Biomedical subjects

B Dupuis

Publications and source records attributed to B Dupuis.

At least 19 recordsLinked to original sources

PubMed2001

Dysregulation of integrin-linked kinase (ILK) signaling in colonic polyposis.

Mutation of the adenomatous polyposis coli (APC) gene and the subsequent dysregulation of beta-catenin are well-documented abnormalities in familial adenomatous polyposis (FAP), as well as sporadic polyposis. Intriguingly, overexpression of the integrin-linked kinase (ILK) has been shown to modulate beta-catenin subcellular localization and function. However, the significance of this finding for human carcinogenesis remains unclear. Here, we report the increased biochemical activity and expression of ILK protein in polyps from FAP patients. Furthermore, dramatic increases in ILK immunoreactivity were observed in all abnormal crypts from sporadic polyps, when compared with the normal appearing crypts within the same resected specimens. As sulindac and aspirin are the two most important therapeutic/chemopreventative agents demonstrated in colorectal carcinogenesis, in both humans and animals, further investigation revealed that these non-steroidal anti-inflammatory drugs (NSAIDs) target ILK and ILK-mediated events in vivo. These include inhibition of, both the biochemical activation of ILK, inhibition of serine 9 GSK3beta phosphorylation and the enhancement of TCF-4 transcriptional activity. In conclusion, ILK protein hyperexpression appears to be an early event in colonic polyposis. Additionally, ILK signaling is shown to undergo modulation by sulindac (and aspirin) for the first time, indicating that it is likely to be one of the targets affected by these agents in vivo.

Adenomatous Polyposis Coli↗

PubMed2001

Analysis of the direct cost of adverse drug reactions in hospitalised patients.

The hospitalised patients in a cardiological hospital (Lille, France) over an 18-month period were subjected to a prospective high-intensity adverse drug reaction (ADR) monitoring in order to assess the additional financial resource utilisation associated with ADRs and analyse the distribution of excess of cost according to ADR nature and therapeutic classes. Over 18 months, among the 16,916 hospitalised patients, 371 verified ADRs detected by self-report stimulated by a special unit of nurses and pharmacologists occurred in 336 patients with an overall ADR rate of 2.2%. This rate increased with age. The most common reactions were cutaneous events (24%), cardiovascular events (21%), metabolic disorders (12%), coagulation disorders (10%) and nervous system impairment (10%). The most common drug classes involved were cardiovascular agents (36%), contrast media (20%), drugs affecting blood clotting (13%) and anti-infectives (14%). Increased ADR-induced costs result especially from prolongation of length of stay and cost increase was evaluated at Euro 4150 per ADR. Among the 371 ADRs, 134 ADRs, which were significantly more severe, induced a prolongation of length of stay. Renal insufficiency and cardiovascular events were significantly over-represented in this sub-group. The most common ADR-inducing drugs associated with a prolongation of length of stay are cardiovascular agents and drugs affecting blood clotting. In contrast, cutaneous ADRs were significantly over-represented in the group of ADRs without prolongation of length of stay. The severity and substantial costs of ADRs in hospital justify investments to prevent these events. Nevertheless, only a portion of ADRs induces cost increases, suggesting that prevention efforts should focus on this limited category of ADRs.

Adult↗

PubMed2001

HER-2/neu in breast cancer: interobserver variability and performance of immunohistochemistry with 4 antibodies compared with fluorescent in situ hybridization.

The immunohistochemistry (IHC) performance of 4 anti-HER-2/neu antibodies was compared with fluorescent in situ hybridization (FISH) analysis of HER-2/neu gene expression in breast cancer patients considered for Herceptin (Trastuzumab) therapy. Interobserver variability in IHC interpretation was measured. Formalin-fixed tissue was received from 24 provincial hospital laboratories. The following anti-Her-2 antibodies were used: DAKO A0485 (polyclonal), Novacastra CB11 (monoclonal), Zymed TAB250 (monoclonal), and DAKO HercepTest (polyclonal). Additional sections were analyzed by FISH (Vysis). Three pathologists blinded to FISH results independently interpreted invasive tumor cell membranous staining on a scale of 0 to +3. The HER-2/neu gene was considered amplified when the FISH signal ratio of HER-2/CEP-17 was > or =2.0. Blocks from all hospitals and of all ages were suitable for IHC and FISH analysis. No interlaboratory analysis variability was noted. The interobserver agreement (kappa) for stain intensity for each antibody was good for 0 and +3 but poor for +1 and +2. Reasonable concordance between IHC and FISH was found with three of the four antibodies. TAB250 was the most sensitive antibody. For the three pathologists, the IHC sensitivities and specificities compared with FISH using 0/+1 as negative and +2/+3 as positive were as follows: A0485, 63-84/95-98; CB11, 63-66/97-98; TAB-250, 82-100/94-95; HercepTest, 59-77/91-93. The positive and negative predictive values varied by stain intensity. Stain scores of 0 and +3 were highly predictive of gene status. Stain scores of +1 and +2 were not sufficiently predictive to classify cases as amplified versus nonamplified. IHC is a reasonable first test to assess HER-2/neu status in patients with breast cancer. For most cases, DAKO A0485, TAB250, and HercepTest adequately predicted gene status. In cases with stain intensity of +1 or +2, the interobserver agreement is poor, and the predictive value is unsatisfactory for clinical use. Additional testing, preferably with FISH, is recommended.

Antibodies, Monoclonal↗

PubMed2000

Increase in endogenous brain superoxide dismutase as a potential mechanism of lipopolysaccharide-induced brain ischemic tolerance.

A low dose (0.5 mg/kg) of lipopolysaccharide (LPS), administered 72 hours before 60-minute middle cerebral artery occlusion, induced a delayed neuroprotection proven by the significant decrease (-35%) of brain infarct volume in comparison with control, whereas infarct volumes remained unchanged in rats treated 12, 24, or 168 hours before ischemia. This delayed neuroprotective effect of LPS was induced only with low doses (0.25 to 1 mg/kg), whereas this effect disappeared with a higher dose (2 mg/kg). The delayed neuroprotection of LPS was induced in the cortical part of the infarcted zone, not in the subcortical part. The beneficial effect of LPS on consequences of middle cerebral artery occlusion was suppressed by dexamethasone (3 mg/kg) and indomethacin (3 mg/ kg) administered 1 hour before LPS, whereas both drugs had no direct effect on infarct volume by themselves, suggesting that activation of inflammatory pathway is involved in the development of LPS-induced brain ischemic tolerance. Preadministration of cycloheximide, an inhibitor of protein synthesis, also blocked LPS-induced brain ischemic tolerance suggesting that a protein synthesis is also necessary as a mediating mechanism. Superoxide dismutase (SOD) could be one of the synthesized proteins because lipopolysaccharide increased SOD brain activity 72 hours, but not 12 hours, after its administration, which paralleled the development of brain ischemic tolerance. In contrast, catalase brain activity remained unchanged after LPS administration. The LPS-induced delayed increase in SOD brain content was suppressed by a previous administration of indomethacin. These data suggest that the delayed neuroprotective effect of low doses of LPS is mediated by an increased synthesis of brain SOD that could be triggered by activation of inflammatory pathway.

Adaptation, Physiological↗

PubMed2000

Chronic amiodarone effects on epicardial conduction and repolarization in the isolated porcine heart.

Amiodarone is a potent antiarrhythmic agent with complex chronic effects, notably on repolarization and conduction, that are not fully understood. Its low arrhythmogenic potential has been related to a lack of increase in repolarization dispersion. Since its effects are not documented in pigs we conducted a mapping study of activation and repolarization in isolated perfused porcine hearts. Amio20 female pigs (n = 7) received amiodarone 20 mg/kg per day over 4 weeks while Amio50 female pigs (n = 7) received 50 mg/kg per day over 4 weeks. Concentrations of the drug encompassed values found in clinical studies. Then, activation patterns and activation-to-recovery intervals (ARI) were mapped epicardially from 128 unipolar electrograms in isolated perfused hearts in corroboration of epicardial action potential recordings. Mean ARI was longer in Amio20 experiments compared to the seven control hearts (325 +/- 11 ms vs 288 +/- 5 ms at 1,000 ms), whereas ARI dispersion was not different, being comprised between 7 and 11 ms and generating smooth gradients. In Amio50 experiments, mean ARI was further prolonged (390 +/- 10 ms at 1,500 ms) with an exaggerated reverse rate dependence concomitant with a depressant effect on the plateau of the action potential. Again, ARI dispersion did not differ from controls. Finally, the drug depressed the maximal rate of depolarization (Vmax) and slowed conduction in a rate dependent and concentration dependent fashion. In conclusion, chronic amiodarone induces Class I and Class III antiarrhythmic effects in ventricular porcine epicardium that are concentration dependent but does not affect dispersion of repolarization. This may partly explain its low arrhythmogenic potential.

Action Potentials↗

PubMed1999

L-arginine and L-NAME have no effects on the reendothelialization process after arterial balloon injury.

OBJECTIVE: Growth regulatory properties of nitric oxide (NO) in cultured endothelial cells is controversial. The aim of our study was to investigate the effect of L-arginine, the endogenous NO precursor, and L-NAME, an inhibitor of NO synthase on the reendothelialization process after angioplasty. METHODS: Fifty-five New Zealand White rabbits underwent denudation of the left iliac artery. After injury the rabbits were randomized in three groups: L-arginine 2.25% (L-arginine, n = 19); NG-nitro-L-arginine methyl ester 15 mg/kg/day (L-NAME, n = 19); and placebo (controls, n = 17). Treatment was solubilized in drinking water. Reendothelialization was evaluated at 4 weeks by macroscopic evaluation of Evans blue staining and endothelial-specific immunostaining (CD-31) on cross sections. Intimal hyperplasia was evaluated by morphometric analysis. RESULTS: Despite a significant increase in plasma arginine (P = 0.001) and a reduction in intimal hyperplasia (P = 0.003) with L-arginine, neither agent had a significant effect on reendothelialization at 4 weeks (controls = 36 +/- 4%, L-arginine = 43 +/- 3%, L-NAME = 33 +/- 4%; NS). CONCLUSION: These results suggest that, in spite of previously demonstrated effects on neointimal hyperplasia, the NO pathway does not influence the regrowth of macrovascular endothelial cells in vivo.

Analysis of Variance↗

PubMed1999

Low dose of lipopolysaccharide induces a delayed enhanced nitric oxide-mediated relaxation in rat aorta.

Delayed effect on vascular reactivity of isolated aorta was studied after injection of a single low dose of lipopolysaccharide (0.5 mg/kg i.p.). The maximal vascular effect was observed 72 h after lipopolysaccharide administration with an increase in maximal endothelium-dependent relaxing response to acetylcholine and parallelly a decrease in contractile response to phenylephrine. The change in contractile response was nullified by endothelium removal as well by in vitro aortic rings incubation with N(omega)-monomethyl-L-arginine but not with indomethacin. A low dose of lipopolysaccharide induces a delayed enhanced nitric oxide-mediated vascular relaxation which could contribute to its delayed anti-ischemic properties in ischemic tolerance phenomenon.

Acetylcholine↗

PubMed1999

Low-risk endometrial carcinoma: assessment of a treatment policy based on tumor ploidy and identification of additional prognostic indicators.

OBJECTIVES: The aims of this study were (1) to assess a treatment policy for patients with low-risk endometrioid endometrial carcinoma where adjuvant treatment decisions have been based on ploidy status of the tumor, and (2) to screen diploid, low-risk tumors for additional features of prognostic significance. METHODS: Between 01/1992 and 08/1996, 406 patients were referred to the B.C. Cancer Agency-Vancouver Clinic with typical endometrial adenocarcinomas limited to <50% myometrial invasion and no vascular space invasion or grade 3 disease on pathology review ("low-risk stage I endometrial carcinoma"). Patients were prospectively assigned to treatment groups based on tumor ploidy. Those patients with aneuploid tumors (n = 91) were treated with adjuvant vaginal vault radiotherapy while those with diploid tumors (n = 315) were followed and treated only at relapse. The hysterectomy specimens from all 14 patients in the untreated, diploid group who relapsed, as well as 28 stage- and grade-matched diploid controls who did not fail, were analyzed by immunohistochemical staining for estrogen receptor (ER), Bcl-2, and p53 proteins. RESULTS: There were no significant differences in the stage (Ia vs Ib) and grade (G1 vs G2) distribution for the diploid and aneuploid groups. Overall median age was 64 years (range 27-90 years) and was also not significantly different for the two groups. The median follow-up for the entire cohort is 45 months (range 1-76 months). There have been 14 failures in the diploid group and 4 failures in the aneuploid group with actuarial 5-year disease-free survival rates of 95.0 and 95.2%, respectively (P = NS). Eight of the failures in the diploid group occurred at the vaginal vault and were all subsequently salvaged with radiotherapy. All but 1 of the failures in the aneuploid group were considered incurable. Of the 14 diploid tumors from patients who failed, 7 stained positively for p53, compared to 4 of 28 diploid controls (P = 0.02). No significant differences were seen in the diploid tumors that recurred, compared to controls, with respect to Bcl-2 or ER expression. CONCLUSIONS: Patients with diploid, low-risk stage I endometrial cancers have excellent prospects for relapse-free and overall survival. Patients with aneuploid tumors treated with adjuvant radiotherapy have the same risk of relapse as untreated patients with diploid tumors; however, their ultimate survival may be lower as a smaller proportion of aneuploid failures are salvageable. While p53 expression in diploid tumors is associated with increased risk of relapse, Bcl-2 and ER are not useful prognostic indicators in this setting.

Adult↗

PubMed1999

Factors affecting epicardial dispersion of repolarization: a mapping study in the isolated porcine heart.

OBJECTIVE: Non-uniform drug-induced prolongation of repolarization predominating in the midmyocardial (M) cell layers has been shown to be responsible for perpetuation of reentry, giving rise to torsade de pointes. However, the absence of M cells in immature animals, especially the pig, suggests other possible underlying mechanisms. We sought to examine, in this species, the effects of predisposing factors to torsade de pointes on the dispersion of epicardial repolarization and their contribution to arrhythmogenesis. METHODS: Computerized mapping of repolarization and activation was conducted on the epicardial surface in 29 Langendorff-perfused hearts of eight-week-old pigs. Activation-recovery intervals were measured simultaneously from 128 unipolar electrograms. RESULTS: Baseline iso-interval maps were dipolar (41%) or multipolar (59%). Dispersion of repolarization was reverse frequency-dependent but was unaffected by lowering [K+]o. DL-Sotalol (0.1 mmol/l) reinforced local gradients and thus increased epicardial dispersion, whereas intramural recordings did not demonstrate any predominant effect in midmyocardial layers. Phenylephrine (1 mumol/l) notably augmented DL-sotalol effects. After [Mg++]o lowering, although dispersion was not significantly increased, DL-sotalol was associated with the spontaneous occurrence of polymorphic ventricular tachycardia in seven out of nine experiments. When maps of repolarization of escape beats were compared with activation maps of first arrhythmic beats, an arc of functional dissociation was observed in the vicinity of a steep gradient of repolarization in two out of nine tachycardias. CONCLUSION: Epicardial dispersion of repolarization is increased by slow rates, DL-sotalol and phenylephrine but is not the only requirement for initiation of polymorphic ventricular tachycardia. In combination with other factors, it helps continuation of the arrhythmia in this model.

Adrenergic alpha-Agonists↗

PubMed1999

Bcl-6 and Bcl-2 protein expression in diffuse large B-cell lymphoma and follicular lymphoma: correlation with 3q27 and 18q21 chromosomal abnormalities.

The bcl-2 gene on chromosome 18 at q21 and the bcl-6 gene on chromosome 3 at q27 are both highly regulated during B-cell differentiation and show an inverse relationship of expression in the normal secondary lymphoid follicle. The objective of this study was to investigate the relationship between bcl-2 and bcl-6 protein expression and the relationship between protein expression and the corresponding chromosomal alterations in malignant lymphomas, including those associated with the germinal center. Expression of bcl-2 and bcl-6 proteins was studied in 55 cases of diffuse large B-cell lymphoma (DLBCL) and 21 cases of follicular lymphoma (FL), and the results correlated with the presence of t(14;18) and 3q27 abnormalities in a subset of 52 cases with cytogenetic analysis. These cases were selected to represent a spectrum of nodal and extranodal lymphomas, including those with and without a t(14;18). It was shown that the neoplastic cells in 71% of DLBCLs and 100% of FLs expressed bcl-6 protein. Expression of bcl-6 was seen more frequently in diffuse large B-cell lymphomas with large noncleaved morphology compared with immunoblastic morphology (82% v 27%, P = .0015), but failed to correlate with 3q27 abnormalities. Thirty-eight percent of cases with 3q27 abnormalities were bcl-6 protein negative, whereas 85% of cases without a 3q27 abnormalities were bcl-6 protein positive. Expression of bcl-2 protein was shown in 51% DLBCLs (nodal v extranodal, 71% v 30%, P = .012). bcl-2 protein was expressed in 89% of FLs with t(14;18), in contrast to 25% of FLs without t(14;18) (P = .016). In DLBCL and FL with t(14;18), the most common pattern of expression was bcl-2+/bcl-6+. In lymphomas without t(14;18), there was not an inverse relationship between bcl-2 and bcl-6 protein expression. In conclusion, these data suggest that mechanisms other than gene rearrangements can deregulate bcl-2 and bcl-6 expression in lymphomas, and there does not appear to be an inverse relationship between these two proteins as seen in the normal germinal center.

Chromosome Aberrations↗

PubMed1999

Role of nitric oxide in restenosis after experimental balloon angioplasty in the hypercholesterolemic rabbit: effects on neointimal hyperplasia and vascular remodeling.

OBJECTIVES: The purpose of this study was to assess the effects of L-arginine and N(G)-nitro-L-arginine methyl ester (L-NAME) on neointimal hyperplasia and vascular remodeling after balloon angioplasty in the hypercholesterolemic rabbit. BACKGROUND: Restenosis after balloon angioplasty is a consequence of both neointimal hyperplasia and vessel remodeling. Nitric oxide inhibits neointimal hyperplasia, but its effect on vessel remodeling is unknown. METHODS: Six weeks after induction of bilateral iliac atherosclerosis, 48 rabbits underwent successful angioplasty in 75 vessels. Eight rabbits (acute group) were sacrificed immediately after angioplasty. The remaining animals received either placebo (chronic control group), or a diet supplemented with either L-arginine (1.5 g/kg/day), or L-NAME (15 mg/kg/day) for 4 weeks after angioplasty. RESULTS: The intimal area was significantly greater in the chronic control group compared to the acute group (2.60+/-1.03 mm2 vs. 1.35+/-0.62 mm2). This increase in intimal area was lower in the L-arginine group (1.79+/-0.61 mm2), and greater in the L-NAME group (3.23+/-0.92 mm2). The area circumscribed by the internal elastic lamina (IEL) increased significantly in the control group compared to the acute group (from 2.52+/-0.66 to 3.33+/-0.85 mm2); a more marked increase occurred in the L-NAME group (3.90+/-0.85 mm2). By contrast, IEL area was unchanged in the L-arginine group (2.41+/-0.62 mm2). As a result, there was no significant difference in lumen area after 4 weeks in the chronic groups (control: 0.74+/-0.38 mm2; L-arginine: 0.50+/-0.43 mm2; L-NAME: 0.48+/-0.42 mm2). CONCLUSIONS: Our results demonstrate that L-arginine inhibits whereas L-NAME stimulates neointimal hyperplasia after experimental balloon angioplasty in the hypercholesterolemic rabbit. However, the lack of vessel enlargement in the L-arginine group resulted in a similar final lumen size in the L-NAME and L-arginine groups.

Angiography↗

PubMed1999

Combined effects of inhaled nitric oxide and hyperoxia on pulmonary vascular permeability and lung mechanics.

OBJECTIVE: To determine whether inhaled nitric oxide (NO) may alter pulmonary vascular permeability and respiratory function in an in vivo model. DESIGN: Prospective, randomized, controlled, experimental study. SETTING: University experimental pharmacology laboratory. SUBJECTS: Mechanically ventilated newborn piglets, 1 to 2 days old, exposed to 100% oxygen for 76 hrs. INTERVENTIONS: The piglets were randomly assigned either to a treatment group receiving 20 ppm inhaled NO from the onset of ventilation (n = 5) or to a control group (n = 6) receiving no treatment. MEASUREMENTS AND MAIN RESULTS: The main variables studied were gas exchange (PaO2/F(IO2) ratio, lung diffusing capacity), respiratory mechanics (static compliance of the respiratory system, stat, quasi-static hysteresis area, functional residual capacity), and pulmonary vascular permeability assessed by simultaneous intravenous administration of iodine-125-labeled albumin and chromium-51-labeled red blood cells. Extravascular albumin space of the lung and dry lung weight were significantly higher in the NO group vs. the control group (albumin space, 1.08+/-0.16 vs. 0.70+/-0.26 [SD] mL/kg body weight [p < .05]; dry lung weight, 3.20+/-0.34 vs. 2.66+/-0.14 g/kg body weight [p < .05]). Moreover, the hysteresis area was higher from 24 hrs of NO exposure. Conversely, NO inhalation altered neither the extravascular lung water content (12.98+/-2.79 mL/kg body weight in the NO group vs. 12.18+/-2.26 mL/kg body weight in the control group [not significant]) nor the main respiratory mechanical variables (static compliance, functional residual capacity) and gas exchange (lung diffusing capacity, PaO2/F(IO2) ratio). CONCLUSION: These results do not support the hypothesis that NO inhalation combined with hyperoxia can alter the main lung-function variables in neonates. However, it may induce an increase in lung vascular protein leakage. The pathophysiologic consequences of this finding remain to be elucidated.

Administration, Inhalation↗

PubMed1999

Relationship between inward rectifier potassium current impairment and brain injury after cerebral ischemia/reperfusion.

Functional alterations of barium-sensitive potassium inward rectifier (KIR) current, which is involved in the vasodilation of middle cerebral arteries (MCA) in rat brain, have been described during brain ischemia/reperfusion (I/R). The authors investigate the effects of I/R on KIR current recorded in isolated myocytes from MCA of control rats and from contralateral and ipsilateral MCA of ischemic rats by the whole-cell patch-clamp technique, and the relationship between its alteration and the severity of brain injury. The vascular smooth muscle cells exhibited similar morphologic features in all conditions, and the KIR was present in the three groups of myocytes, exhibiting a characteristic inward rectification and a normal external potassium dependence. The KIR density was significantly reduced in cell of MCA ipsilateral to occlusion with a maximum at -135 mV, whereas there was no difference between control and contralateral cells. This alteration in KIR density in occluded MCA was significantly correlated with severity of brain injury and brain edema. These results suggest that the alteration of KIR density in MCA myocytes after I/R and the consecutive impaired dilation of MCA may contribute to aggravation of the brain injury.

Animals↗

PubMed1998

Differential effects of quinidine, flecainide, and cibenzoline on anisotropic conduction in the isolated porcine heart.

INTRODUCTION: Anisotropic conduction characteristics, expressed as the ratio of conduction velocities in the longitudinal (Vl) and transverse (Vt) fiber directions, may play a role in the mechanism of some ventricular tachycardias and is influenced by pharmacologic interventions. Discrepancies exist among the reported orientation-dependent effects of available Class I antiarrhythmic drugs. The aim of this study was to assess the respective effects of quinidine (Class IA), flecainide (Class IC), and cibenzoline (not subclassified) on the anisotropic conduction of porcine hearts, in corroboration of their effects on ventricular action potentials. METHODS AND RESULTS: We studied the actions of 3 and 10 microM quinidine, 1 and 3 microM flecainide, and 0.3 and 1 microM cibenzoline on Vl and Vt determined from 128 electrograms recorded with a plaque electrode on the anterior left ventricle of isolated perfused hearts (spacing 2.5 mm). Vl and Vt were computed from isochronal maps displaying ellipsoid activation during stimulation from the center of the plaque. The effects on the maximal rate of depolarization (Vmax) of action potentials were obtained from ventricular muscle exposed to the same drugs. Flecainide [1 microM] and cibenzoline [0.3 microM] did not alter Vl and Vt significantly. Quinidine [3 microM] predominantly depressed Vl at rapid pacing rates, but the Vl/Vt ratio was not significantly altered. Quinidine [10 microM] and flecainide [3 microM] reduced Vl and Vt in a frequency-dependent fashion. Conversely, cibenzoline [1 microM] mostly decreased Vl and thus decreased the Vl/Vt ratio and increased the Vl/Vt at all pacing rates. This different effect was not related to a greater depressant effect on Vmax CONCLUSION: Quinidine and flecainide act similarly on the anisotropic pattern of conduction (both drugs increase the Vl/Vt ratio), whereas cibenzoline exerts opposite effects. Orientation-dependent effects are different among Class I antiarrhythmic drugs and may be of importance in their therapeutic efficacy or proarrhythmic potential.

Action Potentials↗

PubMed1998

Inhaled nitric oxide neither alters oxidative stress parameters nor induces lung inflammation in premature lambs with moderate hyaline membrane disease.

The purpose of this investigation was to examine whether inhaled nitric oxide (NO) may alter oxidative stress parameters and induce lung inflammation in moderate hyaline membrane disease (HMD). Eighteen moderately premature lambs (130 days gestation, term = 147 days) were randomly assigned to treatment with 20 ppm inhaled NO (n = 8) from the onset of ventilation or used as control (n = 10). Except inhaled NO, treatments were intentionally similar to those applied in clinical situations. The main studied parameters were oxidative stress index measurements on lung parenchyma and in circulating blood, lung parenchyma microscopic examination and bronchoalveolar lavage cell count. We found that 20 ppm of inhaled NO for 5 h did not change significantly either malondialdehyde and total antioxidant status levels in circulating blood, or malondialdehyde, reduced glutathione, glutathione peroxidase and glutathione reductase in lung parenchyma. Amino-imino-propene bond generation, which are lipoperoxidation markers, was similar in both groups. Furthermore, no significant changes in the number of inflammatory cells in lung lavage products and in lung parenchyma microscopic examination could be found. Therefore, these data do not support the hypothesis that short-term NO inhalation increases oxidative stress and lung inflammation in an experimental model of moderate HMD.

Administration, Inhalation↗

PubMed1998

Effect of pindolol on onset of action of paroxetine in the treatment of major depression: intermediate analysis of a double-blind, placebo-controlled trial. Réseau de Recherche et d'Expérimentation Psychopharmacologique.

OBJECTIVE: The purpose of this study was to investigate the effect of pindolol to accelerate the onset of action of paroxetine in patients suffering from major depression. METHOD: Patients who met DSM-IV criteria for a nonpsychotic disorder, who had no previously treated episode of major depression episode, and who had a score of at least 18 on the 17-item Hamilton Depression Rating Scale were randomly assigned, for the first 21 days, to treatment with paroxetine (20 mg/day) and either pindolol (5 mg t.i.d.) or placebo. Patients were evaluated with the Hamilton depression scale, the Montgomery-Asberg Depression Rating Scale, and Global Clinical Impression (CGI) on days 0 (baseline), 5, 10, 15, 21, 25, 31, 60, 120, and 180. RESULTS: Intermediate analysis of the first month's results for the first 100 patients (pindolol, N=50; placebo, N=50) was performed. At day 10 there were more improved patients (defined as patients with a maximum score of 10 on the Hamilton depression scale) in the pindolol plus paroxetine group (N=24; 48%) than in the placebo plus paroxetine group (N=13; 26%). At day 5 there was no statistically significant difference, and at day 15 and thereafter, the differences between the two groups disappeared. Hamilton depression scale scores were significantly lower on days 5 and 10 for the pindolol plus paroxetine group (mean=15.7, SD=5.3, and mean=11.7, SD=6.4, respectively) than for the placebo plus paroxetine group (mean=19, SD=5.9, and mean=14.7, SD=6.8); this was also true for Montgomery-Asberg depression scale and CGI scores. CONCLUSIONS: The addition of pindolol to paroxetine treatment significantly accelerates the onset of therapeutic response in patients suffering from major depression. Nevertheless, the mechanism (pharmacodynamic or pharmacokinetic) of this beneficial effect remains unclear.

Adrenergic beta-Antagonists↗

PubMed1998

[Electrophysiologic effects and arrhythmogenic potential of diphemanil methylsulfate on rabbit purkinje fibers. Correlations with clinical observations of QT prolongation in pediatrics].

Serious undesirable cardiac side effects have been reported with treatment with diphemanil methylsulfate (Prantal) in premature babies or neonates. To understand the origin of this problem, the authors undertook an electrophysiological study of the effects of this product in vitro on rabbit Purkinje fibres. In three separate series (N = 5 to N = 8), the effects of increasing concentrations (0.1 microM-30 microM) of diphemanil methylsulfate, different frequencies of stimulation (0.2 Hz, 1 Hz, 2 Hz) and duration of exposition (60 min followed by 120 min washout) were observed on the properties of the action potential. The results show a clearcut antiarrhythmic Class III type action characterised by a concentration-dependent prolongation of the action potential duration with an inverse frequency dependency without significant changes of the other parameters. During stimulation at 0.2 Hz, early post-depolarizations and induced activity were observed in 3/8 of the fibres exposed to 10 microM and 8/8 fibres exposed to 30 microM. The effect did not attain a steady state after 60 min of exposition. It was not reversed by 120 min of washout of the preparation. These results were compatible with the reported cardiac arrhythmic effects of prolongation of the QT interval and torsades de pointe.

Action Potentials↗

PubMed1997

Endothelial derived vasorelaxation is impaired in human APO A-I transgenic rabbits.

Endothelium-derived relaxing factor (nitric oxide: NO) may provide an endogenous defence against atherosclerosis which impairs endothelium-dependent vascular relaxation. Atherosclerosis development is inhibited in cholesterol fed human apo A-I transgenic rabbits (Duverger, N., Circulation, 1996, 94, 713-717). We investigated if endothelium-dependent vascular relaxation is modified in human apo A-I transgenic rabbits by testing in vitro endothelium-dependent receptor-dependent vascular relaxation to acetylcholine and endothelium-dependent receptor-independent vascular relaxation to A23187 of abdominal aorta, precontracted with phenylephrine, in human apo A-I transgenic rabbits (n=4) versus non transgenic littermates (n=4). Endothelium-independent vascular relaxation was investigated with sodium nitroprusside. Vascular precontraction to phenylephrine was significantly increased in human apo A-I transgenic rabbits (p<0.05) while endothelium-independent vascular relaxation to nitroprusside was similar between human apo A-I transgenic rabbits and control rabbits. Endothelium-dependent receptor-dependent and receptor-independent vascular relaxations were reduced in human apo A-I transgenic rabbits (p<0.05). Maximum endothelium-dependent receptor-dependent vascular relaxation was negatively correlated with HDL-cholesterol and total apo A-I (rabbit+ human) plasma levels (r=0.87 and 0.86, p=0.01, respectively) but not with atherogenic plasma lipid (VLDL-cholesterol, LDL-cholesterol, VLDL+LDL cholesterol, triglycerides, apolipoprotein B) levels. These results suggest that the transgenesis of human apo A-I in rabbits impairs signal transduction of endothelial NO synthesis.

Acetylcholine↗