Single Dosis Research Articles

Abstract 224: TRAF-STOP-RHDL-Nanoparticles Reduce Atherosclerosis

Background: Inhibition of the costimulatory CD40-CD40L receptor/ligand dyad drastically reduces atherosclerosis. However, its long-term blockage can result in immune suppression. We recently identified small molecule inhibitors that block the interaction between CD40 and TNF Receptor Associated Factor (TRAF) 6 (TRAF-STOPs), while leaving CD40-TRAF2/3/5 interactions intact, thereby preserving CD40-mediated immunity. We investigated the potential of the TRAF-STOPs to treat atherosclerosis. Results: Treatment of ApoE-/- mice with either TRAF-STOP 6877002 or 6860766 reduced both initial and established atherosclerosis and induced a stable plaque phenotype with increased collagen and VSMC content, decreased lipid core, and a decrease in macrophage number. There were no signs of immune suppression or toxicity. In vitro experiments showed that the TRAF-STOPs reduced inflammation in macrophages, but not in T- or B cells, endothelial cells or vascular smooth muscle cells. Intravital microscopy demonstrated that the TRAF-STOPs reduced monocyte recruitment to the plaque. The CD36-mediated uptake of ox-LDL by macrophages and foam cell formation was also inhibited by TRAF-STOPs. Transcriptomics analysis and Ingenuity pathway analysis of TRAF-STOP-treated bone marrow-derived macrophages revealed that the top ranking canonical pathways for both TRAF-STOPs involved pro-inflammatory immune responses and cholesterol biosynthesis. 6877002 also affected cell cycle regulation. Surface plasmon resonance experiments and mutation studies demonstrated that 6877002 and 6860766 had a different interaction site within the TRAF6 C-domain, which explained the additional effect of 6877002. To target TRAF-STOPs specifically to macrophages, 6877002 was incorporated into rHDL nanoparticles. Flowcytometry and fluorescent microscopy demonstrated accumulation of rHDL-6877002 in plaque macrophages after a single dosis. Six weeks of rHDL-6877002 treatment reduced atherosclerosis in ApoE-/- mice. Conclusions: TRAF-STOP 6877002 and 6860766 can overcome the current limitations of long-term CD40 and CD40L inhibition and nanoparticle-mediated delivery TRAF-STOP to plaque macrophages may become a future therapy for atherosclerosis.

PM064 The introduction of individualised milrinone doses as a cost containment strategy for heart failure patients under a hospital-in-the-home service

O ST E R A B ST R A C T S Introduction: In patients whit advanced cardiac failure under inotropes drugs therapy(IT) the use of negative chronotropic agents like beta blockers, digoxyn or calcium blockers is very restricted Tachycardia above 100 beats pm reduce diastolic time and efficiency of intra aortic baloon conterpusation (IABP). We present our experience with oral ivabradine used to improve the efficiency of IABP in tachycardic acute heart failure patients. Objectives: To evaluate with Swan Ganz catether (SG) the hemodynamic effect of ivabradine used to reduce sinus tachycardia during IT and IABP. Methods: Between January 2011 and August 2013 were prospectively included patients in sinus rhythm with more than 100 heart beat pm admitted in to the U.A.I. critical cardiology unite with decompensated dilated ischemic cardiomyopathy. All patients treated with at least 10gmas/Kg/min of one or more IT (unchanged during measurement period). No less than 2,2 liters/m2 SG measered cardiac index. Optimized IABP setting remain unchanged durin measurement period. Were excluded patients in schock of others causes, infections, renal failure, anemia, requiring or mechanical ventilation support or whith acute digestive desease. SG measurements were performed one hour before and three hours after a single oral dosis of 15mg ivabradine. Results: The study included 22patients (12men). All whith miocardial infarction history. Age average of 65.5 years. Left ejection fraction average was 27.3%. Dose of intravenous inotropic drug average was 17.2Kg/w/min. Three hours after ivabradine heart rate decreased from 123+/-5 to 97+-5 (P0.0003) Increase cardiac output of 4452+-550 ml minute at 4925+-535 ml/min(p0.031). Increase in cardiac index without statistical significance of 2.21+/-0.3 to 2.37+/-0.3 liters/m (p0.08). The average stroke volume increased significantly from 33.9 +-5 to 52.3 +-8 ml(p0.0007). The left ventricule work index increased from 12.9 +-3 to 17.3 +-4 (p0.00003). No differences were observed in the records of right atrial pressure, wedge, systemic vascular and pulmonary resistance. After five ivabradine half-lives suspension no ecg or clinical adverse effects were observed. Conclusion: Ivabradine is useful to moderate sinus tachycardia an and improve efficiency of IABP in advanced heart failure. Ivabradine use did not interfere with IT showing an improvement in some cardiac output parameters. No changes were observed in preload and afterload parameters in this set of patients. No electrocardiographic or clinical adverse effects were observed. Disclosure of Interest: None Declared

Renal effects by a low and single dosis of nickel chloride in adult male rats

Renal effects by a low and single dosis of nickel chloride in adult male rats

Uterus Necrosis after Radiochemotherapy for Locally Advanced Cervical Cancer - A Case Report

Hintergrund: Die simultane platinbasierte Radiochemotherapie ist die Standardbehandlung für lokal fortgeschrittene und/oder nodalpositive Karzinome der Cervix uteri. Umfangreiche Literatur zur therapiebedingten Akut- und Spättoxizität ist verfügbar. Eine radiochemotherapiebedingte Nekrose des Uterus wurde bisher nicht beschrieben. Material, Methoden und Ergebnisse: Wir berichten über eine Patientin, die 2004 aufgrund eines Zervixkarzinoms nach laparoskopischem paraaortalen und pelvinen Staging kombiniert radiochemotherapiert wurde. Es handelte sich um ein Plattenepithelkarzinom der Zervix uteri im Stadium FIGO IIIA (T3a pN1 M0 G2). Die perkutane Strahlentherapie wurde in 3D-geplanter Mehrfeldertechnik bis 54 Gy durchgeführt. Die Patientin erhielt eine Afterloading-Therapie mit 5 × 5 Gy Einzeldosis tumorumschließend sowie eine simultane Chemotherapie mit Cisplatin. Vier Monate nach Therapieende entwickelte die Patientin pelvine Schmerzen, verbunden mit einer CRP-Erhöhung bei normalen Leukozytenwerten. MRT-morphologisch wurde ein Rezidiv vermutet. Zum Ausschluss bzw. Nachweis eines Rezidivs wurde eine erneute Laparoskopie durchgeführt, die eine Uterusnekrose ergab. Aufgrund des intraoperativen Befundes wurde bei der Patientin eine laparoskopisch assistierte Hysterektomie durchgeführt. Schlussfolgerung: Bei Patientinnen nach abgeschlossener Radiochemotherapie eines Zervixkarzinoms mit persistierenden oder neu aufgetretenen Schmerzen im Becken, unklaren Befunden in der bildgebenden Diagnostik und bei erhöhten Entzündungsparametern sollte eine radiogene Nekrose differenzialdiagnostisch in Erwägung gezogen werden. Die Diagnosestellung ist mittels Laparoskopie sicher möglich.

Intraventricular application of rituximab as a treatment option in patients with CNS lymphoma and leptomeningeal disease

1521 Background: Most patients (pts) with primary central nervous system lymphoma (PCNSL) relapse after initial response to treatment, often presenting with leptomeningeal disease. Since the majority of PCNSL are B-cell neoplasms expressing the CD20 surface antigen treatment with the chimeric monoclonal antibody (Mab) rituximab might be reasonable. The primary objective was to evaluate feasibility and safety of direct administration of the anti-CD20 antibody into the cerebro spinal fluid (CSF). Methods: Pts with intracranial lesions and/or leptomeningeal involvement of B-cell neoplasms expressing the CD20 surface antigen were included. In order to define the tolerated single dose, injections of 10–40 mg rituximab in a volume of 1–4 ml were administered over two minutes via an ommaya reservoir (n=4) or intrathecally (n=2). Drug clearance from the CSF was determined by measuring rituximab levels in the CSF and blood by ELISA. Results: Treatment with rituximab at single dosis of up to 35mg thrice weekly was ...

Intraventricular application of rituximab as a treatment option in patients with CNS lymphoma and leptomeningeal disease

1521 Background: Most patients (pts) with primary central nervous system lymphoma (PCNSL) relapse after initial response to treatment, often presenting with leptomeningeal disease. Since the majority of PCNSL are B-cell neoplasms expressing the CD20 surface antigen treatment with the chimeric monoclonal antibody (Mab) rituximab might be reasonable. The primary objective was to evaluate feasibility and safety of direct administration of the anti-CD20 antibody into the cerebro spinal fluid (CSF). Methods: Pts with intracranial lesions and/or leptomeningeal involvement of B-cell neoplasms expressing the CD20 surface antigen were included. In order to define the tolerated single dose, injections of 10–40 mg rituximab in a volume of 1–4 ml were administered over two minutes via an ommaya reservoir (n=4) or intrathecally (n=2). Drug clearance from the CSF was determined by measuring rituximab levels in the CSF and blood by ELISA. Results: Treatment with rituximab at single dosis of up to 35mg thrice weekly was safe and well tolerated in 5/6 pts. Acute neurotoxicity in one pt (PN6) was probably related to a high tumor cell burden in the CSF and a rapid tumor cell lysis after intrathecal rituximab. Measurement of rituximab concentrations in the CSF showed severalfold higher values after intraventricular administration compared to those after intravenous rituximab application. Clearing of tumor cells in the CSF and a complete remission of leptomeningeal lymphoma manifestation was achieved in four pts. However, there was no effect of rituximab on parenchymal lymphoma. Conclusions: Taken together, these data suggest that direct administration of rituximab into the CSF may have a role in the treatment of leptomeningeal disease in pts with CNS lymphoma. However, the therapeutic value of systemic treatment with the antibody remains questionable. To better define the value of rituximab treatment in CNS lymphoma with lymphomatous meningitis, future studies should investigate dose intensification as well as combination with other chemotherapeutic drugs or radiotherapy. No significant financial relationships to disclose.

141 Toxicity assay to single dosis and to repeated dosis of humanized ACMT1HT by endovenous route in CENP:SPRD rats

141 Toxicity assay to single dosis and to repeated dosis of humanized ACMT1HT by endovenous route in CENP:SPRD rats

INTOXICAÇÃO EXPERIMENTAL POR Phytolacca decandra EM OVINOS

Doses únicas de 10 a 25g/kg das folhas verdes de Phytolacca decandra foram administradas oralmente a 11 ovinos. Dois desses ovinos (20 e 25g/kg) morreram 6 horas após a ingestão da planta e os outros nove adoeceram levemente e se recuperaram. Um outro ovino recebeu 4 doses diárias de 5g/kg da mesma planta. Esse ovino e outros dois usados como controles não adoeceram. Os principais sinais clínicos nos ovinos afetados foram dor abdominal, inquietação, manoteio, distúrbios respiratórios, tremores e hiperestesia. As alterações macroscópicas mais importantes em dois ovinos necropsiados estavam restritas ao sistema digestivo e consistiam de avermelhamento difuso da mucosa do rúmen, retículo, abomaso e intestino delgado. Microscopicamente, as alterações eram necrose de coagulação e microabscessos na mucosa dos pré-estômagos e presença de numerosos cristais birrefringentes na luz dos túbulos renais.

Lipid metabolism in experimental animals

Publications are scarce in the way in chich metabolic processes are affected by the ingestion of heated fats used to prepare food. Similarly studies measuring metabolic effects of the consumption on fried food are poorly known. The purpose of this presentation is to summarize information on frying fats and frying foods upon lipid metabolism in experimental animals. Food consumption is equivalent or even higher when oils or the fat content of frying foods are poorly alterated decreasing their acceptability when their alteration degree increase. After 4hr. experiment the digestibility and absorption coefficients of a single dosis of thermooxidized oils were significantly decreased in rats, however the digestive utilization of frying thermooxidized oils included in diets showed very little change in comparison with unused oils by feeding trials on rats. Feeding rats different frying fats induced a slight hypercholesterolemic effect being the magnitude of this effect related to the linoleic decrease in diet produced by frying. However HDL, the main rat-cholesterol carrier, also increased, thus the serum cholesterol/HDL-cholesterol ratio did not change. Results suggest that rats fed frying fats adapt their lipoprotein metabolism increasing the number of HDL particles. Deep fat frying deeply changed the fatty acid composition of foods, being possible to increase their n-9 or n-6 fatty acid and to decrease the saturated fatty acid contents by frying. When olive oil-and sunflower oil-fried sardines were used as the only protein and fat sources of rats-diets in order to prevent the dietary hypercholesterolemia it was provided that both fried-sardine diets showed a powerful check effect on the cholesterol raising effect induced by dietary cholesterol. The negative effect of feeding rats cholesterol plus bovine bile to induce hypercholesterolemia on some cell-damage markers such as lactate dehydrogenase, transaminases, alkaline phosphatase, was significantly check when olive oil- or sunflower oil-fired sardines were used in rats. However, gamma-glutamyltransferase increased when diets containing fried sardines from oils used several times for frying were consumed. In conclusion frying appears to be an useful tool to modify the fatty acid composition of food and the lipoprotein metabolism of consumers, however this culinary procedure has to be gently done to avoid high level of potential toxic compounds.

16 P Chemotherapy induced emesis. management of early and delayed emesis in milder emetogenic regimens

The objective of the study was to examine the problem of control of nausea and vomiting induced by non-cisplatin cyclophosphamide-based chemotherapic regimens in breast cancer patients. This was a randomized double-blind, parallel-group and placebo controlled study comparing the efficacy of four antiemetic therapeutic regimens (A:Ondansetron for 3 days; B:Ondasetron plus Metoclopramide; C:Granisetron given a single dosis and D:Ondansetron given in a single dosis) in breast cancer patients receiving Cyclophosphamide, Methotrexate and 5-Fluoracil (CMF) regimen (174 cycles) and Cyclophosphamide, 4-Epiadryamicin and 5-Fluoracil (FEC) regimen (132 cycles). Both, number of emetic episodies (early and delayed emesis) and quality of life were evaluated. In patients receiving CMF there were no differences between regimens A, B and C in controlling early emesis. The single dose Ondansetron regimen (D) showed the worst resuts (p=0.003). Delayed emesis was best controlled by the “3 days-regimens” (A and B). In patients administered a FEC treatment, the antiemetic efficacy was superior for the single Granisetron regimen (C) if early emesis was considered. Moreover, efficacy of single Granisetron dosis (C) was similar to the 3-days Ondansetron regimen (A) in controlling delayed emesis after FEC treatment. The single Ondansetron regimen showed again the worst results (p=0.007). Despite different antiemetic schedules, nausea and emesis are significant problems in patients receiving cyclophosphamide-based chemotherapy.

Ultrastructure of the lesion induced by toxin T-514 isolated from K. humboldtiana in the alveolar region of the lung

It has been shown in previous studies that the toxin T-514 isolated from K. humboldtiana induces severe damage to the lung in treated rodents. Histopathological findings include edema, and alveolar hemorrage. However, the ultraestructure of the lesion has not been investigated. In this study we used two species of rodents: Hamster and guinea pig, and a primate: Macaca fascicularis. Animals received different single dosis of the toxin via intraperitoneal. Control animals received only the vehicle (propylen glycol). Inmediately after spontaneous death, lung samples were fixed in Karnovsky-Ito fixative, post fixed in osmium tetroxide and embedded in epon. Thin sections were prepared with an Ultratome V LKB, stained with uranly acetate and lead citrate, and studied in an electron microscope Zeiss-EM109.

Morphometric investigations on endocrine glands. VIII. Karyometry in epithelial cells of thyroid glands during inhibition of lactation by quinestrol.

Summary A single dosis of 12.5 mg quinestrol per os post partum causes an inhibition of lactation in rats, which is accompanied by an moderate increase of the nuclear volume of the epithelial cells of the thyroid gland.

Dynamics of Excretion of M. avium and M. intracellulare in Faeces of Experimentally Infected Pigs

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アルコール頭位眼振と傾斜刺激

We performed the tilt chair test with 14 healthy volunteers after giving each two single dosis of whisky (42%,70 ml). We then determined their responses after 30min.,90 min. and 12 hours.After 90 min. alcohol intake,12 persons developed a divergent type of positional nystagmus in the first phase, as described by Aschan. However, only two showed any nystagmus with tilt chair. Positional nystagmus induced by alcohol also proved to suppress the onset of nystagmus due to tilt stimulation in the opposite direction.After 12 hours alcohol intake, all of volunteers showing convergent pos i t ional nystagmus had nystagmus as a result of tilting stimulation.

Relation between 15N excretion in feces following oral 15N urea administration and blood urea concentration in relation to raw fiber intake in swine

9 pigs of a live weight at the beginning of the experiment of 33 kg received in 3 consecutive series of experiments (3 animals/group) a basic barley ration of 1.0-1.2 kg per animal and day. In groups 1 to 9 the following supplements were given: 1 = without N-supplement, 2 = 10.5 g urea, 3 = 79 g dried skim milk, 4 = 11 g urea, 5 = without N-supplement, 6 = 110 g horse bean coarse meal, 7 = without N-supplement, 8 = 95 g dried skim milk, 9 = 120 g horse bean coarse meal. In groups 1-6 the ration was supplemented with 150-165 g DM partly hydrolysed straw meal per animal and day. After 20 days the animals received a single dosis of 0.5 g/kg0.75 15N-urea (72.1 atom-% 15N-excess) with the morning meal of the first day of the experiment. During the four days of the experiment groups 1-6, due to the straw meal supplement, excreted significantly higher N-amounts than the corresponding groups 7-9. In comparison with the first day of the experiment (1 h after the morning meal) urea concentration in the blood decreased to the following percentage in the sequence 1-9: 64; 65; 77; 54; 64; 73; 82; 88; 84 on the second day of the experiment (1 h before the evening meal. Between the excretion of 15N-excess in faeces (y = mg) during the four days of the experiment and the concentration of urea in the blood (x = mmol/l) there was the following significant negative correlation: y = -40.1 X +340.(ABSTRACT TRUNCATED AT 250 WORDS)

Melatonin does not alter human serum gondotropin and testosterone levels, but it increases prolactin levels

Administration of the pineal hormone melatonin (MEL) lowers serum gonadotropin (GN) levels, delays sexual maturation and elicits gonadal atrophy in rodents. In humans an antigonadotropic effect of the pineal has been sought for many years. Recently we reported higher nocturnal serum MEL levels in prepubertal children than in young adults. Now we have examined the immediate effects of exogenous MEL on basal levels of various hormones. After giving informed consent 5 healthy, male adolescents received 80 mg oral MEL at 11:00; 3 volunteers received the same dosis at 11:00,12:00 and 13:00. Serum concentrations of MEL, GN, testosterone (T) and prolactin (PRL) were determined at 30-min. intervals several hours prior to, during, and after MEL administration. Though serum MEL concentrations increased at least 1000 times above basal levels GN and T were not altered. PRL rose from 4.6±0.7 (x±SEM) to 7.6±0.9 ng/ml (p<0.005) after MEL application. To examine the effect of the pineal hormone on the pulsatile secretion patterns of GN and PRL, in 2 adolescents sera were taken at 10-min. intervals for 6 hours before and after MEL treatment. The pulstile secretion pattern of GN was not altered by MEL; again, PRL levels were higher after MEL than before. Thus, a single dosis of MEL does not affect serum GN levels in humans, but it increases PRL serum concentrations.

Immunization attempts with lipopolysaccharides (LS) of gram negative microorganisms against lethal action of LS on rat fetus in utero.

SummaryGroups of rats immunized with doses of LS of E. coli or S. marcescens from g.d. 1 to 7 or 7 to 13, and then injected with a single dosis of LS otherwise lethal to the litters, showed 15% to 43% of fetuses surviving. The serum protein of the experimental animals showed the presence of a globulin antibody which was much reduced within 6 hours after the challenging dosis of LS. Sufficient circulating antibodies against the LS, however, were present 6 hours after the challenging dosis was given, demonstrated by agglutinated and hemolyzed sensitized red cells in dilutions of 1:8500.

Nota preliminar sobre o emprego da piperazina no tratamento da ascaridíase das galinhas

The author reports entirely satisfactory results from the administration of piperazine to three groups of chickens experimentally infested with Ascaridia galli Schrank, 1788. The drug was deposited in crop by means of an oesophagie tube either in a single dosis of 0,25 g or in three partitioned dosis of 0,125 g and 0,08 g given in alternate days. In all cases the anthelmintic effect was very evident.

Inhibition of subcortically released spasmodic potentials by beta-hexachlorcyclohexane

Treatment of rabbits with a single dosis ofβ-Hexachlorcyclohexane prevents, for many days, the apparition in the electro-encephalogramm, of seizure potentials induced by electrical stimulation of an epileptogenic brain area, as well as the apparition of Metrazol seizure potentials. The results of the electrical test showed that theβ-component of the Hexachlorcyclohexane acts chiefly by changing the reactivity of definite diencephalic areas (Thalamus).