Observation of anti-damping spin-orbit torques generated by in-plane and out-of-plane spin polarizations in MnPd3.

Large spin-orbit torques (SOTs) generated by topological materials and heavy metals interfaced with ferromagnets are promising for next-generation magnetic memory and logic devices. SOTs generated from y spin originating from spin Hall and Edelstein effects can realize field-free magnetization switching only when the magnetization and spin are collinear. Here we circumvent the above limitation by utilizing unconventional spins generated in a MnPd3 thin film grown on an oxidized silicon substrate. We observe conventional SOT due to y spin, and out-of-plane and in-plane anti-damping-like torques originated from z spin and x spin, respectively, in MnPd3/CoFeB heterostructures. Notably, we have demonstrated complete field-free switching of perpendicular cobalt via out-of-plane anti-damping-like SOT. Density functional theory calculations show that the observed unconventional torques are due to the low symmetry of the (114)-oriented MnPd3 films. Altogether our results provide a path toward realization of a practical spin channel in ultrafast magnetic memory and logic devices.

Social and interpersonal relationship modifications after renal transplant. A statistic and epidemiologic evaluation.

INTRODUCTION: Kidney and liver transplants are the most frequent transplantation procedures carried out in Italy. We report the result of an epidemiological study on kidney transplanted patients resident in the Province of Messina (Italy). METHODS: Seventy-five patients were enrolled between June 2010 march 2011, interviewed and evaluated using an adapted Italian version short-form 36. Socio-economic characteristics, quality of life modifications and involvement in transplant-related charities were studied. The follow-up period was ranging between 52 and 356 months. All subjects gave written informed consent and all results were analysed by chi-square test. RESULTS: No statistically significant differences were found between sexes, social and interpersonal relationship modifications. DISCUSSION: The benefits obtained on quality of life after transplantation is the prerogative of a small percentage of patients and is related to medium and high socio-economic conditions. The possibility of avoiding the haemodialysis represents the primary benefit for the totality of patients.

Mortality risk factors in elderly patients in intensive care without limitation of therapeutic effort. / Factores de riesgo de mortalidad de los pacientes ancianos en cuidados intensivos sin limitación del esfuerzo de tratamiento.

OUTCOME: To determine mortality prognostic factors in elderly patients who are admitted to intensive care units (ICUs) due to acute critical illness. DESIGN: A prospective cohort study was carried out. SETTING: A polyvalent Intensive Care Unit at a University Hospital in Argentina. PATIENTS OR PARTICIPANTS: We included 249 patients over 65years of age who were consecutively admitted to the ICU and required mechanical ventilation for more than 48hours, between January 2011 and December 2012. Patients with degenerative neurological disease, limitation of therapeutic effort or on chronic mechanical ventilation were excluded. PRINCIPAL VARIABLES OF INTEREST: In-hospital mortality, comorbidity (Charlson index), APACHEII score, and pre-acute illness status were recorded: nutritional status (subjective global assessment), functionality (activities of daily living [ADL] and Barthel index), cognitive abilities (Short Reporting Questionnaire on Cognitive Decline in the Elderly [S_IQCODE]) and quality of life (EQ-5D). RESULTS: The in-hospital mortality rate was 52%. Logistic regression analysis, after adjusting for APACHEII score and age, identified the following independent variables associated to mortality: male gender (OR: 2.46, 95%CI: 1.37-4.42), moderate malnutrition (OR: 2.07, 95%CI: 1.09-3.94), severe malnutrition (OR: 2.20, 95%CI: 1.06-4.59), and ADL<6 (OR: 2.35, 95%CI: 1.16-4.75). CONCLUSIONS: In our study, chronological age was not associated to in-hospital mortality. However, loss of functional independence (assessed by ADL) and malnourishment were shown to be strong prognostic factors; knowing these baseline characteristics from ICU admission would be useful when making decisions regarding the intensity of treatment.

Inhibitors of cyclic AMP phosphodiesterase. 2. Structural variations of N-cyclohexyl-N-methyl-4-[(1,2,3,5-tetrahydro- 2-oxoimidazo[2,1-b]quinazolin-7-yl)-oxy]butyramide (RS-82856).

A series of analogues of the cyclic AMP phosphodiesterase (PDE) inhibitor N-cyclohexyl-N-methyl-4-[(1,2,3,5-tetrahydro- 2-oxoimidazo[2,1-b]quinazolin-7-yl)oxy]butyramide (RS-82856, 1) was prepared by systematic variation of the side-chain substituent, length, position, connecting atom, and the parent heterocycle itself. The compounds were evaluated as inhibitors of cyclic AMP phosphodiesterase from both human platelets and rat or dog heart tissue and as inhibitors of ADP-induced platelet aggregation. Structure-activity correlations for the analogue series revealed significant limitations on the steric bulk of substituents on the 1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one heterocycle and the position and length of the side chain. As inhibitors of cyclic AMP phosphodiesterase (PDE), potency steadily increased with increasingly lipophilic side chains. In platelet aggregation inhibition studies, however, a maximum in activity was reached with 1, while more lipophilic compounds were significantly less active. Major changes in the heterocycle itself, represented by isomeric and other carbonyl variations, also decreased activity. The molecular features defined by this series of analogues of 1 correlate to a high degree with current understanding of the chemical and topographical requirements of the active site of the FIII (type IV) form of cyclic AMP PDE. Selective inhibition of this enzyme has been proposed as the principal component of the positive inotropic action of a number of cardiotonic agents.

Topical nonsteroidal antipsoriatic agents. 2. 2,3-(Alkylidenedioxy)naphthalene analogues of lonapalene.

A series of 2,3-(alkylidenedioxy)naphthalene (5a-p) analogues of lonapalene (RS-43179, 1), a 5-lipoxygenase inhibitor currently under clinical investigation for the treatment of psoriasis, has been prepared and evaluated for topical inhibitory activity against arachidonic acid induced mouse ear edema. The results of these studies demonstrate that introduction of the fused 2,3-alkylidenedioxy ring, in place of the acyclic 2,3-dialkoxy substituent pattern characteristic of the previous series, caused a modest dimunition in overall potency within the series. These results suggest a potential steric intolerance for these extended planar analogues, in comparison with their 2,3-dialkoxy predecessors.

Inhibitors of cyclic AMP phosphodiesterase. 3. Synthesis and biological evaluation of pyrido and imidazolyl analogues of 1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazoline.

Hybridization of structural elements of 1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazoline ring system common to the cyclic AMP (cAMP) phosphodiesterase (PDE) inhibitors lixazinone (RS-82856, 1) and anagrelide (3) with complementary features of other PDE inhibitor cardiotonic agents prompted the design and synthesis of the title compounds 7a-d, 11, 12, and 13a,b. The necessary features of these compounds were determined within the framework of the proposed active-site models for the high affinity form of cAMP PDE inhibited by cGMP (type IV). Evaluation of these targets, both in vitro as inhibitors of platelet or cardiac type IV PDE or in vivo as inotropic agents in the pentobarbital-anesthetized dog model of congestive heart failure, showed that these structure possessed negligibly enhanced activities over the parent heterocyclic system, and remained significantly inferior to 1 in all respects. This difference is ascribed to the absence of the N-cyclohexyl-N-methylbutyramidyl-4-oxy side chain of 1. The proposal that the acidic lactam-type functionality, common to the type IV PDE inhibitor inotropic agents such as 4-6 and 8-10, mimics the polarizable cyclic phosphate moiety of cAMP suggested that the side chain of 1 may function as an effective surrogate for selected characteristics of the adenine portion of cAMP. However, the results of this study show that incorporation of adenine-like hydrogen-bonding functionalities common to other type IV PDE inhibitors into the 1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazoline system did not enhance activity to the levels observed for 1 and analogues. These observations, coupled with the kinetic pattern of inhibition of type IV PDE observed for 1 and analogues, suggest that access to a secondary, lipophilic-tolerant binding site, possibly coincident with the adenine binding domain, and adjacent to the catalytic ribose-phosphate binding site of platelet and cardiac type IV PDE, is responsible for the increased potency of these compounds.

Inhibitors of cyclic AMP phosphodiesterase. 1. Analogues of cilostamide and anagrelide.

Evaluation of a series of lactam heterocyclic analogues of cilostamide (2) as inhibitors of cyclic AMP phosphodiesterase derived from both human platelets and rat heart in comparison with their corresponding methoxy-substituted heterocycles has revealed that the N-cyclohexyl-N-methyl-4-oxybutyramide side chain of 2 is an important lipophilic and/or steric pharmacophore. Attachment of this side chain to the parent heterocycle of the potent cyclic AMP phosphodiesterase inhibitor anagrelide (3) afforded the hybrid structure RS-82856 (1), shown to be more potent than either of its progenitors as an inhibitor of cyclic AMP phosphodiesterase or of ADP-induced platelet aggregation. The available in vitro data suggest that 1 possesses potentially useful antithrombotic and cardiotonic properties.

Inhibitors of cyclic AMP phosphodiesterase. 4. Synthesis and evaluation of potential prodrugs of lixazinone (N-cyclohexyl-N-methyl-4-[(1,2,3,5-tetrahydro-2- oxoimidazo[2,1-b]quinazolin-7-yl)-oxy]butyramide, RS-82856).

The cyclic AMP phosphodiesterase (cAMP PDE) inhibitor and cardiotonic agent lixazinone (N-cyclohexyl-N-methyl-4-[(1,2,3,5-tetrahydro-2- oxoimidazo[2,1-b]quinazolin-7-yl)oxy]butyramide, RS-82856, 1) and its acid and base addition salts were found to be insufficiently soluble in formulations suitable for intravenous administration. These results prompted an investigation into potential prodrugs with enhanced aqueous solubility designed to deliver 1 by three distinct mechanisms: (1) decarboxylation of alpha-carboxamides; (2) hydrolytic loss of a solubilizing N-1-(acyloxy)methyl or (N,N-dialkylamino)methyl moiety; or (3) intramolecular closure of a guanidino ester or amide. The target compounds were evaluated as delivery systems for 1 by three criteria: (1) chemical conversion rate to 1 under physiological conditions; (2) inhibition of type IV cAMP PDE at a fixed time point; and (3) in vivo inotropic activity in anesthetized dogs by both intravenous and oral administration. Release of 1 from 4a (series 1) was found to be too slow to be of value as a prodrug of 1, since decarboxylation could be induced only by strong acid, conditions under which hydrolytic ring opening was found to severely compete. Conversely, 1 was released too readily on exposure of (N,N-dialkylamino)methyl derivatives such as 8d (series 2) to physiological conditions, although no large increase in aqueous solubility was realized. Finally, both the physicochemical and in vitro studies indicated that ring closure of the guanidinium esters and amides 17a-k (series 3) to 1 was quantitative and pH- and time-dependent, suggesting the possibility of delivery of the open, water-soluble prodrug form, followed by closure to 1 in plasma. Detailed examination of these agents in vivo, however, demonstrated that only those compounds that rapidly cyclized to 1, as measured by plasma levels of 1, exhibited inotropic activity, indicating that the open prodrug form was not efficiently absorbed upon oral administration.

Topical nonsteroidal antipsoriatic agents. 1. 1,2,3,4-Tetraoxygenated naphthalene derivatives.

On the basis of previous observations that both 2,3-dihydro-2,2,3,3-tetrahydroxy-1,4-naphthoquinone (oxoline, 1) and 6-chloroisonaphthazarin (2) had demonstrated antipsoriatic activity in vivo, a series of structural derivatives of 2 were prepared and examined in the Scholtz-Dumas topical psoriasis bioassay. Of these six (5, 6, 9a, 10, 11a, 11b), the most effective compound was found to be 6-chloro-1,4-diacetoxy-2,3-dimethoxynaphthalene (RS-43179, lonapalene, 11a). An extensive series of 1,2,3,4-tetraoxygenated naphthalenes (16-74) incorporating variations of the ester, ether, and aryl substituents were prepared as analogues of 11a to examine the structural requirements for activity and were screened in vivo as inhibitors of arachidonic acid induced mouse ear edema, a topical bioassay capable of detecting 5-lipoxygenase inhibitors. Net lipophilicity, hydrolytic stability, and ring substitution play significant roles in determining the observed in vivo activity. Lonapalene (11a) is currently in clinical development as a topically applied nonsteroidal antipsoriatic agent.

Kinetics of gelatin transitions with phase separation: T-jump and step-wise DSC study.

The isothermal gelation (or melting) of gelatin after fast cooling (or heating) steps is studied by using high sensitivity differential scanning micro-calorimetry, in order to determine the dependence of the kinetic and thermodynamic parameters upon changes in composition and in temperature. The calorimetric heat flow curves, obtained according to defined temperature profiles, have been fitted with exponential functions (simple exponentials or stretched exponentials for the step-wise and for T-jump experiments, respectively). The gelation process of gelatin alone for t<300 min shows that the characteristic time tau and the fractional exponent are beta very sensitive to the concentration of gelatin chains and to the microscopic phase segregation due to the presence of another polymeric component.

Lanzamiento de un programa de ECMO en un hospital universitario de la Argentina / Launching a program of ECMO in a hospital University of Argentina

El objetivo de este trabajo es describir el proceso para implementar un programa de ECMO en un hospital universitario de Buenos Aires, y transmitir los resultados a los tres años. Se realizó un análisis retrospectivo de 27 pacientes con ECMO desde enero de 2011: once pacientes con síndrome de dificultad respiratoria aguda y 16 postrasplante de pulmón con hipoxemia. La mediana de la edad era de 43 años (rango intercuartil 23-53); la mediana del puntaje APACHE II fue de 19 (rango intercuartil 14-21), la mediana de la PaFi, 100 (rango intercuartil 78-121) y la tasa de mortalidad, del 29%. Estos programas son factibles en la región con el entrenamiento adecuado.(AU)

The aim of this paper is to describe the process to implement an ECMO program at a university hospital in Buenos Aires, and to transmit the results after three years. A retrospective analysis of 27 patients with ECMO from January 2011 was performed, this includes patients with acute respiratory distress syndrome (n=11) and lung transplantation with hypoxemia (n=16). Patients had a median age of 43 years (IQR: 23-53), with a median APACHE II score of 19 (IQR: 14-21), a median PAFI of 100 (IQR: 78-121) and the mortality rate was 29%. These programs are feasible in the region with the right training.(AU)

Electrochemical evaluation of the interaction between ascorbic acid and the cardiotonic drug RS-82856.

The solution phase interaction between ascorbic acid and the cardiotonic drug N-cyclohexyl-N-methyl-4(7-oxy 1,2,3,5-tetrahydroimidazol[2,1-b] quinazolin-2-one butyramide (RS-82856) was evaluated using a differential pulse voltammetric technique. Shifts in the peak potential of ascorbic acid to higher energy as well as decreases in peak current values were monitored as a function of RS-82856 concentration. The electrochemical data were obtained under conditions where both the drug and the ascorbic acid concentrations exhibited linear relationships with peak current values. The methodology was extended to the study of two other structurally related phosphodiesterase inhibitors cilostamide and anagrelide. The complexation of these drugs with ascorbic acid were also characterized by decreases in the diffusion currents of ascorbic acid as well as by anodic shifts in the peak potential. The significance of these observations may be related to the inhibition of cyclic nucleotide phosphodiesterase activity by both the drugs tested and the ascorbic acid.

Synthesis and biological evaluation of omega-(N,N,N-trialkylammonium)alkyl esters and thioesters of carboxylic acid nonsteroidal antiinflammatory agents.

A series of novel omega-(N,N,N-trialkylammonium)alkyl ester and thioester derivatives [RCOM(CH2)nNR3+ X-, M = O or S. n = 2-6, X = I or Cl] of 11 nonsteroidal antiinflammatory carboxylic acid agents (naproxen, ketorolac, indomethacin, ibuprofen, sulindac, ketoprofen, flufenamic acid, mefenamic acid, zomepirac, etodolac, and tifurac) was prepared and evaluated for their antiinflammatory, analgesic, and gastrointestinal erosive properties. In general, each prodrug retained the antiinflammatory activity characteristic of the corresponding parent drug but exhibited moderately to greatly reduced gastrointestinal erosive properties and significantly reduced analgetic potencies. This profile is likely due to a combination of factors including the rate of hydrolysis of the esters in the stomach, gut, and plasma, changes in the locus of absorption of the prodrug or nonsteroidal antiinflammatory drug (NSAID), and altered metabolic disposition patterns resulting from these changes. The results obtained from the compounds of this series indicate that esters of this general class may offer a means to modulate both the aqueous/lipid solubility and the hydrolytic/enzymatic cleavage indices of NSAID prodrugs which potentially possess a more favorable therapeutic ratio of antiinflammatory to gastrointestinal erosive activities.

Pharmacokinetic studies of cefuroxime in patients with liver cirrhosis.

Blood levels and urinary excretion of 6R,7R-3-carbamoyloxy-methyl-7-(2Z)-2-methoxyimino-(fur-2-yl)-acetamido-ceph-3-em-4-carboxylate sodium salt (cefuroxime) were determined in cirrhotic patients without ascites and in healthy volunteers after an i.m. injection of 750 mg and an i.v. injection of 1 g. An average peak serum level of 23.9 micrograms/ml in the case of cirrhotic patients and 22.5 micrograms/ml in the case of volunteers was reached 0.5 h after the i.m. dose, followed by a gradual decrease. An average serum level of 78.8 micrograms/ml in the case of cirrhotic patients was obtained 5 min after i.v. injection. During the first 6 h after administration of the 750 mg i.m. dose and the first 4 h after the administration of the 1 g i.v. dose, 90% of the administered dose were excreted in the urine, in the case of both cirrhotic patients and volunteers. These results show that the pharmacokinetic features of cefuroxime are not affected in cirrhotic patients without ascites; therefore the antibiotic is particularly suitable for acute infections in hospital, and also for cirrhotic patients without ascites without any difference in the dosage.

Oral and intravenous pharmacokinetics of cimetidine in liver cirrhosis.

The bioavailability of p.o. and i.v. cimetidine was studied in 12 patients with compensated liver cirrhosis in a crossover study. Single doses of 200 and 400 mg cimetidine were used for both administration routes. Plasma concentration and urinary recovery were determined by the HPLC method. The pharmacokinetic data observed in these patients do not differ from those of normal subjects and patients. A positive correlation between AUC and cimetidine oral dose was found. Oral bioavailability of cimetidine was about 94% compared to that of the i.v. route. The p.o. dose of 400 mg produced AUC values similar to the i.v. dose of 400 mg. After 400 mg cimetidine p.o. the mean peak plasma level was higher and the time for which plasma levels remained above 0.5 mg/l was longer. There were no significant differences between plasma cimetidine levels after the intravenous administration of 200 and 400 mg. The urinary recovery of cimetidine was significantly higher after intravenous administration independently of the given dose. The pharmacokinetics of cimetidine does not appear to be altered in liver cirrhosis.

Biliary excretion of simultaneously administered bilirubin and chenodeoxycholic acid in rats.

Crystalline bilirubin and chenodeoxycholic acid were administered intravenously and intraduodenally respectively in 19 anesthetized Sprague-Dawley rats in order to verify whether there exists an interference between their biliary excretion. When these two compounds were administered together, the biliary excretion of bilirubin and bile salts was significantly reduced the conjugation of bilirubin was not impaired while bile flow remained constant during the whole exerpimental period. These data seem to indicate a mutual interference between chenodeoxycholic and bilirubin metabolisms. It could be admitted that the excretory step is involved in determining the observed modifications.

Biliary excretion of simulateously administered bilirubin and chenodeoxycholic acid in rats with porta-caval shunt.

Portacaval shunting influences several metabolic processes of the liver. The aim of this work was to investigate whether bile salts and bilirubin reciprocally interfere with their biliary excretion in this experimental condition. 12 male Sprague-Dawley porta-caval shunted rats received simultaneously crystalline bilirubin (intravenously) and chenodeoxycholic acid (intraduodenally) 20-26 days after intervention. The biliary excretion of these two compounds was then studied. The results seem to indicate that there exists a mutual interference between bile salt and bilirubin excretion in the bile; moreover it is suggested that porta-caval shunting plays a secondary role in determining the observed interaction between bilirubin and bile salts metabolism in the liver.