Electrogastrography : clinical applications

The main aim of this thesis was to investigate whether electrogastrography (EGG), the recording of gastric myoelectrical activity by means of electrodes attached to the abdominal skin, can improve our understanding of gastric myoelectrical activity in disease. The accuracy and reliability of EGG was studied by comparing cutaneous recordings with serosal recordings in a patient after laparotomy, and by performing repeat studies in healthy individuals. The fundamental frequency in the electrogastrogram in man was shown to be of gastric origin and equal to the repetition frequency of the gastric electrical control activity (ECA). The gastric ECA frequency can be measured reliable by EGG. The reliability of measurements of the postprandial amplitude increase of the gastric frequency by EGG (an indicator of gastric motor activity) can be improved by prolonging the fasting recording period but this does not seem to be necessary for clinical applications

Preclinical Evaluation of Anticancer Efficacy and Pharmacological Properties of FBA-TPQ, a Novel Synthetic Makaluvamine Analog

We have recently designed and synthesized a novel iminoquinone anticancer agent, 7-(4-fluorobenzylamino)-1,3,4,8-tetrahydropyrrolo[4,3,2-de]quinolin-8(1<em>H</em>)-one (FBA-TPQ) and initiated its preclinical development. Herein we investigated its efficacy, safety, and pharmacokinetics in <em>in vitro</em> and <em>in vivo</em> models of human pancreatic cancer. Our results demonstrated that FBA-TPQ inhibited pancreatic cancer cell growth, induced apoptosis,<em> </em>and caused cell cycle arrest <em>in vitro</em>. It inhibited the growth of xenograft tumors with minimal host toxicity. To facilitate future preclinical and clinical development of the agent, we also developed and validated a Rapid Resolution Liquid Chromatography (RRLC) method for quantitative analysis of FBA-TPQ in plasma and tissue samples. The method was found to be precise, accurate, and specific. Using this method, we carried out <em>in vitro</em> and <em>in vivo</em> evaluations of the pharmacological properties of FBA-TPQ, including stability in plasma, plasma protein binding, metabolism by S9 enzymes, plasma pharmacokinetics, and tissue distribution. Our results indicate that FBA-TPQ is a potential therapeutic agent for pancreatic cancer, providing a basis for future preclinical and clinical development

Pharmacokinetic Modeling of Non-Linear Brain Distribution of Fluvoxamine in the Rat

Introduction. A pharmacokinetic (PK) model is proposed for estimation of total and free brain concentrations of fluvoxamine. Materials and methods. Rats with arterial and venous cannulas and a microdialysis probe in the frontal cortex received intravenous infusions of 1, 3.7 or 7.3 mg.kg j1 of fluvoxamine. Analysis. With increasing dose a disproportional increase in brain concentrations was observed. Th

Cell cycle phase perturbations and apoptosis in tumour cells induced by aplidine

Aplidine, dehydrodidemnin B, is a marine depsipeptide isolated from the Mediterranean tunicate Aplidium albicans currently in phase II clinical trial. In human Molt-4 leukaemia cells Aplidine was found to be cytotoxic at nanomolar concentrations and to induce both a G1 arrest and a G2 blockade. The drug-induced cell cycle perturbations and subsequent cell death do not appear to be related to macromolecular synthesis (protein, RNA, DNA) since the effects occur at concentrations (e.g. 10 nM) in which macromolecule synthesis was not markedly affected. Ten nM Aplidine for 1 h inhibited ornithine decarboxylase activity, with a subsequently strong decrease in putrescine levels. This finding has questionable relevance since addition of putrescine did not significantly reduce the cell cycle perturbations or the cytotoxicity of Aplidine. The cell cycle perturbations caused by Aplidine were also not due to an effect on the cyclin-dependent kinases. Although the mechanism of action of Aplidine is still unclear, the cell cycle phase perturbations and the rapid induction of apoptosis in Molt-4 cells appear to be due to a mechanism different from that of known anticancer drugs

Revista de Vertebrados de la Estación Biológica de Doñana

Catálogo descriptivo de los anfibios y reptiles de CubaEvolución estacional de la comunidad de aves en un robledal de Sierra NevadaComposición de la comunidad de aves en pinares del Parque Nacional de Doñana (suroeste de España).Alimentación de la pagaza piconegra (Gelochelidon nilotica) en las marismas del GuadalquivirContaminación xenobiótica del Parque Nacional de Doñana. III. Residuos de insecticidas organoclorados, bifenilos policlorados y metales pesados en ciconiformesAlimentación de la lechuza común Tyto alba en la cuenca del Duero, EspañaEstudio de una población rural de (Mus musculus L.) I. La probabilidad de captura y la estima numéricLa reproducción en Gazella dorcasIncidencia del Nemátodo parásito Skrjabingylus Leuckart, 1842 sobre el Mustela en España.Desplazamientos de ungulados silvestres a través de una zona de ecotono en Doñana.Etograma de la cabra montés (Capra pyrenaica) y comparación con otras especies.Sobre comportamiento agresivo de Triturus marmoratus en época de celoEmbarrancamiento masivo de ejemplares de tortuga lad (Dermochelys coriacea L.) en las costas de Ceuta (España, norte de África)Sobre un ejemplar melánico de Podarcis hispanica (Steindachner, 1870)Nuevos datos sobre la distribución de cuatro especies de reptiles en la provincia de Cádiz.Algunos datos sobre la nidificación de Ciconia nigra L. en sierra Morena (S. España)Observación del halcón de Eleonor (Falco eleonorae) en el centro de EspañaNueva localidad de cría del pájaro moscón (Remiz pendulinus) en la Península IbéricaRegistro de aves en el sur de BoliviaNidificación del paiño de Madeira Oceanodroma castro (Harcourt, 1851) en las Islas Canarias.Observación primaveral de Phalaropus fulicarius L. en el SO de EspañaNuevos datos sobre la presencia del nóctulo gigante Nyctalus lasiopterus (Chiroptera, vespertilionidae) en EspañaNote sur l'alimentation de Martes martes a Menorca (Baleares).Peer reviewe

Spisulosine (ES-285) given as a weekly three-hour intravenous infusion: results of a phase I dose-escalating study in patients with advanced solid malignancies

Spisulosine is a marine compound that showed antitumor activity in preclinical studies. We report results of a phase I trial performed in patients with advanced solid tumors with the marine compound, with the aim to determine the maximum tolerated dose (MTD) of a weekly 3-h intravenous (iv.) infusion, and to evaluate the safety, efficacy, and pharmacokinetics (PK) of the compound. Two centers contributed 25 patients to the trial, and 7 dose levels were explored. In dose levels ranging from 4 to 128 mg/mA(2)/day, no dose-limiting toxicities (DLT) were observed. One patient had DLT at 200 mg/mA(2), a reversible grade 3 ALT increase. The MTD was not reached due to early termination of the Spisulosine trial program but is considered to be likely in the range of 200 mg/mA(2) for this schedule. Drug-related adverse reactions included mild to moderate nausea, pyrexia, injection site reactions, and vomiting. One case of grade 4 peripheral motor and sensory neuropathy associated with general weakness and pain was observed during treatment cycle 4 and possibly contributed to the death of the patient. Grade 3 laboratory abnormalities included anemia and lymphopenia and increases in liver enzymes (alkaline phosphatase, transaminases, and bilirubin). Objective responses were not observed, and only four patients had short-lasting stable disease (< 3 months). The PK data indicated a wide distribution, a long residence time, and dose proportionality of the agent. Hepato- and neuro-toxicity are schedule independent dose-limiting adverse events for this marine compound, as illustrated by this and other early clinical trials