus scramble siRNA transfected arteries, decreased by 53 ± 29%, 50 ± 24% and 46 ± 14% at 24, 48 and 72 h, respectively (p < 0.005 for all). No effect was observed on MMP9, pro-MMP9 and TIMP-2 levels. Conclusions The results obtained in the present study suggest that significant inhibition of gene expression can be achieved with local delivery of siRNA in the arterial wall in vivo. Copyright © 2008 John Wiley & Sons, Ltd. [source]

Slow-release nanoparticle-encapsulated delivery system for laryngeal injection,

Vasantha L. Kolachala PhD
Abstract Objectives/Hypothesis: There is a need for a slow-release system for local delivery of therapeutics to the larynx. Most therapeutic substances, such as steroids or chemotherapeutic agents that are injected into the larynx are cleared rapidly. Repeated laryngeal injection of these substances at short intervals is impractical. Injectable encapsulated poly(lactide-co-glycolide) (PLGA) nanoparticles offer a potential slow-release delivery system for biologically active substances in the larynx. Study Design: Controlled animal study. Methods: PLGA nanoparticles were fabricated using a double emulsion method and were loaded with Texas Red-dextran (NPTR), hepatocyte growth factor (NPHGF), and bovine serum albumin (NPBSA). In vitro release of NPTR, NPBSA, and NPHGF was determined over approximately 2 weeks to assess potential duration of PLGA nanoparticle delivery. In vivo release of NPTR was assessed in a murine vocal fold injection model. The transcriptional effect of NPHGF on procollagen was measured in vitro to assess whether released growth factor retained functionality. Results: In vitro release kinetics demonstrated slow release of NPTR, NPBSA, and NPHGF over 12 to 14 days. In vitro NPTR release correlated with in vivo results. In vivo presence of NPTR occurred up to 7 days compared to 1 day for Texas Red control. In addition, NPHGF ameliorated transforming growth factor-, induced procollagen in vitro in 3T3 fibroblast cells. Conclusions: The results demonstrate the potential utility of nanoparticle encapsulation as an effective method for long-term delivery of specific drugs and biologically active substances to the larynx. Laryngoscope, 2010 [source]

Timing of Human Insulin-Like Growth Factor-1 Gene Transfer in Reinnervating Laryngeal Muscle,

Hideki Nakagawa MD
Abstract Objectives/Hypothesis The authors have designed a rat laryngeal paralysis model to study gene transfer strategies using a muscle-specific expression system to enhance local delivery of human insulin-like growth factor-1 (hIGF-1). In preliminary studies, a nonviral vector containing the ,-actin promoter and human hIGF-1 sequence produced both neurotrophic and myotrophic effects 1 month after single injection of plasmid formulation into paralyzed rat thyroarytenoid muscle in vivo. Based on these findings, it is hypothesized that the effects of hIGF-1 will enhance the results of laryngeal muscle innervation procedures. The timing of gene delivery relative to nerve repair is likely to be important, to optimize the results. Study Design Prospective analysis. Methods The effects of nonviral gene transfer for the delivery of hIGF-1 were evaluated in rats treated immediately following recurrent laryngeal nerve transection and repair and in rats receiving a delayed treatment schedule, 30 days after nerve transection and repair. Gene transfer efficiency was determined using polymerase chain reaction and reverse transcriptase,polymerase chain reaction techniques. Muscle fiber diameter, motor endplate length, and percentage of motor endplates with nerve contact were examined to assess hIGF-1 trophic effects. Results Compared with reinnervated untreated control samples, both early and delayed hIGF-1 transfer resulted in significant increase in muscle fiber diameter. Motor endplate length was significantly decreased and nerve/motor endplate contact was significantly increased following delayed gene transfer, but not after early treatment. Conclusion We infer from results of the study that delayed hIGF-1 gene transfer delivered by a single intramuscular injection will enhance the process of muscle reinnervation. The clinical relevance of these findings supports the future application of gene therapy using nonviral vectors for management of laryngeal paralysis and other peripheral nerve injuries. [source]

Liquid chromatography-tandem mass spectrometry method for determination of Sirolimus coated drug eluting nano porous carbon stents

G. Rajender
Abstract Liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has proved to powerful research tool due to its sensitivity, high selectivity, and high throughput efficiency..Sirolimus was extracted from plasma by two-step extraction procedure using chloroform as extracting solvent. Signal intensity was high using ESI+ source provided for the quantitation of samples. Chromatographic separation was performed on phenomenax C-18 column (250 × 4.60,mm 5microns).Mobile phase contains acetonitrile, water (80; 20 v/v) + 0.1% acetic acid, flow rate 1,mL/min. The retention time of Sirolimus 8.4,min, the total run time10,min. Linearity correlation coefficients (r2) curve was 0.997183.calibraction range 10,1000,ng/mL. The UV detection of Sirolimus was at 278(277.78) nm. Sirolimus coated drug eluting stents, MRM (Multiple reaction monitoring) transition of Sirolimus m/z 936.83,208.84 was selected to obtain maximum sensitivity. LC/MS/MS results exhibited consistency in drug content on the stent surface. In-vitro release kinetic indicated the release of Sirolimus in 41 days from the date of implanted. Drug release was found at the first day, burst release was observed at 7th day of implantation. This study involved pharmacological coating of stents, based on the notion that sustained systemic local delivery of anti-proliferative agents. LC-MS/MS method has been successfully used in the pharmacokinetic analysis of Sirolimus coated drug eluting stents. Copyright © 2009 John Wiley & Sons, Ltd. [source]

Effects of local delivery of trapidil on neointima formation in a rabbit angioplasty model

Kai Zacharowski
Smooth muscle cell (SMC) proliferation can result in luminal reduction of a vessel following balloon angioplasty. This study was designed (i) to determine if local administration of trapidil (triazolopyrimidine) into a vessel wall reduces neointima formation, and (ii) to explore the mechanism involved in the subsequent reduction in cell proliferation. Following balloon angioplasty in 40 anaesthetized New Zealand White rabbits, trapidil (50,200 mg) or its vehicle (saline) was injected into the dilated vessel wall of the right femoral artery. Experimental groups and time of investigation: (I) vehicle (2 weeks, n=3), (II) trapidil-100 mg (2 weeks, n=3), (III) vehicle (3 weeks, n=8), (IV) trapidil-50 mg (3 weeks, n=5); (V) trapidil-100 mg (3 weeks, n=9) or (V) trapidil-200 mg (3 weeks, n=7). After 2 weeks, there was a significant reduction of intimal hyperplasia (expressed as intima to media area ratio) in the trapidil group compared with vehicle (0.44±0.04 vs 0.93±0.04, *P<0.05) and also a significant reduction in cell proliferation (% ratio of BrdU-positive cells to total cell number: vehicle 14±2% vs trapidil 6±1%, *P<0.05). After 3 weeks, there was a dose-dependent reduction of intimal hyperplasia in the trapidil groups compared with vehicle (trapidil 50 mg 1.14±0.04; trapidil 100 mg 0.91±0.09*; trapidil 200 mg 0.77±0.09* vs vehicle 1.67±0.23, *P<0.05). Thus, the local administration of trapidil to the rabbit femoral artery reduces the neointima formation, which occurs 2 or 3 weeks after balloon angioplasty via a mechanism, which is dependent on inhibition of cell proliferation. British Journal of Pharmacology (2000) 129, 566,572; doi:10.1038/sj.bjp.0703098 [source]

Clinical Use of Sirolimus-Eluting Stents

Ajay J. Kirtane
ABSTRACT Drug-eluting stents, or intracoronary stents that combine the local delivery of antirestenotic pharmacologic therapies while maintaining the mechanical advantage of bare metal stents over balloon angioplasty alone, are a highly complex technology that have profoundly affected the practice of percutaneous coronary intervention over the last 5 years. These devices were designed specifically to treat the neointimal hyperplasia occurring after conventional bare metal stent placement, and have been remarkably successful in this regard. However, recent concerns have been raised regarding the long-term safety of these devices, particularly when used outside of the specific patient and lesion subsets studied in the pivotal randomized trials that led to device approval by regulatory bodies within the United States and abroad. This review aims to present a brief description of the sirolimus-eluting stent device platform and its mechanism of action, followed by an overview of current data regarding efficacy and safety regarding the clinical use of sirolimus-eluting stent technology. [source]

111Indium-labelled human gut-derived T cells from healthy subjects with strong in vitro adhesion to MAdCAM-1 show no detectable homing to the gut in vivo

SUMMARY Integrin ,4,,7 is the principal gut-homing receptor, and it is assumed that expression of this specific integrin directs lymphocytes to the gut in vivo. Adoptive cellular immunotherapy against inflammatory bowel disease (IBD) may depend on the expression of integrin ,4,,7 to accomplish local delivery of intravenously injected regulatory T cells in inflamed gut mucosa. The present study aimed to investigate whether in vitro expanded human T cells from the colonic mucosa maintain integrin expression, show in vitro adhesion and retain in vivo gut-homing properties during cultivation. Whole colonic biopsies from healthy subjects were cultured in the presence of interleukin-2 (IL-2) and IL-4. The integrin expression of the cultured T cells was determined by flow cytometry and in vitro adhesion was assessed in a mucosal addressin cell adhesion molecule 1 (MAdCAM-1) adhesion assay. We studied the homing pattern after autologous infusion of 3 × 108 111Indium (111In)-labelled T cells in five healthy subjects using scintigraphic imaging. The cultured CD4+CD45RO+ gut-derived T cells express higher levels of integrin ,4,,7 than peripheral blood lymphocytes (PBLs) and show strong adhesion to MAdCAM-1 in vitro, even after 111In-labelling. Scintigraphic imaging, however, showed no gut-homing in vivo. After prolonged transit through the lungs, the T cells migrated preferentially to the spleen, liver and bone marrow. In conclusion, it is feasible to infuse autologous T cells cultured from the gut mucosa, which may be of interest in adoptive immunotherapy. Despite high expression of the gut-homing integrin ,4,,7 and adhesion to MAdCAM-1 in vitro, evaluation by 111In-scintigraphy demonstrated no gut-homing in healthy individuals. [source]

Adjunctive local antibiotic therapy in the treatment of peri-implantitis II: clinical and radiographic outcomes

Giovanni E. Salvi
Abstract Aim: To monitor over 12 months clinical and radiographic changes occurring after adjunctive local delivery of minocycline microspheres for the treatment of peri-implantitis. Material and methods: In 25 partially edentulous subjects, 31 implants diagnosed with peri-implantitis were treated. Three weeks after oral hygiene instruction, mechanical debridement and local antiseptic cleansing using 0.2% chlorhexidine gel, baseline (Day 0) parameters were recorded. Minocycline microspheres (Arestin®) were locally delivered to each implant site with bone loss and a probing pocket depth (PPD) ,5 mm. Rescue therapy with Arestin® was allowed at Days 180 and 270 at any site exhibiting an increase in PPD,2 mm from the previous visit. The following clinical parameters were recorded at four sites/implant at Day 0, 10, 30, 60, 90, 180, 270 and 360: PPD, clinical attachment level (CAL), bleeding on probing (BOP) and plaque index (PlI). Results: Six implants in six subjects were either rescued or exited because of persisting active peri-implantitis. Successful implants showed a statistically significant reduction in both PPD and percentage of sites with BOP between baseline and Day 360 (P<0.05). At mesial implant sites, the mean PPD reduction amounted to 1.6 mm (95% CI: 0.9,2.2 mm, P<0.001) and was accompanied by a statistically significant reduction of the BOP value (P<0.001). Binary regression analysis showed that the clinical parameters and smoking history could not discriminate between successfully treated and rescued or exited implants at any observation time point. Conclusion: Non-surgical mechanical treatment of peri-implantitis lesions with adjunctive local delivery of microencapsulated minocycline led to positive effects on clinical parameters up to 12 months. [source]