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Resumen Introducción: La duodeno pancreatectomía cefálica es una operación compleja cuyos resultados a corto plazo son multifactoriales. Objetivo: Evaluar el impacto de la curva de aprendizaje en los resultados a corto plazo de la duodenopancreatectomía cefálica en un hospital de nivel II. Materiales y Método: Se analizaron los datos obtenidos a partir de una base de datos mantenida prospectivamente desde 2005. Se definieron dos periodos de tiempo: de 2005 a 2011 y de 2012 a 2017. Se compararon la morbilidad, mortalidad y estancia postoperatoria de ambos períodos. Resultados: Durante el período de tiempo estudiado se hicieron 126 duodenopancreatectomías cefálicas, 61 durante la primera etapa y 65 durante la segunda. La tasa de transfusión intraoperatoria se redujo de 33% a 15% (p = 0,011). La tasa de transfusión postoperatoria se redujo de 39 a 23% (p = 0,021). No hubo diferencias significativas con respecto a la incidencia global de complicaciones postoperatorias (59% y 52,3%). La incidencia de abscesos intraabdominales fue significativamente menor en el segundo período (18% y 4,6%, respectivamente; p = 0,038). La tasa de reintervenciones se redujo significativamente, de 22% a 9% (p = 0,049). También se redujo significativamente la tasa de mortalidad, de 6,56% a 0% (p = 0,032). La estancia media postoperatoria disminuyó significativamente en el segundo período, pasando de 19,6 a 15,8 días (p = 0,001), con una mayor proporción de pacientes dados de alta en los 8 primeros días de postoperatorio (11,5% y 38,5%, respectivamente; p = 0,001). Conclusión: La curva de aprendizaje es un factor que permite mejorar los resultados de la duodenopancreatectomía cefálica, en un hospital de nivel II, hasta alcanzar valores similares a los de un hospital de nivel III.

Introduction: The duodenum pancreatectomy cephalic is a complex operation whose short-term results are multifactorial. Aim: To assess the impact of the learning curve on the short-term outcomes of cephalic duodenopancreatectomy at a level II hospital. Materials Method: We analyze the data obtained from a database maintained prospectively since 2005. Two time periods were defined: from 2005 to 2011 and from 2012 to 2017. The morbidity, mortality and postoperative stay of both periods were compared. Results: 126 cephalic duodenopancreatectomies were performed, 61 during the first period and 65 during the second. The intraoperative transfusion rate was reduced from 33% to 15% (p = 0.011). The postoperative transfusion rate was reduced from 39 to 23% (p = 0.021). There were no significant differences with respect to the overall incidence of postoperative complications (59% and 52.3%, respectively). However, the incidence of intra-abdominal abscesses was significantly lower in the second period (18% and 4.6%, respectively, p = 0.038). The rate of reoperations was significantly reduced, from 22% to 9% (p = 0.049). The mortality rate was also significantly reduced, from 6.56% to 0% (p = 0.032). The mean postoperative stay decreased significantly in the second period, from 19.6 to 15.8 days (p = 0.001), with a higher proportion of patients discharged in the first 8 postoperative days (11.5% and 38.5%, respectively, p = 0.001). Conclusion: The learning curve is a factor allows improving the results of cephalic pancreaticoduodenectomy, in a level II hospital, until reaching values similar to those of a level III hospital.

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PURPOSE: Current evidence suggests the need to improve the management of breakthrough cancer pain (BTcP). For this reason, we aimed to assess the opinion of a panel of experts composed exclusively of physicians from pain units, who play a major role in BTcP diagnosis and treatment, regarding the key aspects of BTcP management. METHODS: An ad hoc questionnaire was developed to collect real-world data on the management of BTcP. The questionnaire had 5 parts: (a) organizational aspects of pain units (n = 12), (b) definition and diagnosis (n = 3), (c) screening (n = 3), (d) treatment (n = 8), and (e) follow-up (n = 7). RESULTS: A total of 89 pain-unit physicians from 13 different Spanish regions were polled. Most of them agreed on the traditional definition of BTcP (78.9%) and the key features of BTcP (92.1%). However, only 30.3% of participants used the Davies' algorithm for BTcP diagnosis. Respondents preferred to prescribe rapid-onset opioids [mean 77.0% (SD 26.7%)], and most recommended transmucosal fentanyl formulations as the first option for BTcP. There was also considerable agreement (77.5%) on the need for early follow-up (48-72 h) after treatment initiation. Finally, 65.2% of participants believed that more than 10% of their patients underused rapid-onset opioids. CONCLUSIONS: There was broad agreement among pain experts on many important areas of BTcP management, except for the diagnostic method. Pain-unit physicians suggest that rapid-onset opioids may be underused by BTcP patients in Spain, an important issue that need to be evaluated in future studies.

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Certain gangliosides are tumor-associated antigens that constitute potential targets for cancer immunotherapy. A major drawback in the design of ganglioside-based cancer vaccines, however, is the poor immunogenicity of these glycolipids. Here we report the immunological and physicochemical properties of very small size proteoliposomes (VSSP) obtained by using anionic detergents to incorporate gangliosides into the outer membrane protein complex (OMPC) of N. meningitidis. VSSP of three different gangliosides, GM3, NGcGM3 and GD3, were tested. These gangliosides differ in level of expression in normal tissues and in immunogenicity in different animal species. We show that the immunization with VSSP in an oil adjuvant consistently induced both IgM and IgG anti-ganglioside antibodies. In the mouse, the anti-ganglioside IgG fraction was not restricted to the typical T-independent isotype IgG3. Unexpectedly, significant levels of the T-dependent IgG1, IgG2a and particularly IgG2b were also found. VSSP-mediated enhancement of the immunogenicity was not restricted to the relatively immunogenic ganglioside GD3, satisfactory immune responses against highly tolerated GM3 and NGcGM3 were also obtained. Similar results were achieved in chickens and monkeys. No reactogenicity was observed even when self-gangliosides were used for immunization. VSSP overcame natural tolerance to gangliosides in an adjuvant dependent fashion.

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A double-blind trial was carried out to determine the effect of zolpidem or a placebo on sleep in two groups of insomniac patients with a diagnosis of moderate chronic primary insomnia. Zolpidem was given at a daily dose of 10 mg for 27 nights and was preceded (two nights) and followed (three nights) by a placebo. Zolpidem induced a significant increase of total sleep time, while total wake time and wake time after sleep onset were reduced. Values corresponding to stage 2 sleep were augmented, while stage 3 sleep and REM sleep showed no significant changes. Tolerance did not develop during the zolpidem administration period, and rebound insomnia did not show following abrupt interruption of drug administration. In addition, patients on zolpidem had a more peaceful sleep with no decrement of levels of alertness.

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The polymorphic oxidative metabolism of debrisoquine and sparteine were discovered in the seventies by Mahgoub and Eichelbaum. Since then, many other therapeutic substances were added and one of these drugs is dextromethorphan. The object of this investigation was to ascertain the distribution of the oxidative phenotype of dextromethorphan in the Uruguayan population. The drug and its metabolite, dextrorphan, were quantified in the urine of 165 healthy volunteers by modification of an HPLC method by Chen et al. The metabolic ration was calculated and frequency distribution histograms were drawn. By inspection of the histogram two antimodes can be assigned which determine three sub-populations: on one side the fast extensive metabolizers (n = 30, 18.2%), in the middle the extensive metabolizers (n = 123, 74.5%) and on the other extreme of the histogram the slow metabolizers (n = 12, 7.3%). No other studies have confirmed thus far this trimodal distribution. This research will be continued by genotyping the populations studied in order to confirm these findings and to elucidate the underlying genetic mechanisms of the polymorphism.

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A double blind cross-over design trial was carried out to investigate the effect of simultaneous administration of alcohol (0.5 g/kg) and ritanserin (10 mg) on biological and behavioral functioning. Twenty healthy volunteers were selected to participate in the study. To assess the effect of treatments the following evaluations were performed: psychomotor tests, vital signs, intoxication, euphoria, and mood. In addition, ritanserin and alcohol plasma concentration were measured. Psychomotor performance and vital signs during the ritanserin session did not differ significantly from the placebo session. Similar results were obtained in regard to alcohol intoxication, euphoria, and mood, except for tiredness and alertness, which were significantly different compared to placebo. Differences in blood alcohol concentration between the ritanserin and the placebo sessions did not attain significance. Plasma ritanserin concentration was 143 ng/ml 1 h after alcohol administration and decayed to 53 ng/ml 6 h after alcohol consumption in the active treatment session. Our findings tend to indicate that ritanserin neither enhances the central nervous system depressant effect of alcohol nor produces a pharmacokinetic interaction during acute alcohol ingestion.

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Ritanserin is a thymosthenic agent with an extensive hepatic metabolism and long elimination half life in healthy volunteers. It has been used in abstinent chronic alcoholic patients showing an interesting performance in this condition. Ritanserin pharmacokinetics has only been evaluated in single dose healthy volunteer studies and, on the other hand, chronic use of the drug in alcoholic patients during withdrawal period could be anticipated. Therefore, the objective of the present study, is to assess the cumulating kinetics of the serotonin antagonist during chronic administration. Ten abstinent alcoholic patients were included in an open study. The drug was administered at a daily dose of 10 mg for 28 days and the active phase was preceded by a seven-day wash out period with placebo. Blood samples were taken on the 1st, and 28th, day of treatment, 24 hours after taking the drug. Urine samples were taken during the night before the second and 28th dose. Plasma and urine ritanserin concentration was measured by high performance liquid chromatography. Very large variations in initial and steady state concentrations (CV = 65 and 52% respectively) were found, which is reflected in the large variability of the calculated pharmacokinetic parameters. Ritanserin cumulation factor (R) was 6.9 +/- 8.3 (mean+SEM). Two patients showing extensive accumulation had prolonged elimination half lives (433 and 279 hours) that are explained mostly by an expansion of the volume of distribution and, to a lesser extent, by diminished clearance.

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Ritanserin is a thymosthenic agent with an extensive hepatic metabolism and long elimination half life in healthy volunteers. It has been used in abstinent chronic alcoholic patients showing an interesting performance in this condition. Ritanserin pharmacokinetics has only been evaluated in single dose healthy volunteer studies and, on the other hand, chronic use of the drug in alcoholic patients during withdrawal period could be anticipated. Therefore, the objective of the present study, is to assess the cumulating kinetics of the serotonin antagonist during chronic administration. Ten abstinent alcoholic patients were included in an open study. The drug was administered at a daily dose of 10 mg for 28 days and the active phase was preceded by a seven-day wash out period with placebo. Blood samples were taken on the 1st, and 28th, day of treatment, 24 hours after taking the drug. Urine samples were taken during the night before the second and 28th dose. Plasma and urine ritanserin concentration was measured by high performance liquid chromatography. Very large variations in initial and steady state concentrations (CV = 65 and 52

respectively) were found, which is reflected in the large variability of the calculated pharmacokinetic parameters. Ritanserin cumulation factor (R) was 6.9 +/- 8.3 (mean+SEM). Two patients showing extensive accumulation had prolonged elimination half lives (433 and 279 hours) that are explained mostly by an expansion of the volume of distribution and, to a lesser extent, by diminished clearance.

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Glutathione (GSH) combines with several xenobiotics and its electrophilic metabolites enhancing their elimination in bile and urine. Thus protects cells by preventing binding of these labile intermediary with vital molecules. Some individuals may be susceptible to this deleterious effect according to the intracellular GSHB concentration. In the present study we intend to determine the extent and nature of interindividual variation of human lymphocyte glutathion contents, after oxidative stress with paracetamol. Intracellular basal GSH was measured after one hour of incubation in a cell culture medium additioned with rat liver microsomes and NADPH at 37 degrees C. Each time two batches of lymphocytes were measured in parallel, one without paracetamol (basal) and the other with paracetamol (paracetamol-depleted). In 90 normal adult Caucasians, mean basal GSH concentration of lymphocytes (22.3 mumol/10(7) cells) were higher than in a comparable group of 20 Chinese (19.1 mumol/10(7) cells) or 20 Blacks (17.9 mumol/10(7) cells) subjects. Paracetamol treated lymphocytes were depleted of GSH at the same rate in each group, thus the same differences seen in basal conditions persist post oxidative stress. Probit analysis of values for each ethnic group revealed only a single mode. In otherwise normal Caucasians males with Down's syndrome, mean basal GSH concentration (29.7 mumol/10(7) cells) were higher than those of Caucasians, Chinese and Blacks.

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Glutathione (GSH) combines with several xenobiotics and its electrophilic metabolites enhancing their elimination in bile and urine. Thus protects cells by preventing binding of these labile intermediary with vital molecules. Some individuals may be susceptible to this deleterious effect according to the intracellular GSHB concentration. In the present study we intend to determine the extent and nature of interindividual variation of human lymphocyte glutathion contents, after oxidative stress with paracetamol. Intracellular basal GSH was measured after one hour of incubation in a cell culture medium additioned with rat liver microsomes and NADPH at 37 degrees C. Each time two batches of lymphocytes were measured in parallel, one without paracetamol (basal) and the other with paracetamol (paracetamol-depleted). In 90 normal adult Caucasians, mean basal GSH concentration of lymphocytes (22.3 mumol/10(7) cells) were higher than in a comparable group of 20 Chinese (19.1 mumol/10(7) cells) or 20 Blacks (17.9 mumol/10(7) cells) subjects. Paracetamol treated lymphocytes were depleted of GSH at the same rate in each group, thus the same differences seen in basal conditions persist post oxidative stress. Probit analysis of values for each ethnic group revealed only a single mode. In otherwise normal Caucasians males with Downs syndrome, mean basal GSH concentration (29.7 mumol/10(7) cells) were higher than those of Caucasians, Chinese and Blacks.

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A trial was carried out to determine the effect of ritanserin or a placebo on sleep and mood in two groups of abstinent alcoholic patients. Their condition was characterized by both alcohol dependence and dysthymia, associated with a personality disorder. They were included in the study after 30 days of sobriety. Ritanserin was given at a daily dose of 10 mg for 28 days and was preceded (10 days) and followed (2 days) by a placebo. Plasma ritanserin concentration after administration of the 28th dose was higher than after the first dose. Peak levels of ritanserin from the first to the 28th dose increased approximately three-fold. In the ritanserin group there was a reduction of total waking time. Total sleep time increase was associated with significantly larger amounts of nonrapid eye movement sleep. Slow wave sleep and rapid eye movement sleep (in minutes or as a percent of total sleep time) were not significantly modified. Patients on ritanserin achieved a progressive improvement of their dysthymia. As compared to the placebo group, a statistically significant decrease of the Hamilton Rating Scale for Depression and Hamilton Rating Scale for Anxiety was found in the ritanserin group after 1 week of treatment. The absence of an effect in the placebo-treated group suggests that the clinical response and sleep improvement were mainly related to ritanserin administration.

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Diclofenac and nimesulide are non-steroidal antiinflammatory agents advocated for use in painful and inflammatory rheumatic and certain non rheumatic conditions. In Uruguay, these drugs are administered in doses of 100 mg and 200 mg once a day, respectively. Diclofenac is an effective and safe analgesic and antiinflammatory drug. There are scarce data available on the pharmacokinetic profile of nimesulide. These facts encouraged us to undertake the present study on clinical efficacy, tolerance and pharmacokinetics of nimesulide, controlled with sustained release diclofenac. Twenty patients with osteoarthritis, stage II-III, according to a clinical-radiological evaluation, were selected for the study. Patients were assigned at random to treatment A (Voltaren sustained release, 100 mg) or B (Nodo regular formulation, 200 mg) once a day. A double blind study with active drug and controlled parallel groups was designed. After a washout period of one week patients were treated with active medication during 84 days, and clinical controls every 14 days ensued. Experienced rheumatologists assessed pain and other clinical symptoms. Blood samples were drawn on days 7, 49 and 91 of the study, ten hours after the morning dose, and plasma diclofenac and nimesulide concentrations were measured. On day 7 and 91, blood counts and biochemical laboratory studies were performed (namely, hemoglobin, RBC, WBC, leucocyte differential count, platelet count, alkaline phosphatase, ASAT, ALAT, creatinine, etc.) Already two weeks after the study had begun, significant improvements in clinical parameters assessed were seen for both treatments. A trend to accumulation of diclofenac and nimesulide along the three months of treatment was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

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El diclofenac (liberación sostenida) y la nimesulida (fórmula convencional) son dos antiinflamatorios no esteroideos cuya dosificación es de un comprimido diario en nuestro país. Las escasas referencias en relación a la farmacocinética y duración de la acción de la nimesulida en pacientes añosos nos indujeron a diseñar el presente estudio controlado con diclofenac. Se selecionaron 20 pacientes con gonartrosis grado II-III asignándoles al azar el tratamiento A (diclofenac, liberación controlada 100mg) o B (nimesulida, presentación convencional 200mg). El estudio se desorrolló de acuerdo a un diseño doble ciego con grupos paralelos. Luego de un lavado de 7 días se comenzó con la medicación activa durante 84 días. Cada 14 días se evaluaron el dolor y otros parámetros clínicos. Se tomaron muestras de sangre los días 7, 49 y 91 a las 10 horas de la toma matutina para medir la concentración de los fármacos en plasma. Se realizaron exámenes de laboratório y al final del estudio. Ya a las dos semanas de comenzado el estudio se constataron mejorías estadísticamente significativas para los parámetros clínicos evaluados, que se mantuvieron durante todo el ensayo, en ambos tratamientos. El diclofenac y la nimesulida aumentaron su concentración plasmática durante los tres meses de estudio y se constató una aparente correlación lineal entre algunos parámetros clínicos y los niveles plasmáticos de los fármacos. La tolerancia, los exámenes de laboratório, y la apreciación clínica global del médico y del paciente para ambos grupos no mostraron diferencias estadísticamente significativas

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Diclofenac and nimesulide are non-steroidal antiinflammatory agents advocated for use in painful and inflammatory rheumatic and certain non rheumatic conditions. In Uruguay, these drugs are administered in doses of 100 mg and 200 mg once a day, respectively. Diclofenac is an effective and safe analgesic and antiinflammatory drug. There are scarce data available on the pharmacokinetic profile of nimesulide. These facts encouraged us to undertake the present study on clinical efficacy, tolerance and pharmacokinetics of nimesulide, controlled with sustained release diclofenac. Twenty patients with osteoarthritis, stage II-III, according to a clinical-radiological evaluation, were selected for the study. Patients were assigned at random to treatment A (Voltaren sustained release, 100 mg) or B (Nodo regular formulation, 200 mg) once a day. A double blind study with active drug and controlled parallel groups was designed. After a washout period of one week patients were treated with active medication during 84 days, and clinical controls every 14 days ensued. Experienced rheumatologists assessed pain and other clinical symptoms. Blood samples were drawn on days 7, 49 and 91 of the study, ten hours after the morning dose, and plasma diclofenac and nimesulide concentrations were measured. On day 7 and 91, blood counts and biochemical laboratory studies were performed (namely, hemoglobin, RBC, WBC, leucocyte differential count, platelet count, alkaline phosphatase, ASAT, ALAT, creatinine, etc.) Already two weeks after the study had begun, significant improvements in clinical parameters assessed were seen for both treatments. A trend to accumulation of diclofenac and nimesulide along the three months of treatment was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

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El diclofenac (liberación sostenida) y la nimesulida (fórmula convencional) son dos antiinflamatorios no esteroideos cuya dosificación es de un comprimido diario en nuestro país. Las escasas referencias en relación a la farmacocinética y duración de la acción de la nimesulida en pacientes añosos nos indujeron a diseñar el presente estudio controlado con diclofenac. Se selecionaron 20 pacientes con gonartrosis grado II-III asignándoles al azar el tratamiento A (diclofenac, liberación controlada 100mg) o B (nimesulida, presentación convencional 200mg). El estudio se desorrolló de acuerdo a un diseño doble ciego con grupos paralelos. Luego de un lavado de 7 días se comenzó con la medicación activa durante 84 días. Cada 14 días se evaluaron el dolor y otros parámetros clínicos. Se tomaron muestras de sangre los días 7, 49 y 91 a las 10 horas de la toma matutina para medir la concentración de los fármacos en plasma. Se realizaron exámenes de laboratório y al final del estudio. Ya a las dos semanas de comenzado el estudio se constataron mejorías estadísticamente significativas para los parámetros clínicos evaluados, que se mantuvieron durante todo el ensayo, en ambos tratamientos. El diclofenac y la nimesulida aumentaron su concentración plasmática durante los tres meses de estudio y se constató una aparente correlación lineal entre algunos parámetros clínicos y los niveles plasmáticos de los fármacos. La tolerancia, los exámenes de laboratório, y la apreciación clínica global del médico y del paciente para ambos grupos no mostraron diferencias estadísticamente significativas (AU)

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