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Placental ABCB1 plays an important role in fetal protection against xenobiotics in the maternal circulation. Limited evidence indicates that glucocorticoids regulate ABCB1 expression in other tissues. Since approximately 10% of pregnant women are treated with synthetic glucocorticoids for threatened preterm labour, the effects of synthetic glucocorticoids on placental ABCB1 are important. We hypothesized that placental levels of ABCB1 are reduced in late gestation in the guinea pig and that synthetic glucocorticoids downregulate ABCB1 production. There was a significant decrease in placental Abcbl mRNA expression in late gestation. Treatment of guinea pigs with betamethasone (1 mg/kg) on gestational days 40/41 and 50/51 resulted in a significant decrease in placental Abcbl mRNA and protein expression. No sex differences were observed. Understanding the regulation of ABCB1 function will facilitate the development of treatment strategies for human fetal protection against maternally derived endobiotics and xenobiotics. Key words: multidrug resistance phosphoglycoprotein, guinea pig, placenta, developmental changes, betamethasone, fetal protection. L'ABCB1 placentaire joue un role important dans la protection du foetus contre les xeenobiotiques dans la circulation maternelle. Un nombre limite de resultats indiquent que les glucocorticoides regulent l'expression de l'ABCB1 dans d'autres tissus. Comme approximativement 10 % des femmes enceintes sont traitees avec un glucocorticoide synthetique devant la menace d'un accouchement premature;, il est important de connaitre les effets des glucocorticoides synthetiques sur l'ABCB1 placentaire. Nous avons eemis l'hypothese qu'il y a une diminution de l'expression placentaire d'ACBC1 a l'approche du terme chez les cobayes et que les glucocorticoides synthetiques diminuent l'expression de l'ABCB1. Il y a eu une diminution significative de l'expression de l'ARNm du gene Abcbl placentaire a l'approche du terme. Le traitement des cobayes a l'aide de betamethasone (1 mg/kg) les jours 40/41 et 50/51 de la gestation a cause une diminution significative de l'expression d'Abcbl aux niveaux proteine et ARNm. Aucune difference lieee au sexe n'a ete observee. La comprehension de la regulation de la fonction d'ABCB1 facilitera la mise au point de strategies therapeutiques visant a proteger le foetus humain contre les endobiotiques et les xeenobiotiques dans la circulation maternelle. Mots-cles: phosohoglycoproteine multiresistante, cobaye, placenta, modifications du deeveloppement, betamethasone, protection du fotus. [Traduit par la Redaction] 10.1139/Y09-087, Introduction The placenta plays a critical role in sustaining normal growth and development of the fetus. The site of exchange of essential nutrients occurs within a continuous layer of specialized [...]

Chronic apoptosis activation may participate in abdominal aortic aneurysm (AAA) expansion. Statin treatment slows AAA progression independent of cholesterol lowering. We hypothesized that Atorvastatin treatment alters apoptosis protein expression and activation in AAAs. Protein was isolated from the central and distal portions of end-stage human AAA tissue obtained during surgical repair from non-statin (NST) and Atorvastatin-treated (AT) patients. Expression was compared using immunoblots. Bcl-2 expression was unchanged but Bak (4-fold, p < 0.013) and Bax (3-fold, p < 0.035) expression was increased in AT (n = 12) versus NST (n = 15) patients. No cytochrome c release or caspase 3 activation was detected and Clusterin, GRP78, and BNIP1 expression was similar in NST and AT samples. Bcl-2 and Bax cDNA sequences from AAA tissue (n = 10) and the general population were identical. Thus, the increase in Bax and Bak in ATtreated AAAs did not activate the mitochondria or endoplasmic reticulum mediated apoptosis pathways. Bcl-2, Bax, and Bak have non-apoptosis related functions that include maintenance of endoplasmic reticulum (ER), homeostasis, and adaptation to stress. We speculate that Atorvastatin-mediated increases in Bax and Bak may positively affect their non-apotosis related cell functions to account for the beneficial effect of statins to slow AAA expansion. Key words: atorvastatin, apoptosis, abdominal aortic aneurysm, Bcl-2, Bax, Bak. L'activation chronique de l'apoptose pourrait contribuer a l'expansion des anevrismes aortiques abdominaux (AAA). Un traitement au moyen de statines ralentit la progression des AAA, independamment de l'abaissement du cholesterol. Nous avons emis l'hypothese qu'un traitement par atorvastatine modifie l'expression des proteines apoptotiques ainsi que l'activation des AAA. Nous avons isole des proteines des portions centrale et distale d'AAA en stade avancee, obtenues au cours de chirurgie sur des patients ne prenant pas de statines (NST) et des patients traitesa l'atorvastatine (AT). Nous avons compare; l'expression des proteines par immunobuvardage. L'expression de Bcl-2 est demeuree inchangee, mais celles de Bak (facteur 4, p < 0,013) et de Bax (facteur 3, p < 0,035) ont augmente chez les patients traitesa l'atorvastatine (n = 12) par comparaison a celles des patients non traites aux statines (n = 15). La liberation du cytochrome c ou l'activation de la caspase 3 n'ont pas eetee detectes, et l'expression de la clusterine, de GRP78 et de BNIPI a ete similaire dans les echantillons des patients NST et AT. Les sequences d'ADNc de Blc-2 et de Bax des tissus AAA (n = 10) et de la population geenerale ont ete identiques. Ainsi, l'augmentation de Bax et de Bak dans les AAA traites par l'AT n'a pas active; les voies apoptotiques vehiculees par les mitochondries ou le reticulum endoplasmique. Bcl-2, Bax et Bak ont des fonctions non apoptotiques qui comprennent le maintien du reticulum endoplasmique (RE), l'homeeostasie et l'adaptation au stress. Nous supposons que les augmentations de Bax et de Bak vehiculeees par l'atorvastatine pourraient avoir un effet positif sur leurs fonctions cellulaires non apoptotiques, expliquant l'effet benefique des statines sur la lente progression des AAA. Mots-cles: atorvastatine, apoptose, aneevrisme de l'aorte abdominale, Blc-2, Bax, Bak. [Traduit par la Redaction] 10.1139/Y09-085, Introduction Abdominal aortic aneurysm (AAA) formation is silent and takes decades to develop. Hypercholesterolemia is a major risk factor promoting AAA progression (Golledge et al. 2006; Annambhotla et al. 2008). [...]

We investigated the effects of the centrally acting antitussives dextromethorphan and cloperastine on urinary bladder dysfunction 24 h after cerebral infarction in rats using the cystometry technique. First, cystometrography was performed in conscious male Sprague-Dawley rats. Cerebral infarction was then induced by occlusion of the left middle cerebral artery. Twenty-four hours after cerebral infarction, the effect of each drug on micturition disorder was estimated for 5 parameters: bladder capacity, maximum voiding pressure, micturition latency, flow rate, and urethral resistance. Cerebral infarction markedly reduced bladder capacity, micturition latency, and flow rate and increased urethral resistance. After cerebral infarction, intravenous dosing of saline had no effect on these parameters. Dextromethorphan (20 mg/kg) and cloperastine (2.5 and 5.0 mg/kg) at antitussive effective doses significantly increased bladder capacity and micturition latency. Unlike dextromethorphan, cloperastine ameliorated decreases in flow rate and increases in urethral resistance caused by cerebral infarction. These results suggest that cloperastine may have therapeutic value for the treatment of disorders of the micturition reflex associated with cerebral infarction, and that the drug may become a base compound from which to develop more active drugs for such disorders. Key words: disorders of micturition reflex, cerebral infarction, cystometry, cloperastine, dextromethorphan, conscious, rat. Nous avons examine; par la technique de cystomeetrie les effets des antitussifs d'action centrale, dextromethorphane et cloperastine, sur la dysfonction du canal urinaire 24 h apres un infarctus cerebral chez des rats. Nous avons d'abord effectuee une cystometrographie chez des rats Sprague-Dawley males conscients, puis nous avons induit un infarctus cerebral par l'occlusion de l'artere cerebrale moyenne gauche. Vingt-quatre heures apres l'induction de l'infarctus, nous avons e value l'effet de chaque medicament sur le trouble mictionnel, en considerant les 5 parametres suivants : capacite vesicale, pression de miction, latence mictionnelle, debit et resistance uretrale. L'infarctus cerebral a significativement reduit la capacite vesicale, la latence mictionnelle et le debit, et augmente la resistance uretrale. Apres l'infarctus cerebral, l'administration d'une solution saline par voie intraveineuse n'a pas eu d'effet sur ces parametres. Le dextromethorphane (20 mg/kg) et la cloperastine (2,5 et 5,0 mg/kg), aux doses antitussives efficaces, ont augmente considerablement la capacite vesicale et la latence mictionnelle. Contrairement au dextromethorphane, la cloperastine a attenue les diminutions du debit et les augmentations de la resistance uretrale causees par l'infarctus. Ces resultats donnent a penser que la cloperastine pourrait avoir une valeur theerapeutique en ce qui concerne le traitement des troubles du reflexe mictionnel associesa l'infarctus cerebral et qu'elle pourrait devenir un compose; de base pour la mise au point de medicaments de plus grande efficacite;. Mots-cles: troubles du reflexe mictionnel, infarctus cerebral, cystometrie, clopeerastine, dextromethorphane, conscient, rat. [Traduit par la Redaction], Introduction Diseases in the central nervous system such as cerebral infarction and Parkinsonism are often associated with disorders of the micturition reflex. Recently, much attention has been given to controlling [...]

5-HT and noradrenaline are important neurotransmitters that control increase in body mass and are involved in the pathophysiology of obesity and depression. Sibutramine, an established anti-obesity agent, and duloxetine, an anti-depressant agent, are serotonin noradrenaline reuptake inhibitors (SNRIs). The objective of the present study was to compare the anti-obesity effect of duloxetine with sibutramine along with its effect on blood pressure and depression in obese rats. The secondary objective of the study was to determine if a relationship exists between obesity and depression. Obesity was induced by high-fat diet (HFD) in healthy male Sprague-Dawley rats. After 5 weeks of feeding HFD, animals were overweight (17.57%) with high food intake (57.15%) in comparison with normal animals. These obese animals were treated with duloxetine (30 mgx[kg.sup.-1], p.o.) and sibutramine (5 mgx[kg.sup.-1], p.o.) for 4 weeks. Control animals were treated with duloxetine alone (30 mgx[kg.sup.-1], p.o.). Our results depict that duloxetine was as effective as sibutramine in reducing food intake, body mass, and relative adiposity, and increasing rectal temperature with an added advantage of decreasing blood pressure, which sibutramine failed to do. Besides reduction in body mass, unlike sibutramine, duloxetine improved depressive state as evaluated by despair swimming test, tail suspension test, and open field test, speculating its use as an anti-obesity agent in obese-depressive animals. Since obese control animals reflected decreased locomotor activity, a positive relationship can be speculated to exist between obesity and depression. Further studies on various antidepressant models are required to confirm this relationship. Key words: duloxetine, sibutramine, SNRIs, hypothalamic-pituitary axis (HPA), HFD, anti-obesity activity, anti-depressant activity. La 5-HT et la noradrenaline sont d'importants neurotransmetteurs qui regulent la prise de poids et qui sont impliquees dans la pathophysiologie de l'obeesitee et de la depression. La sibutramine, un agent anti-obesite etabli, et la duloxetine, un antidepresseur, sont des inhibiteurs de la recapture de la serotonine-noradrenaline (IRSN). La presente etude a eu deux objectifs : (i) comparer l'effet anti-obesite de la duloxetine avec celui de la sibutramine, ainsi que son effet sur la TA et la depression chez des rats obeses; (ii)determiner s'il existe une relation entre l'obeesite et la depression. L'obeesite a ete induite par un regime riche en lipides (RRL) chez des rats Sprague-Dawley males en sante. Apres 5 semaines de RRL, les animaux ont presente un excedent de poids (17,57 %) et un niveau eleve de consommation d'aliments (57,15 %) comparativement aux animaux normaux. Les animaux obeses ont ete; traitees avec de la duloxetine (30 mgx[kg.sup.-1], p.o.) et de la sibutramine (5 mgx[kg.sup.-1], p.o.) pendant 4 semaines. Les animaux teemoins ont aussi ete traitees avec de la duloxetine (30 mgx[kg.sup.-1], p.o.). Nos resultats indiquent que la duloxetine a ete aussi efficace que la sibutramine pour ce qui est de diminuer le niveau de consommation d'aliments, le poids corporel et l'adiposite relative, et d'augmenter la temperature rectale, mais qu'elle a de plus diminuee la TA, ce que n'a pu faire la sibutramine. En plus de diminuer le poids corporel, la duloxetine, contrairement a la sibutramine, a attenue l'etat depressif evaluee par le test d'analyse de deesespoir comportemental (test de nage forcee), le test de suspension par la queue et le test en espace ouvert, ce qui permet d'envisager son utilisation comme agent anti-obesite chez les animaux obeses-deepressifs. Les animaux temoins obeses ayant montre une diminution de l'activite locomotrice, il y a lieu de s'interroger sur la possibilite d'une relation positive entre l'obesite et la depression. D'autres etudes sur divers modeles antideepresseurs sont neecessaires pour confirmer cette relation. Mots-cles: duloxetine, sibutramine, IRSN, HPA, RRL, activite anti-obesite, activite antidepresseur. [Traduit par la Redaction] 10.1139/Y09-080, Introduction Obesity is a common chronic physical illness of modern society, and depression is the most prevalent psychological condition. Despite the high prevalence of these conditions concomitantly, sufficient exploration of [...]

Abstract Membranous glomerulonephritis (MGN) remains the most common cause of adult-onset nephrotic syndrome in the world and up to 40% of untreated patients will progress to end-stage renal disease. Although [...]

Abstract Eugenol, the principal chemical component of clove oil from Eugenia aromatica has been long known for its analgesic, local anesthetic, anti-inflammatory, and antibacterial effects. The interaction of the eugenol [...]

September 2009 WHO convenes technical meetings (1) in February and September every year to recommend the composition of influenza vaccines (2) for the northern and southern hemispheres, respectively. This recommendation [...]

Doxorubicin (Dox) is frequently used as a frontline chemotherapeutic agent against a variety of cancers. Tremendous progress has been made on its optimal usage over the last 40 years. However, cardiotoxicity still remains a major concern. The great promise in this matter is that the mechanisms leading to antitumor activity appear to be different from those leading to Dox-induced cardiomyopathy. In this regard, various cardioprotective agents have been discussed. Attention should be drawn to probucol, a lipid-lowering agent with potent antioxidant properties, which provides complete protection against Dox-induced cardiomyopathy in rats without interfering with the antitumor properties of Dox in an experimental setting. Clinical trials employing Dox therapy in combination with probucol are needed to determine whether the outstanding findings in animal experiments can be extrapolated to clinical results. We have much further to go before the establishment of cancer therapies without any risk of cardiac side effects. Key words: congestive heart failure, antioxidants, oxidative stress. Resume : La doxorubicine (Dox) est frequemment utiliseee comme agent chimiotherapique de premiere ligne de soins dans le traitement de certains cancers. Meme si au cours de 40 dernieres annees on a realise d'enormes progres dans l'utilisation optimale de cet agent, sa cardiotoxicite demeure un probleme important. Cependant, le mecanisme responsable de l'action antitumorale semble different de celui a la base de la cardiomyopathie induite par la Dox. A cette fin, divers agents cardioprotecteurs ont ete etudies. On devrait porter une attention particuliere au probucol, un agent hypolipidemiant aux proprietes antioxydantes qui, chez des rats dans un contexte experimental, procure une protection complete contre la cardiomyopathie induite par la Dox tout en n'entravant pas les proprietes antitumorales. Des essais cliniques combinant le traitement therapeutique au Dox et au probucol sont neecessaires pour determiner si ces observations de premiere importance dans des etudes animales se transposent dans un contexte clinique. Il y a encore beaucoup de travail a faire avant d'etre en mesure d'offrir des traitements therapeutiques du cancer ne presentant aucun effet secondaire sur le coeur. Mots-cles: insuffisance cardiaque congestive, antioxydants, stress oxydatif. [Traduit par la Redaction], Introduction Doxorubicin (Dox) was introduced in cancer therapy in the late 1960s. It has emerged as one of the most potent broad-spectrum antitumor anthracycline antibiotics. Dox can be administered as [...]

Abstract In this study we investigated a synergistic effect between the essential oils Origanum vulgare, Pelargonium graveolens and Melaleuca alternifolia and the antifungal compound Nystatin. Nystatin is considered a drug [...]

The cholesterol controversy continues. Every day we're barraged with news about this enigmatic and potentially frightening topic. Whether it's in the newspaper with an article about a new fad diet, [...]

Individuals with idiopathic Parkinson's disease (IPD) have long been treated with dopamine-based medications such as levodopa. While dopaminergic medication is considered to be quite successful in treating the limb motor [...]

In the present work, the effect of isoproterenol on the electrical properties of the rat heart and on the cytoarchitecture of the surviving cardiomyocytes was studied. Myocardial remodelling was induced by the daily administration of 5 mg/kg isoproterenol (Iso) for 7 days. Administration resulted in a significant increase (52%) in the ratio of left ventricular weight to body weight. ECG voltage criteria confirmed the presence of left ventricular hypertrophy. QT interval prolongation by 23% and 58% was found in Iso rats and in the corresponding isolated hearts, respectively. Spontaneously beating Iso hearts had a higher incidence of dysrhythmias. The surviving cardiomyocytes showed an irregular shape with cytoplasmic processes rich in ribosomes and rough endoplasmic reticulum. In these regions, myofibril disorganization and mitochondrial fission were observed. A greatly increased incidence of caveolae was seen in the plasma membrane and in the mouth of t-tubules. The membranes of t-tubules showed vesiculation, especially near the dyads. Repeated administration of isoproterenol led to hypertrophy, characterized by the existence of myocytes with simultaneous signs of both mature and postnatally developing cardiomyocytes. Structural microheterogeneities at the level of individual cells may represent one of the factors leading to electrical imbalance in the myocardial tissue remodelled by isoproterenol. Key words: heart, isoproterenol, hypertrophy, ECG, contractile dysfunction, ultrastructure, plasma membrane, mitochondria, t-tubules. Dans le present travail, on a examine l'effet de l'isoproterenol sur les proprieteeselectriques du coeur de rat et sur la cytoarchitecture des cardiomyocytes survivants. Le remodelage myocardique a ete induit par l'administration quotidienne de 5 mg/kg d'isoproterenol (Iso) durant 7 jours. L'administration de l'Iso a cause; une augmentation significative (de 52 %) du rapport poids ventriculaire gauche a poids corporel. Les criteres de voltage ECG ont confirme la presence de l'hypertrophie ventriculaire gauche. De plus, une prolongation de l'intervalle QT de 23 et 58 % s'est produite chez les rats ayant recju l'Iso et dans les coeurs isoles correspondants, respectivement. Les Iso-coeurs a battements spontanees ont eu une plus forte incidence de dysrythmies. Les cardiomyocytes survivants avaient une forme irreguliere ainsi qu'un cytoplasme riche en ribosomes et en reticulum endoplasmique granulaire. Dans ces regions, une desorganisation myofibrillaire et une fission mitochondriale ont ete observeees. De tres grandes quantitees de caveeoles ont ete releveees dans la membrane plasmatique et a l'entree des tubules T. Les membranes des tubules T ont montre une vesiculation, en particulier pres des dyades. L'administration repetee d'isoproterenol a entraine une hypertrophie caracteerisee par la presence de myocytes montrant des signes de cardiomyocytes tant developpesa la naissance que matures. Les microheeterogeneeites structurales au niveau des cellules individuelles pourraient representer l'un des facteurs menant a un deseequilibre electrique dans le tissu myocardique remodele par l'isoproterenol. Mots-cles: coeur, isoproterenol, hypertrophie, ECG, dysfonction contractile, ultrastructure, membrane plasmatique, mitochondries, tubules T. [Traduit par la Redaction], Introduction Left ventricular hypertrophy is an independent adaptive response to hemodynamic overload (Wang et al. 2003; Diwan and Dorn 2007) and a risk factor for sudden cardiac death. Experimental myocardial [...]

Doxorubicin (DXR) is a chemotherapeutic agent used effectively in the treatment of several childhood malignancies. During treatment, cardiotoxicity caused by cell damage due to the free oxygen radicals that are generated is a major limiting factor. This study was undertaken to determine whether DXR-induced cardiotoxicity could be prevented by natural foods with antioxidant properties such as aged garlic extract (AGEX), grape seed proanthocyanidin (PA), and hazelnut. Wistar albino male rats were assigned randomly to 9 groups each consisting of 15 rats. AGEX, PA, and hazelnut groups received these antioxidants in addition to their standard rat diet. They were also treated with cumulative intraperitoneal (i.p.) injections according to 2 different regimens: either a high-dose of 15 mg/kg DXR (3.75 mg/kg per week for 4 weeks) or a low-dose of 7.5 mg/kg DXR (1.875 mg/kg per week for 4 weeks). The control group received i.p. 0.9% saline. AGEX, PA, or hazelnut supplements were given orally to the groups for a 6-week period starting 1 week before the DXR treatment and ending 1 week after the treatment. One week after the last DXR injection, heart tissue samples were analyzed to determine malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and xanthine oxidase (XO) levels, and serum samples were taken for creatine kinase (CK). There were no significant changes in MDA levels among the control, DXR-treated groups, or supplemented groups that received additional natural antioxidant foods. SOD enzyme levels were decreased in rats treated with DXR. PA prevented the decrease at low doses of DXR. DXR treatment decreased CAT enzyme levels, but additional PA and hazelnut consumption increased these levels at low cumulative doses. XO enzyme levels were decreased in AGEX and hazelnut groups, but PA prevented the decrease. CK levels were elevated after DXR administration, indicating myocardial injury, but PA significantly reversed this. Although there were no differences histopathologically between AGEX, PA, and hazelnut groups, the protective effects of AGEX and PA were evident in electron microscopy. In conclusion, the positive effects of natural antioxidant foods on the prevention of DXR-induced cardiac injury could not be clearly shown on the basis of antioxidant enzymes. However, the electron microscopic changes clearly demonstrated the protective effects of AGEX and PA. The supplementation of these antioxidant foods over longer periods may show more definitive results. Human studies with different doses are needed to evaluate the effects of these foods on the human heart. Key words: aged garlic extract, grape seed proanthocyanidin, hazelnut, doxorubicin, cardiotoxicity. La doxorubicine (DXR) est un agent chimiotherapeutique utilise efficacement dans le traitement de plusieurs tumeurs malignes de l'enfant. Durant le traitement, la cardiotoxicite causee par l'alteration cellulaire liee a la production des radicaux libres de l'oxygene est un important facteur limitant. La presente etude a eu pour but de determiner si la cardiotoxicite induite par la DXR pourrait etre prevenue par l'ingestion d'aliments naturels ayant des proprietes antioxydantes, tels l'extrait d'ail vieilli (AGEX), la proanthocyanidine extraite de pepins de raisin (PA) et la noisette. On a reparti aleatoirement des rats albinos Wistar dans neuf groupes composes de 15 rats chacun. Les groupes AGEX, PA et noisette ont recu ces antioxydants en plus de leur ration normale. Ils ont aussi ete traitees avec deux schemas posologiques differents : une injection intraperitoneale (i.p.) cumulative de 15 mg/kg (3,75 mg/kg par semaine pendant 4 semaines) de DXR, suivi d'une injection de 7,5 mg/kg (1,875 par semaine pendant 4 semaines) de DXR. Le groupe temoin a recu une solution saline par voie i.p. (0,5 mL/200 mg). L'AGEX, la PA et la noisette ont ete administres par voie orale pendant une periode de six semaines, a partir de la semaine precedant le traitement par DXR jusqu'a une semaine apres le traitement. Une semaine apres la derniere injection de DXR, les animaux ont ete decapites et des echantillons de tissus cardiaques ont ete; preleves pour determiner les taux de malondialdehyde (MDA), de superoxyde dismutase (SOD), de catalase (CAT) et de xanthine oxydase (XO). Des echantillons seriques ont ete preleves pour l'analyse de la creatine kinase (CK) a titre d'indice de lesion cardiaque. Il n'y a pas eu de modifications significatives dans les taux de MDA chez les groupes temoin, traite a la DXR et les groupes ayant recu des aliments antioxydants naturels en supplement. Les taux de SOD ont diminue chez les rats traites a la DXR. La PA a prevenu la diminution aux faibles doses de DXR. Le traitement a la DXR a diminue les taux de l'enzyme CAT, mais l'ingestion additionnelle de PA et de noisettes a augmente; ces taux aux faibles doses cumulatives. Les taux de XO ont diminue; chez les groupes AGEX et noisette, mais la PA a prevenu la diminution. Les taux de CK ont augmente apres l'administration de DXR, une indice de lesion myocardique. Bien qu'aucune difference n'ait ete observee sur le plan histopathologique entre les groupes AGEX, PA et noisette, les effets protecteurs de l'AGEX et de la PA ont ete; manifestes au microscope electronique. En conclusion, les effets positifs des aliments antioxydants naturels sur la prevention de la lesion cardiaque induite par la DXR n'ont pu etre clairement montres a partir des enzymes antioxydantes. Toutefois, les modifications observees au microscope electronique ont nettement demontre; les effets protecteurs de l'AGEX et de la PA. L'ingestion de ces aliments antioxydants sur de longues periodes pourrait apporter des resultats plus concluants. Des etudes chez les etres humains en utilisant differentes doses de ces aliments seraient necessaires pour evaluer leurs effets sur le c?ur humain. Mots-cles: extrait d'ail vieilli, proanthocyanidine extraite de pepins de raisin, noisette, doxorubicine, cardiotoxicite. [Traduit par la Redaction], Introduction Doxorubicin (DXR) is an effective chemotherapeutic agent used in the treatment of various cancers. However, cardiac toxicity is a serious dose-limiting factor. One of the mechanisms of DXR-induced cardiac [...]

Glucagon-like peptide-1 (GLP-1) ameliorates the symptoms of diabetes through stimulation of insulin secretion. We have investigated the possible components of cellular mechanism triggered by exendin-4, a potent GLP-1 receptor agonist, in streptozotocin (STZ) induced diabetic mice pancreas. BALB/c male mice were divided into four groups for this investigation. The first group was given citrate buffer only, the second group was administered exendin-4 alone, the third group rece ived STZ, and the fourth group was given both STZ and exendin-4. Exendin-4 (3 µg/kg) was administered by daily subcutaneous injection for 30 days after the animals were rendered diabetic by administration of STZ (200 mg/kg). With exendin-4 treatmen t on diabetic mice, the following results were noted: (i) exendin-4 suppressed the increase in plasma glucose and inhibited somatostatin expression induced by STZ, (ii) reduction of insulin prevalence was inhibited, while expression of p75 neurotrophin r eceptor ([p75.sup.NTR]), pancreatic nerve growth factor (NGF), and NGF-positive islet cell prevalence increased, (iii) there were no alterations in the severity of proliferated cell nuclear antigen positive or apoptotic beta cells in pancreatic islets, a nd (iv) pancreatic catalase, glutathione peroxidase, and superoxide dismutase activities significantly increased. In conclusion, these data suggest that exendin-4 might exert its actions through the NGF/[p75.subp.NTR] system and decrease somatostatin expression. Key words: exendin-4, insulin, NGF, [p75.sup.NTR], somatostatin. Resume: Le peptide GLP-1 (< glucagon-like peptide-1 >) ameliore les symptomes du diabete en stimulant la secretion d'insuline. Nous avons examine les composantes possibles des mecanismes cellulaires actives par l'exendin-4, un agoniste puissant du recepteur du GLP-1, dans le pancreas de souris dont le diabete a ete induit par la steptozotocine (STZ). Des souris males BALB/c ont ete divisees en quatre groupes pour cette recherche. Le premier groupe a recu du tampon citrate seul ement, le deuxieme groupe a ete traite a l'exendin-4 seul, le troisieme groupe a recu la STZ et le quatrieme groupe a recu la STZ et l'exendin-4. L'exendin-4 (3 µg/kg) a ete administre par injections sous-cutanees quotidiennes pendant 30 jours apre s que les animaux aient ete rendus diabetiques par l'administration de STZ (200 mg/kg). Le traitement des souris diabetiques a l'exendin-4 a genere les resultats suivants : (i) l'exendin-4 a empeche l'augmentation de glucose plasmatique et a inhibe l'exp ression de somatostatine induite par la STZ, (u) la reduction de la concentration d'insuline a ete inhibee, alors que l'expression du recepteur de la neurotrophine [p75.sup.NTR], du NGF pancreatique ainsi que le nombre de cellules des ilots positives au NFG ont augmente, (iii) il n'y avait pas de changements dans le nombre de cellules beta des ilots pancreatiques positives a l'antigene nucleaire PCNA ou de cellules apoptotiques et (iv) l'activite de la catalase pancreatique, de la gluthation peroxydase et de la superoxyde dismutase a augmente de facon significative. En conclusion, ces resultats sugg erent que l'exendin-4 exerce son action via le systeme NGF/[p75.sup.NTR] et qu'il diminue l'expression de la somatostatine. Mots-cles : exendin-4, insuline, NGF, [p75.sup.NTR], somatostatine. [Traduit par la Redaction], Introduction Exendin-4 is an agonist of the glucagon-like peptide-1 (GLP-1) receptor. Importantly, it has a significant longer half-life than GLP-1 and it could be significant in the treatment of diabetes [...]

Previous studies have shown that the phosphatidylinositol 3-kinase/Akt/endothelial nitric oxide synthase/NO (PI3K/Akt/eNOS/NO) pathway is involved in high glucose-induced endothelial cell apoptosis and rosiglitazone has a protective effect on endothelium. In the present study, we investigated the antiapoptotic effect of rosiglitazone on human umbilical vein endothelial cells (HUVECs) exposed to high glucose and explored its possible mechanism. Treatment of high glucose (33 mmol/L) for 48 h significantly induced the apoptosis of HUVECs, concomitantly with increased caspase-3 activity. High glucose treatment also decreased Akt and eNOS phosphorylation levels with subsequent NO production. All these alterations induced by high glucose were attenuated by rosiglitazone (1 mmol/L). Interestingly, the antiapoptotic effect of rosiglitazone was inhibited by PI3K inhibitor (LY294002, wortmannin) or eNOS inhibitor [N.sup.G]-L-nitro-arginine methyl ester (L-NAME). The reverse effects of rosiglitazone on phosphorylation of Akt and eNOS with subsequent NO production were also inhibited by LY294002, wortmannin or L-NAME, respectively. These findings suggest that rosiglitazone inhibits high glucose-induced apoptosis in HUVECs through the PI3K/Akt/eNOS pathway. Key words: rosiglitazone, PI3K, Akt, eNOS, NO, caspase-3. Des etudes arterieures ont montre; que la voie phosphatidylinositol 3-kinase (PI3K)/Akt/monoxyde d'azote synthase (NO) endotheliale (eNOS)/NO joue un role dans l'apoptose des cellules endotheeliales induite par le glucose; ces etudes ont aussi indique: que le rosiglitazone a un effet protecteur sur l'endothelium. Dans la presente etude, nous avons etudiee l'effet antiapoptotique du rosiglitazone sur les cellules endotheliales de la veine ombilicale humaine (HUVEC) exposees a une forte concentration de glucose, et examinee son meecanisme potentiel. Un traitement dans un milieu a forte teneur en glucose (33 mmol/L) pendant 48 h a provoque une forte apoptose des HUVEC et augmente; l'activitee de la caspase-3. Le traitement a de plus induit une diminution des taux de phosphorylation de l'Akt et de eNOS, et la production subsequente de NO. Le rosiglitazone (1 [micron]mol/L) a atteenue toutes ces modifications. Fait interessant, l'effet antiapoptotique du rosiglitazone a ete bloque par un inhibiteur de la PI3K (LY294002, wortmannine) ou l'inhibiteur de eNOS, [N.sup.G]-L-nitroarginine methylester (L-NAME). Les effets du rosiglitazone sur la phosphorylation de l'Akt et de eNOS, et la production subsequence de NO ont aussi ete inhibes par LY294002, la wortmannine ou L-NAME, respectivement. Ces resultats donnent a penser que le rosiglitazone inhibe par la voie PI3K/Akt/eNOS l'apoptose des HUVEC induite par une forte concentration de glucose. Mots-cles: rosiglitazone, PI3K, Akt, eNOS, NO, caspase-3. [Traduit par la Redaction], Introduction Endothelial dysfunction plays a key role in the development of diabetic vascular complications (King 1996). It has been reported that high glucose triggers endothelial cell apoptosis (Zhang et al. [...]

The present study investigated the role of the endogenous cystathionine γ-lyase (CSE)/hydrogen sulfide pathway in the pathogenesis of pulmonary fibrosis. Rats treated with intratracheal bleomycin were exposed either to the [H.sub.2]S donor NaHS or to saline. The results on day 7 showed that plasma [H.sub.2]S concentration and pulmonary CSE activity ([H.sub.2]S production rate) were significantly lower in rats treated with bleomycin and saline (fibrosis-alone) than in controls, whereas on day 28 plasma [H.sub.2]S concentration was higher and pulmonary CSE activity was the same as that of controls. The relative CSE mRNA level in the lungs of rats treated with bleomycin was significantly higher than control values on days 7 and 28. After exposure to NaHS, the total lung hydroxyproline content and the malondialdehyde (MDA) content were both significantly lower, with no difference observed between NaHS high-dose and low-dose treatments. Further, MDA formation stimulated by the free radical-generating system (FRGS) in vitro was lower in lung tissue incubated with NaHS than it was in tissue incubated with FRGS alone. These results suggest that NaHS administration ameliorated the pulmonary fibrosis induced by bleomycin in rats and that this protective effect of [H.sub.2]S may be mediated by its antioxidative action. Key words: bleomycin, fibrosis, hydrogen sulfide, [H.sub.2]S, oxidative stress. La presente etude a examine; le role de la voie cystathionine γ-lyase (CSE)/sulfure d'hydrogene endogene dans la pathogenese de la fibrose pulmonaire. Des rats traites par bleomycine intratracheeale ont ete exposesa un donneur (NaHS) de [H.sub.2]S ou a une solution saline. Les resultats ont montre; que la concentration plasmatique de [H.sub.2]S et l'activite pulmonaire de la CSE (taux de production de [H.sub.2]S) des rats traiteesa la bleomycine ont etee nettement plus faibles le jour 7; toutefois, le jour 28, elles ont ete respectivement plus eeleveeeet leegerement plus eeleveee quoique de maniere non significative que celles des temoins. Le taux relatif de l'ARNm de la CSE pulmonaire des rats traiteesa la bleomycine a ete significativement plus elevee que celui des temoins les jours 7 et 28. Les concentrations pulmonaires totales d'hydroxyproline et de malondialdehyde (MDA) ont etee consideerablement plus faibles apres une exposition au NaHS (doses faibles et fortes), et aucune difference n'a ete observeee entre les expositions. De plus, la formation de MDA stimuleee par le systeme generant des radicaux libres (SGRL) a etee plus faible dans le tissu pulmonaire incube avec le NaHS qu'avec le SGRL seulement in vitro. Ces resultats donnent a penser que l'administration de NaHS a attenue la fibrose pulmonaire induite par la bleomycine chez les rats et que cet effet protecteur du [H.sub.2]S pourrait etre veehiculee par son action antioxydante. Mots-cles: bleeomycine, sulfure d'hydrogene, [H.sub.2]S, stress oxydatif. [Traduit par la Redaction], Introduction Idiopathic pulmonary fibrosis is a chronic, progressive lung disease with unknown etiology, characterized by fibro-proliferation and destruction of the lung parenchyma. These lung injuries may be exacerbated by concurrent [...]

Oxidative stress plays a dominant role in the pathogenesis of cardiac cell apoptosis in diabetic patients. Sildenafil has been demonstrated to have antioxidant effects. In this study, the effects of sildenafil on diabetes-induced cardiac cell apoptosis and the antioxidant status of diabetic mouse hearts were investigated. Diabetic mice showed lower body weight gains and heart weights compared with control mice, and sildenafil treatment did not increase these parameters in diabetic mice. Although apoptotic rates, caspase-3 enzyme activity, and malondialdehyde levels were significantly higher in diabetic mouse hearts than in controls, they were reduced in diabetic mice after sildenafil treatment. At the end of the first week, we observed no significant differences in antioxidant enzyme activities (CAT, GSH-Px, and SOD) in diabetic and control groups, whereas at the end of the second week of sildenafil treatment, antioxidant enzyme activities were higher in the diabetic group. In conclusion, our study indicated that sildenafil was beneficial to hearts of diabetic mice by reducing cardiac cell apoptosis, partially because of its antioxidant effects in the heart. Key words: antioxidant, apoptosis, diabetes, heart, mice, reactive oxygen species, sildenafil. Le stress oxydatif joue un role important dans la pathogenese de l'apoptose des cellules cardiaques chez les diabetiques. Des etudes ont demontre; que le sildenafil a des effets antioxydants. Dans la presente etude, nous avons examine; les effets du sildenafil sur l'apoptose des cellules cardiaques induite par le diabete de meme que sur le statut antioxydant des coeurs de souris diabetiques. Les souris diabetiques ont montre; des gains de poids corporel et des poids cardiaques plus faibles que ceux des teemoins, et le traitement au sildenafil n'a pas augmente ces parameetres chez les souris diabetiques. Bien que les taux d'apoptose, l'activitee de la caspase-3 et les taux de malondialdehyde aient etee significativement plus eleves chez les souris diabetiques que chez les souris temoins, le traitement au sildenafil a pu reduire ces parametres dans les coeurs des souris diabetiques. A la fin de la premiere semaine, aucune difference significative n'a etee observee entre les activite;s des enzymes antioxydantes (CAT, GSH-Px et SOD) chez les groupes diabetiques et teemoins, tandis qu'a la fin de la deuxieeme semaine, ces activitees ont augmente. Le traitement au sildenafil a pu induire cette augmentation chez le groupe diabeetique. Ainsi, notre etude a indique que le sildenafil a etee beenefique pour les coeurs des souris diabetiques, en diminuant l'apoptose des cellules cardiaques, en partie grace a ses effets antioxydants dans le coeur. Mots-cles: antioxydant, apoptose, diabeete, coeur, souris, espeeces reactives de l'oxygeene, sildenafil. [Traduit par la Redaction], Introduction Diabetes is strongly associated with various cardiovascular diseases, which are the primary cause of morbidity and mortality among patients with diabetes (Cai and Kang 2001). Although the majority of [...]

The effects of enalapril and sodium depletion on renin synthesis and secretion were studied in mice with a left hydronephrotic kidney caused by unilateral ureteral ligation (UUL). In the control animals, there was no difference in plasma renin concentration between the right and left renal veins. In mice with left ureteral ligation, the renin concentration in the vein draining the hydronephrotic kidney was similar to or lower than that in the aorta under control conditions and after either stimulation with enalapril or depletion of sodium. Enalapril and sodium restriction increased plasma renin concentration, and this increase was due to secretion from the nonhydronephrotic kidney. The renin concentration per gram of kidney tissue and the mRNA for renin per gram of kidney tissue were similar in both the control and hydronephrotic kidney, and the values rose 3-1-fold in both kidneys after enalapril or sodium depletion. Immunostaining for renin confirmed these findings and indicated that renin per glomerulus was higher in the hydronephrotic kidney. Thus, removal or reduction of angiotensin II activity or depletion of sodium stimulated synthetic activity to a similar extent in the normal and hydronephrotic kidneys; however, secretion from the kidney without a macula densa (hydronephrotic) was not increased. Thus, the signals that control synthesis and secretion are different, and for these stimuli, secretion appears to require an intact macula densa. Key words: renin synthesis, sodium depletion, ACE inhibitor, hydronephrosis. On a examine les effets d'une depletion d'enalapril et de sodium sur la synthese et la secretion de la renine chez des souris presentant un hydronephrose du rein gauche induite par une ligature unilaterale de l'uretere (LUU). Chez les animaux temoins, les concentrations de renine plasmatique (CRP) dans les veines reinales droites et gauches ont ete similaires. Chez les souris, la concentration de renine dans la veine drainant le rein hydronephrotique a este similaire ou inferieure a celle de l'aorte, dans des conditions temoins, apres une stimulation au moyen d'enalapril, ou apres une depletion sodique. La restriction en enalapril et en sodium a augmente la concentration de renine plasmatique, et cette augmentation aete causee par une secretion du rein non hydronephrotique. La concentration de renine par g de rein et l'ARNm de la renine par g de tissu reinal ont ete similaires dans les reins temoin et hydronephrotique, et les valeurs ont augmente; d'un facteur 3-4 dans les deux reins apresla deepleetion d'eenalapril et de sodium. L'immunocoloration de la renine a confirmee ces observations et suggere que le rapport renine/glomerule a ete plus eleve dans le rein hydronephrotique. Ainsi, la suppression ou la diminution de l'activite de l'angiotensine II ou la depletion de sodium ont stimule l'activite de synthase a un degree similaire dans les reins normal et hydronephrotique. Toutefois, la seecreetion du rein sans macula densa (hydronephrotique) n'a pas augmente. Ainsi, les signaux qui regulent la synthese et la secreetion sont differents, et, pour ces stimuli, la secretion neecessite une macula densa intacte. Mots-cles: synthase de la renine, depletion sodique, inhibiteur de l'ECA, hydronephrose. [Traduit par la Redaction], Introduction The renin--angiotensin system (RAS) has an important role in controlling arterial blood pressure and regulating electrolyte homeostasis (Balcells et al. 1997; Paul et al. 2006). Renin and its substrate [...]

Introduction The chemical element vanadium was first discovered by Spanish-born Mexican mineralogist, Andres Manuel del Rio, in 1801. He originally named the element 'panchromium' because of the spectrum of colors [...]

Introduction Panax ginseng, used medicinally for thousands of years in China, Korea, and Japan, (1) is well known as an adaptogen and a restorative tonic that is widely used in [...]

Rapamycin represents a recognized drug-based therapeutic approach to treat cardiovascular disease. However, at least in the female heart, rapamycin may suppress the recruitment of putative signalling events conferring cardioprotection. The present study tested the hypothesis that rapamycin-sensitive signalling events contributed to the cardioprotective phenotype of the female rat heart after an ischemic insult. Rapamycin (1.5 mg/kg) was administered to adult female Sprague-Dawley rats 24 h after complete coronary artery ligation and continued for 6 days. Rapamycin abrogated p70S6K phosphorylation in the left ventricle of sham rats and the noninfarcted left ventricle (NILV) of 1-week postmyocardial-infarcted (MI) rats. Scar weight (MI 0.028 ± 0.006, MI+rapamycin 0.064 ± 0.004 g) and surface area (MI 0.37 ± 0.08, MI+rapamycin 0.74 ± 0.03 [cm.sup.2]) were significantly larger in rapamycin-treated post-MI rats. In the NILV of post-MI female rats, rapamycin inhibited the upregulation of eNOS. Furthermore, the increased expression of collagen and TGF-[β.sub.3] mRNAs in the NILV were attenuated in rapamycin-treated post-MI rats, whereas scar healing was unaffected. The present study has demonstrated that rapamycin-sensitive signalling events were implicated in scar formation and reactive fibrosis. Rapamycin-mediated suppression of eNOS and TGF-[β.sub.3] mRNA in post-MI female rats may have directly contributed to the larger infarct and attenuation of the reactive fibrotic response, respectively. Key words: fibrosis, gender, infarction, ischemia. L'utilisation de la rapamycine constitue une approche therapeutique reconnue pour traiter les maladies cardiovasculaires. Toutefois, du moins dans le coeur des rats femelles, la rapamycine pourrait supprimer le recrutement d'evenements de signalisation conferant une cardioprotection. La presente etude a verifie l'hypothese que les evenements de signalisation sensibles a la rapamycine ont contribue au phenotype cardioprotecteur du coeur des rats femelles apres une atteinte ischemique. On a administre la rapamycine (1,5 mg/kg) a des rats femelles Sprague-Dawley 24 h apres une ligature complete de l'artere coronaire, et poursuivi l'administration pendant une periode de 6 jours. La rapamycine a supprime la phosphorylation de p70S6K dans le ventricule gauche des femelles operees de maniere fictive et dans le ventricule gauche non infarci (VGNI) des femelles en post-infarctus du myocarde (IM) d'une semaine. Le poids de la cicatrice (IM 0,028 [+ o -] 0,006 contre IM+rapamycine 0,064 [+ ou -] 0,004 grammes) et la surface (IM 0,37 [+ ou -] 0,08 contre IM+rapamycine 0,74 [+ ou -] 0,03 [cm.sup.2]) ont ete significativement plus importants chez les femelles post-IM traitees a la rapamycine. Dans le VGNI de ces femelles, la rapamycine a inhibe l'augmentation de eNOS et attenue la surexpression des ARNm du collagene et du TGF- [β.sub.3], mais elle n'a pas influe sur la cicatrisation. Cette etude a demontre que les evenements de signalisation sensibles a la rapamycine ont joue un role dans la cicatrisation et la fibrose reactive. La suppression des ARNm de eNOS et du TGF-[β.sub.3] vehiculee par la rapamycine chez les rats femelles post-IM pourrait avoir contribue directement a l'augmentation de la taille de l'infarctus et a l'attenuation de la reponse fibreuse, respectivement. Mots-cles : fibrose, sexe, infarctus, ischemie. [Traduit par la Redaction], Introduction It is well established that the risk of cardiovascular disease is lower in premenopausal women than in age-matched men (Hayward et al. 2000). However, after the onset of menopause, [...]

Preventing and delaying the emergence of drug resistance is an essential goal of antimalarial drug development. Monotherapy and highly mutable drug targets have each facilitated resistance, and both are undesirable in effective long-term strategies against multi-drug-resistant malaria. Haem remains an immutable and vulnerable target, because it is not parasite-encoded and its detoxification during haemoglobin degradation, critical to parasite survival, can be subverted by drug--haem interaction as in the case of quinolines and many other drugs (1-5). Here we describe a new antimalarial chemotype that combines the haem-targeting character of acridones, together with a chemosensitizing component that counteracts resistance to quinoline antimalarial drugs. Beyond the essential intrinsic characteristics common to deserving candidate antimalarials (high potency in vitro against pan-sensitive and multi-drug-resistant Plasmodium falciparum, efficacy and safety in vivo after oral administration, inexpensive synthesis and favourable physicochemical properties), our initial lead, T3.5 (3-chloro-6-(2-diethylamino-ethoxy)-10-(2-diethylamino-ethyl)acridone), demonstrates unique synergistic properties. In addition to 'verapamil-like' chemosensitization to chloroquine and amodiaquine against quinoline-resistant parasites, T3.5 also results in an apparently mechanistically distinct synergism with quinine and with piperaquine. This synergy, evident in both quinoline-sensitive and quinoline-resistant parasites, has been demonstrated both in vitro and in vivo. In summary, this innovative acridone design merges intrinsic potency and resistance-counteracting functions in one molecule, and represents a new strategy to expand, enhance and sustain effective antimalarial drug combinations., While feeding in the host red blood cell, malaria parasites ingest and degrade vast amounts of haemoglobin as a source of amino acids, consequently releasing toxic free haem as a [...]

Abstract Diabetes mellitus is associated with an increase in sialic acid concentration along with other complications. Sialic acid changes in NIDDM patients were investigated following bitter melon (55 ml/24 h) [...]

Objective: For important reasons, lorazepam (Ativan) and chlordiazepoxide (Librium) are both popular treatments for alcohol-withdrawal syndrome. Nevertheless, there is little literature directly comparing the two drugs. A formal comparison is desirable because of pharmacokinetic and other differences that could affect safety and efficacy considerations relevant to practice in developing countries. Method: One hundred consecutive consenting male inpatients in a state of moderately severe, uncomplicated alcohol withdrawal at screening were randomized to receive either lorazepam (8 mg/day) or chlordiazepoxide (80 mg/day) with dosing down-titrated to zero in a fixed-dose schedule across 8 treatment days. Double-blind assessments of withdrawal-symptom severity and impairing adverse events were obtained during treatment and for 4 days afterward. Results: One chlordiazepoxide patient developed withdrawal delirium. Lorazepam and chlordiazepoxide showed similar efficacy in reducing symptoms of alcohol withdrawal as assessed using the revised Clinical Institute Withdrawal Assessment for Alcohol scale. During withdrawal, irritability and dizziness were more common with lorazepam, and palpitations were more common with chlordiazepoxide. No difficulties in drug discontinuation or differences in impairing adverse events were observed with either drug. Conclusions: With the treatment schedule used in this study, lorazepam is as effective as the more traditional drug chlordiazepoxide in attenuating uncomplicated alcohol withdrawal. Lorazepam, therefore, could be used with confidence when liver disease or the inability to determine liver function status renders chlordiazepoxide therapy problematic. The absence of clinically significant withdrawal complications with lorazepam in this large study contrasts with findings from previously published studies and suggests that higher doses of lorazepam than those formerly used may be necessary during alcohol withdrawal., THE GOAL OF MEDICALLY ASSISTED alcohol withdrawal (alcohol detoxification) is to relieve the immediate symptoms of withdrawal, prevent delirium and other life-threatening complications of withdrawal, treat associated medical or psychiatric [...]

Clostridium difficile is the leading cause of infectious diarrhoea in hospitals worldwide, because of its virulence, spore-forming ability and persistence (1,2). C. difficile-associated diseases are induced by antibiotic treatment or [...]

The clinical development of an inhibitor of cellular proteasome function suggests that compounds targeting other components of the ubiquitin-proteasome system might prove useful for the treatment of human malignancies. NEDD8-activating enzyme (NAE) is an essential component of the NEDD8 conjugation pathway that controls the activity of the cullin-RING subtype of ubiquitin ligases, thereby regulating the turnover of a subset of proteins upstream of the proteasome. Substrates of cullin-RING ligases have important roles in cellular processes associated with cancer cell growth and survival pathways. Here we describe MLN4924, a potent and selective inhibitor of NAE. MLN4924 disrupts cullin-RING ligase-mediated protein turnover leading to apoptotic death in human tumour cells by a new mechanism of action, the deregulation of S-phase DNA synthesis. MLN4924 suppressed the growth of human tumour xenografts in mice at compound exposures that were well tolerated. Our data suggest that NAE inhibitors may hold promise for the treatment of cancer., The ubiquitin-proteasome system (UPS) is responsible for the regulated degradation of intracellular proteins with important roles in a broad array of cellular functions (1). One drug which targets the UPS, [...]

Abstract The antiulcer effect of bisdemethoxycurcumin, a yellow pigment found mainly in rhizomes of Curcuma longa, was compared with curcumin in gastric ulcer model systems to validate its clinical application [...]

Inhaled isoflurane is one of many chemical immobilizing agents available for field anesthesia of wildlife. We examined the use of inhaled isoflurane for field immobilization of mesopredators. Five species of mammals were anesthetized in a wetland complex in south-central Nebraska with isoflurane; we developed an induction chamber to use with a portable anesthesia machine to provide anesthesia at the capture location. Sixteen raccoons (Procyon lotor), 20 striped skunks (Mephitis mephitis), 4 Virginia opossums (Didelphis virginiana), 2 American badgers (Taxidea taxus) and 1 mink (Mustela vison) were captured and immobilized; we radio-marked 11 raccoons and 9 skunks. Induction was smooth and uneventful for all species immobilized. Mean induction times for raccoons and skunks were 10.7 min (SD = 1.1) and 11.0 min (SD = 2.4) respectively. Mean handling times (post-induction) were 7.1 min (SD = 3.9) for raccoons and 7.3 min (SD = 4.8) for skunks. All animals, with the exception of opossums, were fully recovered within 15 min (raccoon mean recovery: 11.1 min, SD = 3.5; skunk mean recovery: 10.9 min, SD = 3.7). Recovery times for radio-collared animals and uncollared animals did not differ, and individuals with longer handling times did not require longer recovery times. Although isoflurane requires more equipment than injectable anesthesia methods, its short recovery time and wide safety margins deem it practical for use in a variety of field applications., INTRODUCTION Immobilizing agents for field anesthesia of wildlife are available in a variety of combinations, each varying in effectiveness relative to species, body weight, specific combinations and dosages (Seal and [...]

This essay examines Leonora Carrington's Down Below through a psychiatric lens. In particular, it looks at clinical accounts of Cardiazol-induced shock treatments next to Carrington's own testimony of the helplessness imposed upon the mentally ill and the socially transgressive. Cardiazol--an analeptic drug used to induce seizures strong enough to fracture vertebrae and stop the heart--is often mentioned in Carrington scholarship, but scholars have not delved into the drug's protocol. In fact, theorists have too readily accepted the details of psychiatric treatment in Carrington's piece as symbolic, metonymic, or simply fantastic recollections from a damaged mind. They concentrate on her more lucid interpretations after she has healed from her ordeal. However, when set beside clinical descriptions of Cardiazol treatment, the text appears more realistic than previously supposed. Down Below presents one of the most comprehensive and accurate patient descriptions of treatment with the psychiatric drug Cardiazol in existence today. Keywords: Carrington / Surrealism / women / autobiography / psychiatry, Beauty will be convulsive, or it will not be at all. --Andre Breton, Nadja Leonora Carrington's Down Below is the autobiography of the author's traumatic mental breakdown in 1939 and [...]

Abstract The process by which SSRIs reduce "depressive symptoms" remains obscure. Biochemical, functional, and taker self-assessment evidences for the "corrective" nature of this process are inconclusive and ultimately incapable of [...]

Abstract Purpose: The purpose of the study was to investigate the safety and efficacy of lemon juice and lemon grass (Cymbopogon citratus) in the treatment of oral thrush in HIV/AIDS [...]

Abstract Introduction: Hemorheological factors play an important role in the pathomechanism of ischemic cerebrovascular disorders. Abnormal rheological conditions in patients with chronic cerebrovascular disease predispose for recurrent strokes. Vinpocetine (VP), [...]

This article, based on an undergraduate dissertation, consists of a literature review to identify, contextualise and critique the body of evidence relating to the use of midazolam as an epilepsy [...]

Conventional wisdom long held that the human immune system was no match for cancer. Born of native cells, the logic went, cancer fooled the immune system into concluding it was [...]

The present study was designed to pharmacologically investigate the possible role of nuclear factor kappa B (NF-κB) in the reversal of global cerebral injury induced by ischemia and reperfusion after ischemic postconditioning. Bilateral carotid artery occlusion for 17 min followed by reperfusion for 24 h was employed to produce ischemia- and reperfusion-induced cerebral injury in mice. Cerebral infarct size was measured by using triphenyltetrazolium chloride staining. Memory was evaluated using the Morris water maze test. The rotarod test was employed to assess motor incoordination. Bilateral carotid artery occlusion followed by reperfusion produced a marked increase in cerebral infarct size, impairment of memory, and motor coordination. A set of 5 episodes of carotid artery occlusion for a period of 10 s and reperfusion of 10 s (ischemic postconditioning) significantly prevented ischemia--reperfusion-induced cerebral infarct size and behavioral deficits measured in terms of loss of memory and motor coordination. Diethyl dithiocarbamic acid sodium salt trihydrate (DDA) (100 mg/kg, i.p.), an inhibitor of NF-κB, given 30 min before ischemia attenuated the beneficial effects of ischemic postconditioning. It may be concluded that the beneficial effects of ischemic postconditioning on global cerebral ischemiaand reperfusion-induced cerebral injury and behavioral deficits may involve activation of the NF-κB-linked pathway. Key words: ischemic postconditioning, cerebral ischemia, nuclear factor kappa B, diethyl dithiocarbamic acid. La presente etude a ete concue pour examiner sur le plan pharmacologique le role possible du facteur nucleaire kappa B (NF-κB) dans le renversement induit par le postconditionnement ischemique de la lesion cerebrale globale induite par ischemie-reperfusion chez des souris. On a induit la lesion d'ischemie-reperfusion cerebrale par l'occlusion bilaterale des arteres carotides durant 17 min, suivie d'une reperfusion durant 24 h. On a mesure la taille de l'infarctus cerebral par coloration au chlorure de triphenyltetrazolium, evalue la memoire par le test de labyrinthe aquatique de Morris et estimer l'incoordination motrice par le test de la tige tournante. L'occlusion bilaterale des arteres carotides et la reperfusion ont provoque une augmentation marquee de la taille de l'infarctus cerebral, du dysfonctionnement de la memoire et de la coordination motrice. Une serie de 5 episodes d'occlusion d'arteres carotides pendant une periode de 10 s et de reperfusion pendant 10 s (postconditionnement ischemique) a diminue considerablement la taille de l'infarctus cerebral induit par l'ischemie-reperfusion et les deficits comportementaux mesures en termes de perte de memoire et de coordination motrice. Le sel de sodium trihydrate de l'acide diethyldithiocarbamique (DDA) (100 mgikg, i.p.), un inhibiteur du NF-κB, administre 30 min avant l'ischemie, a attenue les effets benefiques du postconditionnement ischemique. On peut conclure que les effets benefiques du postconditionnement ischemique sur la lesion cerebrale globale induite par ischemie-reperfusion et sur les deficits comportementaux pourraient impliquer l'activation de la voie associee au facteur nucleaire κ-B. Mots-cles : postconditionnement ischemique, ischemie cerebrale, facteur nucleaire kappa B, acide diethyldithiocarbamique. [Traduit par la Redaction], Introduction Ischemic stroke is a syndrome characterized by rapid onset of neurologic injury due to interruption of blood flow to the brain (Baker et al. 1998). Although mortality from ischemic [...]

A recombinant adenovirus serotype 5 (rAd5) vector-based vaccine for HIV-1 has recently failed in a phase 2b efficacy study in humans (1,2). Consistent with these results, preclinical studies have demonstrated [...]

Today, on university campuses around the world, students are striking deals to buy and sell prescription drugs such as Adderall and Ritalin--not to get high, but to get higher grades, [...]

Crosstalk between the oestrogen receptor (ER) and ERBB2/HER-2 pathways has long been implicated in breast cancer aetiology and drug response (1), yet no direct connection at a transcriptional level has [...]

Cardioprotection due to angiotensin enzyme inhibitors is attributed, at least in part, to the inhibition of bradykinin breakdown and the preconditioning effect of the elevated endogenous bradykinin level. We have previously shown that in patients undergoing percutaneous coronary intervention, one 120-second balloon inflation is insufficient to precondition the heart. The objective of the present study was to examine whether the administration of enalaprilat to these patients results in protection. Twenty patients underwent two 120-second coronary artery occlusions separated by a reperfusion interval of 10 min. Ten patients were given 50 µg x [min.sup.-1] enalaprilat in an intracoronary infusion between the balloon inflations, whereas the others received an infusion of saline. In the latter control patients, there were no significant differences in ST-segment elevation between the consecutive occlusions (peak ST: 1.61 ± 0.17 vs. 1.61 ± 0.16 mV; time to reach 0.5 mV ST elevation: 16 ± 4 vs. 22 ± 7 s; mean ST: 1.03 ± 0.12 vs. 1.02 ± 0.11 mV). In the patients who received enalaprilat before the second balloon inflation, the ST-segment elevation was significantly less pronounced and slower during the second inflation than during the first (peak ST: 1.80 ± 0.18 vs. 1.41 ± 0.19 mV; time to reach 0.5 mV ST elevation: 18 ± 4 vs. 30 ± 4 s; mean ST: 1.04 ± 0.11 vs. 0.85 ± 0.14 mV). We conclude that enalaprilat administered during percutaneous coronary intervention provides protection to patients who do not have a protective response to the initial balloon inflation Key words: preconditioning, angioplasty, intracoronary ECG, ST-segment changes, enalaprilat La cardioprotection induite par les inhibiteurs de l'enzyme de conversion de l'angiotensine est attribuee, du moins en partie, a l'inhibition de la degradation de la bradykinine et a l'effet de preconditionnement du taux eleve de bradykinine endogene. Nous avons deja demontre que, chez les patients soumis a une intervention coronaire percutanee, le gonflement du ballonnet pendant 120 s ne suffit pas pour preconditionner le ccour. La presente etude a pour objectif d'examiner si l'administration d'enalaprilat a ces patients entraine une protection. Vingt patients ont subi deux occlusions de l'artere coronaire d'une duree de 120 s, separees par une reperfusion de 10 min. Dix patients ont rerqu 50 µg x [min.sup.-1] d'enalaprilat sous forme de perfusion intracoronaire entre les gonflements du ballonnet, alors que les autres ont rerqu une perfusion de solution saline. Chez le groupe temoin, il n'y a eu aucune difference significative dans l'elevation du segment ST entre les occlusions (elevation ST maximale : 1,61 ± 0,17 vs. 1,61 ± 0,16 mV; temps pour atteindre une elevation du segment ST de 0,5 mV : 16 ± 4 vs. 22 ± 7 s; elevation ST moyenne: 1,03 ± 0,12 vs. 1,02 ± 0,11 mV). Chez les patients ayant recu l'enalaprilat avant le deuxieme gonflement du ballon, l'elevation du segment ST a ete significativement moins prononcee et plus lente durant le deuxieme gonflement que durant le premier (elevation ST maximale : 1,80 ± 0,18 vs. 1,41 ± 0,19 mV; temps pour atteindre une elevation du segment ST de 0,5 mV : 18 ± 4 vs. 30 ± 4 s; elevation ST moyenne 1,04 ± 0,11 vs. 0,85 ± 0,14 mV). L'administration d'enalaprilat durant une intervention coronaire percutanee assure une protection aux patients qui ne repondent an premier episode de gonflement du ballonnet Mots-cles : preconditionnement, angioplastie, ECG intracoronaire, modifications du segment ST, enalaprilat. [Traduit par la Redaction], Introduction Ischemic preconditioning was originally defined as an endogenous adaptive response to brief periods of ischemic stress that protects the myocardium against the severe consequences of a subsequent and more [...]

The aim of the study was to investigate the therapeutic effect and mechanism of proanthocyanidins from grape seeds (GSPE) in the treatment of ulcerative colitis (UC). Rats were intragastrically administered different doses of GSPE (100, 200, and 400 mg/kg) per day for 7 days after UC was twice-induced by intracolonic injection of 2,4,6trinitrobenzene sulfonic acid (TNBS)dissolved in 50% ethanol. Sulfasalazine (SASP) at 200 mg/kg was used as a positive control drug. Macroscopic and microscopic damage scores and changes in weight/length ratio (mg/mm) of colon segments were analyzed. The levels of malonyldialdehyde (MDA), interleukin (IL)-1 β, IL-2, IL-4, and myeloperoxidase (MPO) activity in the colon tissues and MPO activity in the serum were all measured by biochemical methods or double antibody sandwich ELISA methods. Compared with the TNBS control group, GSPE treatment facilitated recovery of pathologic changes in the colon after insult with TNBS, as demonstrated by increased body weight (p < 0.01) and decreased colonic weight/ length ratio (p < 0.01); GSPE also notably reduced the colonic macroscopic and microscopic damage scores (p < 0.01). The MPO activity in colon tissues and serum of rats treated with GSPE was significantly lower than that in the TNBS control group. The MDA and IL-1 β levels of colon tissues were also decreased in GSPE groups. The intestinal antiinflammatory effect of GSPE was accompanied by a significant improvement of IL-2 and IL-4 levels in the colon tissues of rats in the high-dose GSPE group (p < 0.05). Compared with the SASP group, GSPE groups had no significant difference in the therapeutic effect (p > 0.05). GSPE exerts a beneficial anti-inflammatory effect in the acute phase of TNBS-induced colitis in rats by downregulating some of the mediators involved in the intestinal inflammatory response, inhibiting inflammatory cell infiltration and antioxidation damage, promoting damaged tissue repair to improve colonic oxidative stress, decreasing production of proinflammatory cytokines IL-1 β, and increasing production of anti-inflammatory cytokines IL-2 and IL-4. Key words: proanthocyanidins from grape seeds, ulcerative colitis, trinitrobenzene sulfonic acid, antiinflammatory, antioxidation, interleukin. Pour examiner l'effet therapeutique et le mecanisme des proanthocyanidines extraites des graines de raisin (GSPE) chez des rats souffrant de colite ulcereuse (CU) induite par l'acide 2,4,6-trinitrobenzene sulfonique (TNBS), on leu a administre differentes doses de GSPE (100, 200 et 400 mg/kg) par voie intragastrique, tons les jours pendant 7 jours, apres que la CU a ete induite deux fois par l'injection intracolique de TNBS dissous dans de l'ethanol 50 %. La sulfasalazine (200 mg/kg, SASP) a servi de medicament temoin positif. Puis les rats ont ete sacrifies. Les scores des lesions microscopiques et macroscopiques, et les modifications de la relation poids/longueur (mg/mm) des segments de colon ont ete analyses. Les taux de malonyldyaldehyde (MDA), interleukine-1 β (IL-1β), interleukine-2 (IL-2), interleukine- 4 (IL-4) et l'activite de la myeloperoxydase (MPO) dans les tissus coliques ainsi que l'activite MPO dans le serum ont tons ete mesures par des methodes biochimiques et des tests ELISA sandwich. Comparativement a ce qui a ete observe chez le groupe temoin TNBS, le traitement avec les GSPE a facilite la regression des modifications pathologiques induites par le TNBS, comme demontre par une augmentation de poids (p < 0,01), une diminution de la relation poids/longueur (p < 0,01) colique et une reduction considerable des scores microscopiques et macroscopiques du colon (p < 0,01). L'activite MPO dans les tissus coliques et le serum des rats traites avec les GSPE a ete nettement plus faible que celle du groupe temoin TNBS. Les taux de MDA et d'IL-1 β dans les tissus coliques ont aussi diminue chez les groupes GSPE. L'effet antiinflammatoire intestinal des GSPE a ete accompanne d'une augmentation significative des taux d'IL-2 et d'IL-4 dans les tissus coliques des rats du groupe GSPE 400 mg/kg (p < 0,05). Comparativement an groupe SASP, les groupes GSPE n'ont pas montre de difference significative dans l'effet therapeutique (p > 0,05). Les GSPE ont un effet antiinflammatoire benefique dans la phase aigue de la colite induite par le TNBS, en diminuant un certain nombre de mediateurs impliques dans la resonse inflammatoire intestinale, en inhibant l'infiltration cellulaire inflammatoire, les dommages oxydatifs, en favorisant la reparation du tissu lese pour diminuer le stress oxydatif colique, en diminuant la production des cytokines proinflammatoires IL-1 β et en augmentant celle des cytokines antiinflammatoires IL-2 et IL-4. Mots-cles : proanthocyanidines extraites des graines de raisin, colite ulcereuse, acide trinitrobenzene sulfonique, antiinflammatoires, antioxydation, interleukine. [Traduit par la Redaction], Introduction Ulcerative colitis (UC) is a multifactorial inflammatory disease of the colon and rectum with an unknown etiology (Cho 2001; Kankuri et al. 2003). Many factors have been implicated in [...]

Beneficial effects of an antioxidant (N-acetyl-i,-cysteine, NAC) and an angiotensin 1-converting enzyme (ACE) inhibitor (ramipril) were assessed in a rat model of insulin resistance induced by 10% glucose feeding for 20 weeks. Treatments with NAC (2 g/kg per day) and ramipril (1 mg/kg per day) were initiated at 16 weeks in the drinking fluid. Systolic blood pressure, plasma levels of insulin and glucose, and insulin resistance were significantly higher in rats treated with glucose for 20 weeks. This was associated with a higher production of superoxide anion and NADPH oxidase activity in aorta and liver and with a marked reduction in protein expression of skeletal muscle insulin receptor substrate-1 (IRS-1) in the gastrocnemius muscle. NAC prevented all these alterations. Although ramipril also reversed high blood pressure, it had a lesser effect on insulin resistance (including IRS-1) and blocked superoxide anion production only in aorta. Ramipril, in contrast to NAC, did not reduce NADPH oxidase activity in aorta and liver or plasma levels of 4-hydroxynonenal and malondialdehyde. Results suggest that the inhibition of the oxidative stress in hypertensive and insulin-resistant states contributes to the therapeutic effects of NAC and ramipril. Whereas NAC exerts effective antioxidant activity in multiple tissues, ramipril appears to preferentially target the vasculature. Key words: ACE inhibitor, hypertension, insulin resistance, N-acetyl-i,-cysteine, oxidative stress, ramipril. On a evalue les effets benefiques d'un antioxydant (N-acetyl-i,-cysteine, NAC) et d'un inhibiteur de l'enzyme de conversion de l'angiotensine-1 (ECA) (Rmpril) dans un modele de rats presentant une resistance a l'insuline induite par l'ingestion de 10 % de glucose pendant 20 semaines. On a incorpore la NAC (2 g/kg par jour) et le ramipril (1 mgikg par jour) durant la 16' semaine dans le liquide de consommation. La pression arterielle systolique, les taux plasmatiques d'insuline et de glucose et la resistance a l'insuline ont ete significativement plus eleves chez les rats traites avec le glucose pendant 20 semaines. Ce resultat a ete associe a une augmentation de la production d'anions superoxyde et de l'activite de la NADPH oxydase dans l'aorte et le foie, et a une reduction marquee de l'expression de la proteine substrat du recepteur de l'insuline (IRS-1) musculaire squelettique dans le muscle gastrocnemien. La NAC a prevenu toutes ces modifications. Bien que le ramipril ait aussi renverse l'hypertension, il a eu un plus faible effet sur la resistance a l'insuline (y compris 1'IRS-1) et a bloque la production d'anions superoxyde dans l'aorte seulement. Le ramipril n'a pas diminue l'activite de la NADPH oxydase dans l'aorte et le foie ou les taux plasmatiques de 4-hydroxynonenal et de malondialdehyde, contrairement a la NAC. Les resultats donnent a penser que l'inhibition du stress oxydatif durant l'hypertension et la resistance a l'insuline contribue aux effets therapeutiques de la NAC et du ramipril. La NAC exerce une activite antioxydante efficace dans de multiples tissus, alors que le ramipril semble davantage cibler le systeme vasculaire. Mots-cles : inhibiteur de PECA, hypertension, resistance a l'insuline, N-acetyl-i,-cysteine, stress oxydatif, ramipril. [Traduit par la Redaction], Introduction The 'metabolic syndrome' is an emerging epidemic worldwide that consists of an association of multiple cardiovascular risk factors (Giugliano et al. 1995). These factors, including hypertension, insulin resistance, and [...]

Glucocorticoids may improve lung function in newborns with meconium aspiration syndrome (MAS), but information on the acute side effects of glucocorticoids in infants is limited. In this study using a rabbit model of MAS, we addressed the hypothesis that systemic administration of dexamethasone causes acute cardiovascular changes. Adult rabbits were treated with 2 intravenous doses of dexamethasone (0.5 mg/kg each) or saline at 0.5 h and 2.5 h after intratracheal instillation of human meconium or saline. Animals were oxygen-ventilated for 5 h after the first dose of treatment. Blood pressure, heart rate, and short-term heart rate variability (HRV) were analyzed during treatment, for 5 min immediately after each dose, and for the 5 h of the experiment. In the meconium-instilled animals, dexamethasone increased blood pressure, decreased heart rate, increased HRV parameters, and caused cardiac arrhythmia during and immediately after administration. In the saline-instilled animals, the effect of dexamethasone was inconsistent. In these animals, the acute effects of dexamethasone on blood pressure and cardiac rhythm were reversed after 30 min, whereas heart rate continued to decrease and HRV parameters continued to increase for 5 h after the first dose of dexamethasone. These effects were more pronounced in meconium-instilled animals. If systemic glucocorticoids are used in the treatment of MAS, cardiovascular side effects of glucocorticoids should be considered. Key words: meconium aspiration, glucocorticoids, dexamethasone, blood pressure, heart rate, heart rate variability, nongenomic effects. Les glucocorticoides pourraient ameliorer la fonction pulmonaire dans le syndrome d'aspiration meconiale (SAM), mais il existe peut d'information sur leurs effets secondaires aigus. Dans le present article, nous verifions l'hypothe se que l'administration systemique de dexamethasone entraine des modifications cardiovasculaires aigues dans le mode le de SAM chez le lapin. Des lapins adultes ont recu deux doses de dexamethasone (0,5 mg/kg chacune) ou une solution saline par voie intraveineuse 0,5 h et 2,5 h apres une instillation intratechale de meconium humain ou de solution saline. Les animaux ont recu de l'oxygene pendant 5 h apres l'administration de la premiere dose. La pression arterielle, la frequence cardiaque et la variabilite de la frequence cardiaque (VFC) a court terme ont ete analysees durant et immediatement apres chaque dose, et ce, jusqu'a 5 h apres l'administration. Chez les animaux instilles de meconium, le dexamethasone a augmente la pression arterielle, diminue la frequence cardiaque, augmente les parametres de la VFC, et provoque une arythmie cardiaque durant et immediatement apres l'administration. Chez les animaux instilles de solution saline, l'effet du dexamethasone a ete irregulier. Les effets aigus du dexamethasone sur la pression arterielle et le rythme cardiaque ont ete renverses apres 30 min. A l'oppose, la frequence cardiaque a diminue et les parametres de la VFC ont augmente pendant 5 h apres la premiere dose de dexamethasone, et ces effets ont ete plus prononces chez les animaux instille s au meconium. Les effets secondaires des glucocorticoides sur le systeme cardiovasculaire devraient etre pris en compte quand ils sont utilises dans le traitement du SAM. Mots-cles : aspiration du meconium, glucocorticoides, dexamethasone, pression arterielle, frequence cardiaque, variabilite de la frequence cardiaque, effets non genomiques. [Traduit par la Redaction], Introduction Meconium aspiration syndrome (MAS) is a serious neonatal disease with complex pathophysiology. Aspirated meconium obstructs the airways and causes ventilation and perfusion mismatch, hypoxemia, and acidosis. Progressive inflammation, dysfunction [...]

Citalopram (CITA) is available as a racemic mixture or as (+)-(S)-CITA. In humans, CITA is metabolized to demethylcitalopram (DCITA) by CYP2C19, CYP2D6, and CYP3A and to didemethylcitalopram by CYP2D6. There are no data regarding the enzymes involved in CITA and DCITA metabolism in rats. The present study investigated the influence of CYP inhibitors on the enantioselective metabolism of CITA in rats. Male Wistar rats (n = 6) received a single dose of 20 mg*[kg.sup.-1] CITA after pretreatment with 80 mg*[kg.sup.-1] quinidine, 10 mg*[kg.sup.-1] fluvoxamine, 50 mg*[kg.sup.-1] ketoconazole, or vehicle (control). Blood samples were collected up to 20 h after CITA administration. The CITA and DCITA enantiomers were analyzed by LC-MS/MS using a Chiralcel OD-R column. The kinetic disposition of CITA was enantioselective in rats ([AUC.sub.S/R] ratio = 0.4). Coadministration with quinidine resulted in non-enantioselective inhibition of the metabolism of CITA. Coadministration with fluvoxamine or ketoconazole, however, inhibited only the metabolism of (+)-(S)-CITA, but not of (-)-(R)-CITA when the racemic drug was administered to rats. Key words: citalopram, pharmacokinetics, enantiomers, quinidine, ketoconazole, fluvoxamine. Le citalopram (CITA) est disponible sous forme de melange racemique ou sous forme (+)-(S)-CITA. Chez les humains, CITA est metabolise en demethylcitalopram (DCITA) par CYP2C19, CYPD26 et CYP3, et en didemethylcitalopram par CYPD6. Il n'existe pas de donnees sur les enzymes participant au metabolisme de CITA et DCITA chez les rats. La presente etude a examine l'influence des inhibiteurs de CYP sur le metabolisme enantioselectif de CITA chez les rats. Des rats Wistar males (n = 6) ont recu une seule dose de 20 mg*[kg.sup.-1] de CITA ou ont ete pretraites avec 80 mg*[kg.sup.-1] de quinidine, 10 mg*[kg.sup.-1] de fluvoxamine, 50 mg*[kg.sup.-1] de ketoconazole, ou le vehicule temoin. Des echantillons sanguins ont ete preleves jusqu'a 20 h apres l'administration de CITA. Les enantiomeres de CITA et de DCITA ont ete analyses par LC-MS/MS sur une colonne Chiralcel OD-R. L'elimination cinetique de CITA a ete enantioselective (rapport de la surface sous la courbe [(SSC).sub.S/R] = 0,4). La coadministration avec la quinidine a provoque une inhibition non enantioselective du metabolisme de CITA. Toutefois, la coadministration avec la fluvoxamine ou avec le ketoconazole a inhibe seulement le metabolisme de (+)-(S)-CITA, et pas de (-)-(S)-CITA, lorsque le medicament racemique a ete administre aux rats. Mots-cles: citalopram, pharmacocinetique, enantiomeres, quinidine, ketoconazole, fluvoxamine. [Traduit par la Redaction], Introduction Citalopram (CITA), a drug used for the treatment of depression, is available as a racemic mixture or as the pure enantiomer (+)-(S)-CITA. Its antidepressive action is related to (+)-(S)-CITA [...]

Diet can be an important factor that influences risks for cardiovascular disease. Genistein (4',5,7-trihydroxyisoflavone), rich in soy, is one candidate that may benefit the cardiovascular system. Here, we explored the effect of genistein in atherosclerosis (AS) development in an in vivo mouse model. Low-density lipoprotein receptor (LDLR) knockout mice were allocated to control, model, and genistein groups. Our results showed that genistein significantly reduced the formation and development of atherosclerotic plaques ((4.68 ± 1.18) x [10.sup.6] versus (6.65 ± 1.51) x [10.sup.6] µ[m.sup.2], p < 0.05). In the genistein group, compared with the model group, total antioxidant capacity (TAC) level was 85.5 ± 15.6 versus 203.4 ± 32.6 mmol/L (p < 0.01); malondialdehyde (MDA) level was 3.79 ± 0.28 versus 3.06 ± 0.31 mmol/L (p < 0.01), and superoxide dismutase (SOD) activity was 86.1 ± 6.1 versus 139.1 ± 25.1 U/mL (p < 0.01). Therefore, genistein was able to enhance serum antioxidative ability in our mouse model. Genistein had no influence, however, on serum cholesterol and lipid profiles. Genistein also markedly downregulated the expression of nuclear factor (NF)-KB and vascular cell adhesion molecule (VCAM)-1 in aortas of mice (p < 0.05). These observations suggest that genistein may inhibit AS in [LDLR.sup.-/-] mice via enhancing serum antioxidation and downregulating NF-κB and VCAM-1 expression in the aorta. Key words: genistein, atherosclerosis, NF-κB, VCAM-1, LDLR knockout mice. La diete peut etre un facteur de risque important de maladies cardiovasculaires. La genisteine (4',5,7-trihydroxyisoflavone), riche en soya, est un candidat qui pourrait etre d'une grande utilite pour le systeme cardiovasculaire. Dans le present article, nous avons explore l'effet de la genisteine sur le developpement de l'atherosclerose (AS) dans des modeles in vivo. Nous avons reparti des souris au gene LDLR invalide (knockout) dans trois groupes : temoin, modele et genisteine. Nos resultats ont montre que la genisteine a diminue de facon significative la formation et le developpement des plaques d'atherosclerose ((4,6 ± 1,18) x 10-6 contre (6,65 ± 1,51) x [10.sup.6] µ[m.sup.2], p < 0,05). Chez le groupe genisteine, l'indice TAC a ete de 85,5 ± 16,6 contre 203,4 ± 32,6 mmol/L (p < 0,01), le taux de MDA de 3,79 ± 0,28 contre 3,06 ± 0,31 mmol/L (p < 0,01) et l'activite SOD de 86,1 ± 6,1 contre 139,1 ± 25,1 U/mL (p < 0,01) par rapport au groupe modele, respectivement. Ainsi, la genisteine a pu stimuler la capacite antioxydative serique dans les modeles de souris. Toutefois, elle n'a pu influer sur les profils des lipides et du cholesterol seriques. La genisteine a aussi diminue considerablement l'expression de NF-κB et de VCAM-1 dans les aortes de souris (p < 0,05). Ces observations donnent a penser que la genisteine pourrait inhiber l'AS chez les souris [LDLR.sup.-/-] en stimulant l'antioxydation serique et en diminuant l'expression de NF-κB et de VCAM-1 dans l'aorte. Mots-cles : genisteine, atherosclerose, NF-κB, VCAM-1, souris knockout LDLR. [Traduit par la Redaction], Introduction Diet can be an important factor that influences the risks for cardiovascular disease (Keys et al. 1986), and consumption of a traditional Asian diet high in soy may play [...]

Objective: The purpose of this study was to examine the nature of the effect of placebo medication plus accompanying medical management in the treatment of alcohol dependence. Method: The National Institute on Alcohol Abuse and Alcoholism COMBINE (Combining Medications and Behavioral Interventions) study, a randomized controlled double-blind trial of 1,383 alcohol-dependent patients, compared combinations of medications (acamprosate [Campral] and naltrexone [ReVia]) and behavioral therapy (medical management and specialist-delivered behavioral therapy) for alcohol dependence. This report focuses on a subset of that study population (n = 466) receiving (1) specialized behavioral therapy alone (without pills), (2) specialized behavioral therapy + placebo medication + medical management, or (3) placebo + medical management. Results: During 16 weeks of treatment, participants receiving behavioral therapy alone had a lower percentage of days abstinent (66.6%) than did the participants receiving placebo and medical management (73.1%) or those receiving specialized behavioral therapy + placebo + medical management (79.4%). The group receiving behavioral therapy alone relapsed to heavy drinking more often (79.0%) than those receiving behavioral therapy + placebo + medical management (71.2%). This report focuses on potential explanations for this finding. The two groups of participants receiving placebo + medical management were more likely to attend Alcoholics Anonymous meetings during treatment (32.7% and 32.0% vs 20.4%) and were less likely to withdraw from treatment (14.1% and 22.9% vs 29.3%). Conclusions: There appeared to be a significant 'placebo effect' in the COMBINE Study, consisting of pill taking and seeing a health care professional. Contributing factors to the placebo response may have included pill taking itself, the benefits of meeting with a medical professional, repeated advice to attend Alcoholics Anonymous, and optimism about a medication effect., THE USE OF PLACEBOS in medication studies is common (Temple and Ellenberg, 2000), although controversial (Rothman and Michels, 1994). The purpose of placebo is to ensure that the superiority of [...]

The purpose of this review was to explore whether the weight gain caused by clozapine was purely pharmacodynamic or whether there other factors were involved. Issues such as why people [...]

In accordance with its mandate to provide guidance to Member States on health-policy matters, WHO issues a series of regularly updated position papers on vaccines and vaccine-combinations against diseases that [...]

WHO convenes technical meetings (1) in February and September each year to recommend the composition of seasonal influenza vaccines (2) for the northern and southern hemispheres, respectively. This recommendation relates [...]

Therapeutic effect of rosiglitazone has been reported to result from an improvement of insulin sensitivity and inhibition of glucose synthesis. As the latter process occurs in both liver and kidney cortex the aim of this study was to elucidate the rosiglitazone action on glucose formation in both tissues. Primary cultured cells of both liver and kidney cortex grown in defined medium were use throughout. To identify the mechanism responsible for drug-induced changes, intracellular gluconeogenic intermediates and enzyme activities were determined. In contrast to hepatocytes, the administration of a 10 mmol/L concentration of rosiglitazone to renal tubules resulted in about a 70% decrease in the rate of gluconeogenesis, accompanied by an ~75% decrease in alanine utilization and a 35% increase in lactate synthesis. The effect of rosiglitazone was not abolished by GW9662, the PPAR-γ irreversible antagonist, indicating that this action is not dependent on PPAR-γ activation. In view of rosiglitazone-induced changes in gluconeogenic intermediates and a diminished incorporation of [sup.14][CO.sub.2] into pyruvate, it is likely that the drug causes a decline in flux through pyruvate carboxylase and (or) phosphoenolpyruvate carboxykinase. It is likely that the hypoglycemic action of rosiglitazone is PPAR-γ independent and results mainly from its inhibitory effects on renal gluconeogenesis. Key words: diabetes, rosiglitazone, glucose synthesis, PPAR-γ, primary cultures. L'effet therapeutique de la rosiglitazone semble resulter d'une amelioration de la sensibilite a l'insuline et de l'inhibition de la synthese de glucose. Puisque ce dernier processus se produit dans le foie et le cortex renal, le but de cette etude etait d'elucider l'action de la rosiglitazone sur la formation de glucose dans ces deux tissus. Des cultures primaires de foie et de cellules du cortex renal cultivees dans un milieu defini ont ete utilisees pour toutes les experiences. Afin d'identifier le mecanisme responsable des changements induits par le medicament, les intermediaires intracellulaires et l'activite des enzymes de la neoglucogenese ont ete determines. Contrairement aux hepatocytes, l'administration de 10 mmol/L de rosiglitazone aux tubules renaux a resulte en une diminution d'environ 70 % du taux de neoglucogenese, accompagne e par une diminution de 75 % de l'utilisation de l'alanine et d'une augmentation de 35 % de la synthese du lactate. L'effet de la rosiglitazone n'etait pas aboli par le GW9662, un antagoniste reversible du PPAR-γ, indiquant que cette action etait independante de l'activation du PPAR-γ. Considerant les changements induits par la rosiglitazone chez les interme diaires de la neoglucogenese et la diminution de l'incorporation de [sup.14][CO.sub.2] dans le pyruvate, il est probable que le medicament cause un declin du flux via la pyruvate carboxylase et (ou) la phosphoenolpyruvate carboxykinase. Il est aussi probable que l'action hypoglycemiante de la rosiglitazone soit independante du PPAR-γ et qu'elle resulte principalement de ses effets inhibiteurs de le neoglucogenese renale. Mots-cles : diabete, rosiglitazone, synthese de glucose, PPAR-γ, cultures primaires. [Traduit par la Redaction], Introduction Diabetic hyperglycemia results from β-cell dysfunction, insulin resistance of the liver and peripheral tissues, including skeletal muscle and adipose tissue, and glucose overproduction because of an acceleration of gluconeogenesis [...]

The mechanisms by which cells undergo proliferation arrest or cell death in response to hypoxia are still not completely understood. Originally, we showed that HeLa and Hep3B carcinoma cells undergo different proliferation responses in hypoxia. We now show that these 2 cell lines also have different cell death responses to severe hypoxia, with HeLa showing both cell cycle arrest and apoptosis (as early as 12 h after hypoxia treatment), and Hep3B showing resistance to both. Hypoxia-induced apoptosis in Hela was associated with decreases of both phospho-S473- and -T308-AKT and loss of AKT function, whereas Hep3B cells were resistant to hypoxia-induced apoptosis and did not lose phosphoAKT or AKT function. We then decided to test if our observations were confirmed using a hypoxia mimic, desferoxamine. Desferoxamine treatment yielded cell cycle arrest in HeLa and moderate arrest in Hep3B but, surprisingly, did not induce notable apoptosis of either cell line with up to 24 h of treatment. Hypoxia-treated normal human mammary epithelial cells also showed hypoxia-induced apoptosis. Interestingly, in these cell lines, there was a complete correlation between loss of phospho-AKT and (or) total AKT, and susceptibility to hypoxia-induced apoptosis. Our data suggests a model in which regulated loss of active AKT at a precise time point in hypoxia may be associated with apoptosis in susceptible cells. Key words: AKT, apoptosis, cell cycle, desferoxamine, hypoxia. Les mecanismes par lesquels les cellules s'engagent vers l'arret de la proliferation ou la mort cellulaire en reponse a l'hypoxie ne sont pas encore completement compris. A l'origine, nous avons demontre que les cellules de carcinome HeLa et Hep3B repondent de facon differente a l'hypoxie en ce qui a trait a la proliferation. Nous demontrons maintenant que ces deux lignees cellulaires repondent aussi differemment quant a la mort cellulaire suite a une hypoxie severe, les HeLa repondant par un arret du cycle cellulaire et par l'apoptose (aussi toet que 12 h apres un traitement hypoxique) alors que les Hep3B etaient resistantes aux deux phenomenes. L'apoptose induite par l'hypoxie chez les HeLa etait associee a une diminution des formes phospho-S473- et -T308-AKT et a une perte de fonction de l'AKT, alors que chez les cellules Hep3B resistantes a l'apoptose induite par l'hypoxie, les formes phosphorylees de l'AKT n'etaient pas diminue es et la fonction de l'AKT n'etait pas perdue. Nous avons alors decide de verifier si nos observations se confirmaient avec un agent mimant l'apoptose, la desferoxamine. Le traitement a la desferoxamine causait un arret du cycle cellulaire des HeLa et un arret modere des Hep3B, mais, de facon surprenante, il n'induisait l'apoptose chez aucune de ces deux ligne es apres un traitement allant jusqu'a 24 h. Des cellules epitheliales mammaires humaines normales soumises a l'hypoxie entraient egalement en apoptose. Fait interessant, chez ces lignees cellulaires, il existait une correlation complete entre la perte des formes phosphorylees de l'AKT et (ou) de l'AKT totale et la susceptibilite a l'apoptose induite par l'hypoxie. Nos resultats suggerent l'existence d'un modele dans lequel une perte regulee d'AKT active a des moments precis de l'hypoxie peut etre associee a l'apoptose dans les cellules sensibles. Mots-cles : AKT, apoptose, cycle cellulaire, desferoxamine, hypoxie. [Traduit par la Redaction], Introduction Hypoxia plays a critical role in the development, progression, and treatment of a large number of cancers. In the initial stages of tumour formation, small tumours can quickly outstrip [...]