No description available.

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / Chylothorax is defined as the accumulation of chyle within the pleural space. Originally described in 1917 by Pisek, it is the most common cause of pleural effusion in the neonatal period. The leading cause of chylothorax is laceration of the thoracic duct during surgery, which occurs in 0.85% to 6.6% of children undergoing cardiothoracic surgery. Few authors of reports in the literature have looked at etilefrine, a relatively unknown sympathomimetic, as an option for the medical treatment of chylothorax. In this case report, we review the clinical course of 2 infants with type III esophageal atresia who developed chylothorax after thoracic surgery and were successfully treated with intravenous etilefrine after failing initial dietary and pharmacological management. / Revisión por pares

Background & Aims: Vasoactive agents with endoscopic therapy are used to treat acute variceal bleeding (AVB). There are two main groups of vasoactive agents: terlipressin and vasopressin (T-V), and octreotide and somatostatin (O-S). However, the benefit/harm balance is unclear. Our aim was to assess the efficacy and safety of T-V versus O-S for the management of AVB. Methods: We performed a systematic search for randomized controlled trials (RCTs) in PubMed, Scopus, and CENTRAL. Our main outcomes were mortality and adverse events. Secondary outcomes were bleeding control, rebleeding, blood transfusion, hospital stay. We evaluated the certainty of evidence using GRADE methodology. Results: We included 21 RCTs. The risk of mortality (RR: 1.01; 95%CI: 0.83-1.22), bleeding control (RR: 0.96; 95%CI: 0.91-1.02; I2=53%), early rebleeding (RR: 0.91; 95%CI: 0.66-1.24: I2=0%), late rebleeding (RR: 0.94; 95 CI: 0.56-1.60; I2=0%), blood transfusion (MD: 0.04; 95%CI:-0.31-0.39; I2=68%) and hospital stay (MD:-1.06; 95%CI:-2.80-0.69; I2=0%) were similar between T-V and O-S groups. Only 15 studies reported adverse events, which were significantly higher in the T-V compared to the O-S group (RR 2.39; 95%CI: 1.58-3.63; I2=57%). The certainty of evidence was moderate for the main outcomes, and low or very low for others. Conclusions: In cirrhotic patients with AVB, those treated with T-V had similar mortality risk compared to O-S. However, the use of T-V showed an increased risk of adverse events compared to O-S. / Revisión por pares

A sublingual electronic pill is a novel device designed to enhance delivery of drugs/biologics sublingually utilizing low-current electrical stimulation. Our primary aim was to explore safe limits of oral electrical stimulus in animals and conduct a randomized, sham-controlled animal study to quantify benefits of electrical stimulation on sublingual absorption of octreotide (a small peptide) as a first step in the development of this technology. A system to deliver low-current alternating and direct current stimuli to the oral mucosa of rabbits was constructed, and five groups were studied to determine the significance of sublingual octreotide diffusion in the presence of three different electrical stimulation scenarios: +DC (+4 mA), -DC (-4 mA), and AC (2 mA peak-to-peak, 20 Hz square wave). These were compared to an Oral Baseline Absorption Group (sublingual diffusion in the absence of stimulation) to determine statistical significance of electrical stimulus; and a Subcutaneous Control Group (bolus injection) to discern therapeutic significance. +DC stimulation (4mA) increased serum concentration 28x with high statistical significance (p-value=0.0008). -DC stimulation (-4mA) increased serum concentration by 19x with borderline significance (p=0.032). AC (20 Hz) stimulus (2mA peak-peak) increased serum concentration by 10x, but was not statistically significant. The absorption rate of octreotide was also calculated for each group and compared at t=10 minutes and t=30 minutes. The absorption rate of the +DC group was 28x greater than that of Baseline Group and was statistically significant (p=0.0008). The absorption rate of the -DC group was 19x greater than that of the Baseline Group and was statistically significant (p=0.032). The absorption rate of the AC group was 10x greater than the Baseline Group but was not statistically significant (p=0.135). While none of the sublingual groups reached therapeutically significant serum concentrations, therapeutic levels of sublingually-delivered octreotide could potentially be achieved by extending octreotide exposure and stimulation time, coupled with utilizing sublingual octreotide in higher concentrations. This research was a necessary first step in successful realization of the SEP device.

The ability to deliver DNA to target cells creating therapeutic effects remains an important goal in the field of gene therapy. A majority of clinical trials to overcome this issue have utilized viral vectors due to their efficiency at DNA delivery and ability to create high levels of gene expression. However, their inherent toxicity and a several clinical trials leading to patients contracting new diseases from the treatment have greatly hindered the progress of viral gene therapy. Non-viral gene delivery agents have a much better safety profile, but are also much less efficient at delivering DNA, leading to low gene expression. The reason for this low expression is the numerous barriers that must be overcome to achieve gene expression: circulation, tissue specific accumulation, internalization, release of DNA cargo, and nuclear localization. While peptides are currently being improved upon, enhancing binding and the ability to protect DNA, they are still deficient when it comes to tissue specificity. Numerous targeting methods, including the use of lectins, antibodies, aptamers, and peptides, have been designed to deliver molecules to a specific research. Research to incorporate targeting ligands onto non-viral gene delivery vectors is abundant in the literature; however, successful site specific gene delivery has not been achieved. The somatostatin receptor 2 (SSTR2) ligand, octreotide, is a well-researched eight amino acid peptide that has extensive SAR data available. Also, the receptors have been well characterized and octreotide is used clinically in the radioscintigraphy imaging of brain tumors. While well researched, there are unexplored opportunities to utilize octreotide to enhance non-viral gene delivery vectors. The overall scope of this thesis is to develop and synthesize non-viral gene delivery peptides conjugated to octreotide creating receptor mediated targeting of DNA polyplexes to create tissue specific accumulation. Initial experiments indicated that attachment of octreotide to the polycationic peptide WK18 does not inhibit affinity for the SSTR2 receptor. Therefore, peptides were designed and synthesized to attach octreotide onto polyacridine peptide (Acr-Lys)6. Polyplex characteristics were unchanged by the incorporation of octreotide, and exhibited very low genotoxic effects compared to the in vitro gene delivery agent PEI. Competitive binding assays suggested a stoichiometric, ligand, and temperature dependent accumulation of polyplex on SSTR2 expressing cells, but gene expression could not be achieved. The success of (Acr-Lys)6octreotide, led to the synthesis of a di-maleimide-PEG attached to each end by (Acr-Lys4)3Acr-Lys-Cys or Cys-Gly5octreotide in attempts to create distance, and better ligand availability for the receptor, by expressing octreotide away from the polyplex. Testing of this peptide in PEGylated polyplex ad-mixtures verified that separating the DNA binding peptide from octreotide did lead to better inhibition of binding to DAOY cells in a competitive binding study. However, transfection assays with this compound showed background levels of gene expression. Although gene expression was not achieved, the synthetic strategy to create a molecule incorporating a DNA binding peptide, ligand, and PEG to create better ligand presentation to its receptor when incorporated into PEGylated polyplexes is an important step in the design of gene delivery vectors.

1. Adénomes hypophysaires somatotropes : Elaboration d'un modèle in vitro et in vivo d'études du récepteur SST2 et des voies de signalisation somatostatinergiques.Afin de préciser l'étude du récepteur SST2, nous avons mis en place un modèle d'étude in vitro et in vivo, en établissant une lignée polyclonale exprimant le récepteur SST2 humain à de hauts niveaux. Ce modèle nous permettra de tester de nouveaux agonistes somatostatinergiques comme le pasiréotide et d'étudier de façon approfondie les voies de signalisation.2. Méningiomes : Mise en place d'un modèle de culture primaire de méningiome in vitro et étude de l'effet de l'octréotide, du pasiréotide et de l'everolimus sur la prolifération cellulaire et les voies de signalisation intracellulaire.Etant donné la forte expression du récepteur SST2, nous avons démontré in vitro un effet anti-prolifératif de l'octréotide sur les cellules de méningiomes via une inhibition de la voie Pi3kinase-Akt-mTOR. L'octréotide a significativement amélioré l'inhibition par l'everolimus de la prolifération cellulaire.Un effet additif des 2 drogues a été observé. Ces résultats ont permis la mise en place d'une étude clinique . Par ailleurs, on observe un meilleur effet du pasiréotide comparé à celui de l'octréotide.3. Chordomes : Mise au point d'un modèle de culture primaire de cellules de chordomes in vitro et études préliminaires.Les premiers résultats avec octréotide, pasiréotide et everolimus sont concluants, mettant en évidence une diminution de la prolifération cellulaire, et nous incitent à poursuivre les investigations. / 1.Somatotroph adenomas : Development of an in vitro and in vivo model to study SST2 receptor and somatostatin pathway.To precise SST2 role in tumorigenesis, we developed an in vitro and in vivo model, using a polyclonal cell line with high and stable SST2 expression level. This model will provide to test new somatostatin agonists as pasireotide and further studies on intracellular pathway in ''somatotroph'' context.2. Meningiomas : Development of a model of meningioma primary culture in vitro with study of octreotide, pasireoide and everolimus effects on cell proliferation and intracellular pathways. Given the strong SST2 expression, we demonstrated an in vitro antiproliferative effect of octreotide on meningioma cells via an inhibition of Pi3kinase-Akt-mTOR pathway.In vitro, we observed that octreotide significantly improved everolimus induced cell proliferation inhibition. An additive effect of the 2 drugs was observed in each tested tumor. These results supported the development of a clinical trial. Pasireotide provided a better effect than octreotide, alone or in combination with everolimus on cell proliferation and intracellular pathways.3. Chordomas : Development of an in vitro model of chordoma cell primary culture with preliminary studies.We developed a model of in vitro chordoma cell culture. This model is reliable and stable, providing study of different drugs. SST2 receptor expression was lower than in meningiomas but SST2 expression remained significant in the majority of the tumors. First results with octreotide, pasireotide and everolimus are relevant, with a decrease in cell proliferation leading to further studies.

<p>Different prosthetic groups containing a trialkylstannyl- and an electrophilic group have been synthesised and labelled with the accelerator produced ⁷⁶Br (T_1/2=16 h) through oxidative bromination. The labelled prosthetic groups were conjugated to amino-containing macromolecules such as proteins and 5´-modified oligonucleotides.</p><p><i>N</i>-Succinimidyl 4-[⁷⁶Br]bromobenzoate <b>14 </b>was synthesised in 65 % radio-chemical yield and was conjugated to 5´-hexylamino-modified phosphodiester and phosphorothioate oligonucleotides in 12-19 % isolated radiochemical yield. The stability of the ⁷⁶Br-oligonucleotide-conjugates <i>in vivo</i> in rats was investigated. No degradation from the 5´-end, resulting in labelled, low molecular weight compounds was detected. Compound <b>14</b> has also been used for labelling of different proteins in 23-61% radiochemical yield.</p><p><i>N</i>-Succinimidyl-5-[⁷⁶Br]bromo-3-pyridinecarboxylate <b>17</b> and methyl-4-[⁷⁶Br]bromo-benzimidate <b>15 </b>were synthesised from the corresponding trimethylstannyl-compound in 25% and 40 % yield respectively. Compounds <b>14 </b>and <b>17</b> were conjugated to ε-Boc-octreotide in 55 and 50% isolated radiochemical yield respectively after microwave heating. Compound <b>15</b> did not react with octreotide under the conditions investigated. The two ⁷⁶Br-labelled octreotide derivatives showed different lipophilicity and different binding-properties to tissue from meningiomas.</p><p>Hyaluronic acid, a polysaccharide, was modified with tyramine and labelled by oxidative bromination using ⁷⁶Br in 10% radiochemical yield.</p><p>The generator produced ⁶⁸Ga (T_1/2=68 min) was used to label octreotide and oligonucleotides modified with the metal chelating group 1,4,7,10-tetraazacyclo-dodecane-1,4,7,10-tetraacetic acid (DOTA). ⁶⁸Ga-DOTA-octreotide was isolated in 65% radiochemical yield and a phosphorothioated ⁶⁸Ga-DOTA-oligonucleotide was isolated in 35% radio-chemical yield after 30 min synthesis time.</p><p>Compound<b> 14 </b>was reacted with 3-aminomethylbenzylamine to give compound <b>18</b>. The specific radioactivity<b> </b>of<b> 18 </b>was determined to be 36 GBq/µmol by measuring the ratio between the mass-peaks for the ⁷⁶Br and ⁷⁹Br-compounds using packed-capillary LC-MS.</p>

Different prosthetic groups containing a trialkylstannyl- and an electrophilic group have been synthesised and labelled with the accelerator produced 76Br (T1/2=16 h) through oxidative bromination. The labelled prosthetic groups were conjugated to amino-containing macromolecules such as proteins and 5´-modified oligonucleotides. N-Succinimidyl 4-[76Br]bromobenzoate <b>14 </b>was synthesised in 65 % radio-chemical yield and was conjugated to 5´-hexylamino-modified phosphodiester and phosphorothioate oligonucleotides in 12-19 % isolated radiochemical yield. The stability of the 76Br-oligonucleotide-conjugates in vivo in rats was investigated. No degradation from the 5´-end, resulting in labelled, low molecular weight compounds was detected. Compound <b>14</b> has also been used for labelling of different proteins in 23-61% radiochemical yield. N-Succinimidyl-5-[76Br]bromo-3-pyridinecarboxylate <b>17</b> and methyl-4-[76Br]bromo-benzimidate <b>15 </b>were synthesised from the corresponding trimethylstannyl-compound in 25% and 40 % yield respectively. Compounds <b>14 </b>and <b>17</b> were conjugated to ε-Boc-octreotide in 55 and 50% isolated radiochemical yield respectively after microwave heating. Compound <b>15</b> did not react with octreotide under the conditions investigated. The two 76Br-labelled octreotide derivatives showed different lipophilicity and different binding-properties to tissue from meningiomas. Hyaluronic acid, a polysaccharide, was modified with tyramine and labelled by oxidative bromination using 76Br in 10% radiochemical yield. The generator produced 68Ga (T1/2=68 min) was used to label octreotide and oligonucleotides modified with the metal chelating group 1,4,7,10-tetraazacyclo-dodecane-1,4,7,10-tetraacetic acid (DOTA). 68Ga-DOTA-octreotide was isolated in 65% radiochemical yield and a phosphorothioated 68Ga-DOTA-oligonucleotide was isolated in 35% radio-chemical yield after 30 min synthesis time. Compound<b> 14 </b>was reacted with 3-aminomethylbenzylamine to give compound <b>18</b>. The specific radioactivity<b> </b>of<b> 18 </b>was determined to be 36 GBq/µmol by measuring the ratio between the mass-peaks for the 76Br and 79Br-compounds using packed-capillary LC-MS.

Title from PDF of title page (University of Missouri--Columbia, viewed on Feb 25, 2010). The entire thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file; a non-technical public abstract appears in the public.pdf file. Dissertation advisor: Dr. Silvia Jurisson and Dr. Mike Lewis. Vita. Includes bibliographical references.

Este estudo analisa a expressão dos subtipos de receptores da somatostatina (SSTR) em 39 adenomas secretores de GH. Em 19 pacientes acromegálicos, a resposta clínica, laboratorial e radiológica ao análogo da somatostatina (AS) octreotide-LAR foi comparada à expressão dos SSTR. O SSTR mais freqüentemente expresso foi o SSTR5, seguido pelos SSTR3, SSTR2, SSTR1 e SSTR4. O SSTR1 e SSTR2 foram mais expressos nos pacientes que normalizaram GH e IGF-I. Houve correlação positiva entre o grau de redução tumoral e a expressão dos SSTR1, SSTR2 e SSTR3. Portanto, AS específicos para os SSTR´s poderão contribuir para o tratamento de acromegálicos resistentes aos AS atualmente disponíveis / This study aimed to analyze the expression of somatostatin receptor subtypes (SSTR) in 39 GH-secreting pituitary adenomas. In 19 acromegalics the clinical, laboratorial and radiological responses to the somatostatin analog (SA) octreotide-LAR were compared to SSTR´s expression. The most expressed SSTR was SSTR5, followed by SSTR3, SSTR2, SSTR1 and SSTR4. SSTR1 and SSTR2 were more expressed in patients who achieved GH and IGF-I normalization. There was a positive correlation between the degree of tumor reduction with SSTR1, SSTR2 and SSTR3 expression. Therefore, the development of specific SA could contribute to treatment improvement in resistant acromegalics patients to available SA