E Bellissant

Publications (53)227.54 Total impact

• Source

  Available from: ccforum.com

  Article: Effects of epinephrine compared to dobutamine-norepinephrine on gastric perfusion in septic shock

  P Seguin, E Bellissant, Y Le Tulzo, B Laviolle, R Thomas, Y Mallédant
  Critical Care 04/2012; 6:1-2. · 4.93 Impact Factor
• Article: Reduced-dose tacrolimus with mycophenolate mofetil vs. standard-dose tacrolimus in liver transplantation: a randomized study.

  K Boudjema, C Camus, F Saliba, Y Calmus, E Salamé, G Pageaux, C Ducerf, C Duvoux, C Mouchel, A Renault, P Compagnon, R Lorho, E Bellissant
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  ABSTRACT: We conducted a multicenter randomized study in liver transplantation to compare standard-dose tacrolimus to reduced-dose tacrolimus with mycophenolate mofetil to reduce the occurrence of tacrolimus side effects. Two primary outcomes (censored criteria) were monitored during 48 weeks post-transplantation: occurrence of renal dysfunction or arterial hypertension or diabetes (evaluating benefit) and occurrence of acute graft rejection (evaluating risk). Interim analyses were performed every 40 patients to stop the study in the case of increased risk of graft rejection. One hundred and ninety-five patients (control: 100; experimental: 95) had been included when the study was stopped. Acute graft rejection occurred in 46 (46%) and 28 (30%) patients in control and experimental groups, respectively (HR = 0.59; 95% CI: [0.37-0.94]; p = 0.024). Renal dysfunction or arterial hypertension or diabetes occurred in 80 (80%) and 61 (64%) patients in control and experimental groups, respectively (HR = 0.68; 95% CI: [0.49-0.95]; p = 0.021). Renal dysfunction occurred in 42 (42%) and 23 (24%) patients in control and experimental groups, respectively (HR = 0.49; 95% CI: [0.29-0.81]; p = 0.004). Leucopoenia (p = 0.001), thrombocytopenia (p = 0.017) and diarrhea (p = 0.002) occurred more frequently in the experimental group. Reduced-dose tacrolimus with mycophenolate mofetil reduces the occurrence of renal dysfunction and the risk of graft rejection. This immunosuppressive regimen could replace full-dose tacrolimus in adult liver transplantation.
  American Journal of Transplantation 04/2011; 11(5):965-76. · 6.39 Impact Factor
• Article: Biological and hemodynamic effects of low doses of fludrocortisone and hydrocortisone, alone or in combination, in healthy volunteers with hypoaldosteronism.

  B Laviolle, P Le Maguet, M-C Verdier, C Massart, E Donal, F Lainé, A Lavenu, D Pape, E Bellissant
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  ABSTRACT: Low doses of hydrocortisone (HC) and fludrocortisone (FC) administered together improve the prognosis after septic shock; however, there continues to be disagreement about the utility of FC for this indication. The biological and hemodynamic effects of HC (50 mg intravenously) and FC (50 microg orally) were assessed in 12 healthy male volunteers with saline-induced hypoaldosteronism in a placebo-controlled, randomized, double-blind, crossover study performed according to a 2 x 2 factorial design. HC and FC significantly decreased urinary sodium and potassium levels (from -58% at 4 h to -28% at 10 h and from -35% at 8 h to -24% at 12 h, respectively) with additive effects. At 4 h after administration, HC significantly increased cardiac output (+14%), decreased systemic vascular resistances (-14%), and slightly increased heart rate (+4 beats/min), whereas FC had no hemodynamic effect. At doses used in septic shock, HC induced greater mineralocorticoid effect than FC did. HC also induced transient systemic hemodynamic effects, whereas FC did not. New studies are required to better define the optimal dose of FC in septic shock.
  Clinical Pharmacology &#38 Therapeutics 08/2010; 88(2):183-90. · 6.04 Impact Factor
• Article: Effects of phlebotomy therapy on cytochrome P450 2e1 activity and oxidative stress markers in dysmetabolic iron overload syndrome: a randomized trial.

  F Lainé, J M Reymann, F Morel, S Langouët, M Perrin, A Guillygomarc'h, P Brissot, V Turmel, C Mouchel, D Pape, E Bellissant, Y Deugnier
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  ABSTRACT: To assess the effects of iron removal on cytochrome P450 2E1 activity and oxidative stress in dysmetabolic iron overload syndrome. Forty-eight patients were randomized to phlebotomy therapy consisting of removal of 300-500 mL of blood every 14 days until serum ferritin levels dropped under 100 microg/L or to follow-up without phlebotomy therapy. Cytochrome P450 2E1 activity was measured at baseline and at the end of treatment by using the 6-hydroxychlorzoxazone/chlorzoxazone blood metabolic ratio, 2 h after the intake of 500 mg of chlorzoxazone. In the treatment group, a mean of 3.9 +/- 1.3 L of blood was removed and serum ferritin levels dropped from 715 +/- 397 to 74 +/- 34 microg/L. Variation of cytochrome P450 2E1 activity was not significantly different between the 2 groups (0.07 +/- 0.26 vs. 0.03 +/- 0.19, P = 0.36). In the treatment group, low-density lipoprotein cholesterol and vitamin E were lowered after treatment compared with control group (-0.15 +/- 0.51 vs. 0.24 +/- 0.58, P = 0.002 and -1.3 +/- 4.4 vs. 2.3 +/- 5.2, P = 0.03, respectively). Inversely, vitamin C was increased (0.5 +/- 3.5 vs. -1.8 +/- 3.9, P = 0.03). In dysmetabolic iron overload syndrome, reduction of iron stores does not significantly influence cytochrome P450 2E1 activity but is associated with a significant decrease of low-density lipoprotein cholesterol, suggesting that venesection therapy may be a suitable option in these patients.
  Alimentary Pharmacology & Therapeutics 11/2006; 24(8):1207-13. · 3.77 Impact Factor
• Source

  Available from: Jean-Michel Reymann

  Article: Placebo controlled, randomised, double blind study of the effects of botulinum A toxin on detrusor sphincter dyssynergia in multiple sclerosis patients.

  P Gallien, J-M Reymann, G Amarenco, B Nicolas, M de Sèze, E Bellissant
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  ABSTRACT: The purpose of the study was to evaluate the efficacy and safety of botulinum A toxin in the treatment of detrusor sphincter dyssynergia in multiple sclerosis patients. This was a multicentre, placebo controlled, randomised, double blind study. Patients with chronic urinary retention were included if they had post-voiding residual urine volume between 100 and 500 ml. They received a single transperineal injection of either botulinum A toxin (100 U Allergan) or placebo in the sphincter and also 5 mg slow release alfuzosin bid over 4 months. Main endpoint was post-voiding residual urine volume assessed 1 month after injection. Follow up duration was 4 months. Statistical analysis was performed using a sequential method, the triangular test. The study was stopped after the fourth analysis (86 patients had been included: placebo: 41, botulinum A toxin: 45). At inclusion, there was no significant difference between groups whichever variable was considered. Mean (standard deviation) post-voiding residual urine volume was 217 (96) and 220 (99) ml in placebo and botulinum A toxin groups, respectively. One month later, post-voiding residual urine volume was 206 (145) and 186 (158) ml (p = 0.45) in placebo and botulinum A toxin groups, respectively. However, compared to placebo, botulinum A toxin significantly increased voiding volume (+54%, p = 0.02) and reduced pre-micturition (-29%, p = 0.02) and maximal (-21%, p = 0.02) detrusor pressures. Other secondary urodynamic endpoints and tolerance were similar in the two groups. In multiple sclerosis patients with detrusor sphincter dyssynergia, a single injection of botulinum A toxin (100 U Allergan) does not decrease post-voiding residual urine volume.
  Journal of Neurology Neurosurgery &amp Psychiatry 01/2006; 76(12):1670-6. · 4.76 Impact Factor
• Article: Effect of pre-operative oral sustained-release morphine sulfate on post-operative morphine requirements in elective spine surgery

  E. Bellissant, J. P. Estebe, V. Sebille, C. Ecoffey
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  ABSTRACT: Background: Sustained-release morphine sulfate (SRMS) is a painkiller used in oncology. The purpose of our study was to assess its efficacy on post-operative morphine requirements in elective spine surgery.Methods: This was a placebo-controlled, randomized, double-blind study. Adults scheduled for spine surgery under general anaesthesia were orally administered SRMS (30 mg) or a placebo 2h before surgery. Primary endpoint was post-operative cumulated morphine consumption through patient-controlled analgesia (PCA) during the 12h following extubation. Statistical analysis was performed using a sequential method, the triangular test.Results: The study was stopped after the sixth analysis (51 patients had been included; placebo: 26, SRMS: 25). Patients' characteristics were similar in the two groups. Morphine consumption through PCA during the 12h following extubation was significantly lower in SRMS group (meanSD: 10.57.6 mg) compared to placebo group (15.66.0 mg, P=0.016, sequential analysis). Morphine consumption through PCA during the 24h following extubation was also significantly lower in SRMS group (15.912.7 mg) compared to placebo group (23.810.9 mg, P=0.032). Vigilance, nausea and respiratory rate 3 and 6h after extubation were similar in the two groups.Conclusion: A pre-operative oral administration of SRMS (30 mg) induces a 33% reduction of post-operative morphine requirements in patients scheduled for spine surgery without inducing side effects.
  Clinical Pharmacology &#38 Therapeutics 01/2005; 77(2):P8-P8. · 6.04 Impact Factor
• Article: Differential effects of two types of antidepressants, amitriptyline and fluoxetine, on anorectal motility and visceral perception.

  L Siproudhis, M Dinasquet, V Sébille, J M Reymann, E Bellissant
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  ABSTRACT: Although antidepressants are used for functional gastrointestinal disorders, the mechanisms of their effects on gut are incompletely understood. To assess the effects of two types of antidepressants (tricyclic, serotoninergic) on anorectal motility and visceral perception. A placebo-controlled, randomized, double-blind, crossover study was performed in 12 healthy male volunteers who received a single oral dose of amitriptyline (80 mg), fluoxetine (40 mg) or placebo. Drug effects were assessed using phasic isobaric distensions of the rectum with an electronic barostat (11 levels from 1 to 51 mmHg) 4 h after drug intake. Maximal rectal volume and pressure, mean and residual pressures at upper anal canal, mean pressure at lower anal canal, defecation sensation (5-level scale) and visceral perception (visual analogue scale) were recorded at each level of distending pressure. Ten subjects completed the study. Compared with placebo, neither amitriptyline nor fluoxetine modified rectal compliance or visceral perception. Compared with placebo, antidepressants significantly reduced mean and residual pressures at upper anal canal (-18%, P = 0.0019, and -27%, P = 0.0002, respectively, for amitriptyline; -26%, P = 0.0001, and -33%, P = 0.0001, respectively, for fluoxetine) whereas only amitriptyline significantly reduced mean pressure at lower anal canal (-16%, P = 0.0008). Both antidepressants similarly relaxed the internal anal sphincter, probably through a non-specific mechanism, without modifying visceral perception. Only amitriptyline relaxed the external anal sphincter.
  Alimentary Pharmacology & Therapeutics 10/2004; 20(6):689-95. · 3.77 Impact Factor
• Article: Corticosteroids for treating severe sepsis and septic shock.

  D Annane, E Bellissant, P E Bollaert, J Briegel, D Keh, Y Kupfer
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  ABSTRACT: Sepsis may be complicated by impaired corticosteroid production. Giving corticosteroids could potentially benefit patients. To examine the effects of corticosteroids on death at one month in patients with severe sepsis and septic shock. We searched the Cochrane Infectious Diseases Group's trial register (August 2003), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2003), MEDLINE (August 2003), EMBASE (August 2003), LILACS (August 2003), reference lists of articles, and also contacted trial authors. Randomized and quasi-randomized controlled trials of corticosteroids versus placebo or supportive treatment in severe sepsis and septic shock. Two pairs of reviewers agreed the eligibility of trials. One reviewer extracted data, which was checked by the other reviewers and the primary author of the paper whenever possible. We obtained some missing data from the trial authors. We assessed trial methodological quality. We identified 15 trials (n =2023). Corticosteroids did not change 28-day all-cause mortality (15 trials, n = 2022, relative risk (RR) 0.92, 95% confidence interval (CI) 0.75 to 1.14; random effects model) and hospital mortality (13 trials, n = 1418, RR 0.89, 95% CI 0.71 to 1.11; random effects model); however, there was statistically significant heterogeneity, with some evidence that this was related to the dosing strategy. Corticosteroids reduced intensive care unit mortality (4 trials, n = 425, RR 0.83, 95% CI 0.70 to 0.97), increased the proportion of shock reversal by day 7 (6 trials, n = 728, RR 1.22, 95% CI 1.06 to 1.40) and by day 28 (4 trials, n = 425, RR 1.26, 95% CI 1.04 to 1.52), without increasing the rate of gastroduodenal bleeding (10 trials, n = 1321, RR 1.16, 95% CI 0.82 to 1.65), superinfection (12 trials, n = 1705, RR 0.93, 95% CI 0.73 to 1.18), and of hyperglycaemia (6 trials, n = 608, RR 1.22, 0.84 to 1.78). Overall, corticosteroids did not change 28-day mortality and hospital mortality in severe sepsis and septic shock. Long course of low dose corticosteroids reduced 28-day all-cause mortality, and intensive care unit and hospital mortality.
  Cochrane database of systematic reviews (Online) 02/2004; · 5.72 Impact Factor
• Article: Lack of effficacy of botulinum toxin in chronic anal fissure.

  L Siproudhis, V Sébille, F Pigot, P Hémery, F Juguet, E Bellissant
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  ABSTRACT: Hypertonicity of internal anal sphincter plays a major role in the persistence of chronic anal fissure. Botulinum toxin could induce internal anal sphincter relaxation without the adverse effects of surgery (long-term faecal incontinence) or topical nitrates (anal burning, headaches, hypotension). We conducted a placebo-controlled, randomised, double-blind study to assess the efficacy of a single injection of botulinum toxin in the internal anal sphincter of patients with chronic anal fissure in six ambulatory care clinics. Eligibility criteria included a mean value of post-defecation anal pain >or= 30 mm on a 100 mm visual analogue scale over the week preceding inclusion. Main endpoint was the proportion of patients with symptomatic improvement during the fourth week after inclusion (post-defecation anal pain below 10 mm). Forty-four patients (22 in each group) were included. At inclusion, there was no significant difference between groups on age, sex ratio, pain duration, post-defecation anal pain, analgesic consumption and stool frequency. Ten (45%) and 11 (50%) patients reported symptomatic improvement on the main endpoint (P=0.76) in placebo and botulinum toxin groups, respectively. Ten patients (five in each group) had healed fissure at week 4 and ten patients (five in each group) required surgical treatment between weeks 4 and 12. Similarly, there was no significant difference between groups on other variables between weeks 4 and 12. The efficacy of a single injection of botulinum toxin in the internal anal sphincter does not differ from that of a placebo in patients with chronic anal fissure.
  Alimentary Pharmacology & Therapeutics 09/2003; 18(5):515-24. · 3.77 Impact Factor
• Article: Ritonavir-saquinavir dual protease inhibitor compared to ritonavir alone in human immunodeficiency virus-infected patients.

  C Michelet, A Ruffault, V Sébille, C Arvieux, P Jaccard, F Raffi, C Bazin, J M Chapplain, J P Chauvin, E Dohin, F Cartier, E Bellissant
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  ABSTRACT: The objective of this study was to evaluate the antiretroviral efficacy and safety of ritonavir (600 mg twice a day [b.i.d.])-saquinavir (400 mg b.i.d.) compared to ritonavir (600 mg b.i.d.) in patients pretreated and receiving continued treatment with two nucleoside analogs. The study was placebo controlled, randomized, and double blind. Inclusion criteria included protease inhibitor naive status and a viral load of >10,000 copies/ml. The main end point was viral load at week 24. Forty-seven patients were included (25 given ritonavir and 22 given ritonavir-saquinavir) and monitored until week 48. At inclusion, 23% had had at least one AIDS-defining event. Previous treatment durations (mean and standard deviation) were 42 +/- 25 and 37 +/- 23 months, viral loads were 4.75 +/- 0.62 and 4.76 +/- 0.50 log(10) copies/ml, and CD4 cell counts were 236 +/- 126 and 234 +/- 125/mm(3) in the ritonavir and ritonavir-saquinavir groups, respectively. At week 24, viral loads were 2.81 +/- 1.48 and 2.08 +/- 1.14 log(10) copies/ml (P = 0.04) and CD4 cell counts were 330 +/- 151 and 364 +/- 185/mm(3) (P = 0.49) in the ritonavir and ritonavir-saquinavir groups, respectively. Similar results were observed at week 48. Moreover, at week 48, 40 and 68% (P = 0.05) and 28 and 59% (P = 0.03) of patients achieved viral suppression at below 200 and 50 copies/ml in the ritonavir and ritonavir-saquinavir groups, respectively. At week 24, six patients in the ritonavir group but only one in the ritonavir-saquinavir group had key mutations conferring resistance to protease inhibitors. Clinical and biological tolerances were similar in both groups. In nucleoside analog-pretreated patients, ritonavir-saquinavir has higher antiretroviral efficacy than and is as well tolerated as ritonavir alone.
  Antimicrobial Agents and Chemotherapy 01/2002; 45(12):3393-402. · 4.84 Impact Factor
• Article: Comparison of the two-sided single triangular test to the double triangular test.

  V Sébille, E Bellissant
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  ABSTRACT: Comparative clinical trials are designed to determine whether a new treatment has either superior or different efficacy than a standard, that is, if theta represents a measure of treatment difference, to test the null hypothesis H(0): theta = 0 against the alternative hypothesis H(1) of either superior (theta > 0, one-sided) or different (theta not equal 0, two-sided with H(1)(+): theta > 0 and H(-)(1): theta < 0) efficacy. The triangular test (TT), a group sequential method, allows for early stopping of such trials. Its one-sided version (single TT) and two-sided version (double TT) were implemented in the first release of PEST software. The third release of PEST proposed a modification of the single TT, allowing rejection of H(0) in favor of H(-)(1) when very early data show strong inferiority of the new treatment as compared with the standard. Thus, our aim was to compare this modified single TT, referred to as a two-sided test in PEST 3, with the double TT and two-sided single-stage design (SSD). The statistical properties of the SSD and double TT were perfectly similar under all hypotheses. The modified single TT was underpowered as compared to the two others (the probability of falsely accepting H(0) strictly under H(-)(1) was 0.65 instead of 0.05), but the average sample number function was lower than the one of the double TT under all H(-)(1) hypotheses (-56% strictly under H(-)(1)). We conclude that the modified single TT offers a two-sided conclusion with many fewer patients than the double TT, but at the expense of a strong decrease in power under H(-)(1).
  Controlled Clinical Trials 10/2001; 22(5):503-14.
• Article: Pharmacokinetic-pharmacodynamic model for perindoprilat regional haemodynamic effects in healthy volunteers and in congestive heart failure patients.

  E Bellissant, J F Giudicelli
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  ABSTRACT: We compared the relationships between the plasma concentrations (C) of perindoprilat, active metabolite of the angiotensin I-converting enzyme inhibitor (ACEI) perindopril, and the effects (E) induced on plasma converting enzyme activity (PCEA) and brachial vascular resistance (BVR) in healthy volunteers (HV) and in congestive heart failure (CHF) patients after single oral doses of perindopril. Six HV received three doses of perindopril (4, 8, 16 mg) in a placebo-controlled, randomized, double-blind, crossover study whereas 10 CHF patients received one dose (4 mg) in an open study. Each variable was determined before and 6-12 times after drug intake. E (% variations from baseline) were individually related to C (ng ml(-1)) by the Hill model E=Emax x Cgamma/(CE50gamma + Cgamma). When data showed a hysteresis loop, an effect compartment was used. (means+/-s.d.) In HV, relationships between C and E were direct whereas in CHF patients, they showed hysteresis loops with optimal k(e0) values of 0.13 +/- 0.16 and 0.13 +/- 0.07 h(-1) for PCEA and BVR, respectively. For PCEA, with Emax set to -100%, CE50 = 1.87 +/- 0.60 and 1.36 +/- 1.33 ng ml(-1) (P = 0.34) and gamma = 0.90 +/- 0.13 and 1.11 +/- 0.47 (P = 0.23) in HV and CHF patients, respectively. For BVR, Emax= -41 +/- 14% and -60 +/- 7% (P = 0.02), CE50 = 4.95 +/- 2.62 and 1.38 +/- 0.85 ng ml(-1) (P = 0.02), and gamma = 2.25 +/- 1.54 and 3.06 +/- 1.37 (P = 0.32) in HV and CHF patients, respectively. Whereas concentration-effect relationships were similar in HV and CHF patients for PCEA blockade, they strongly differed for regional haemodynamics. This result probably expresses the different involvements, in HV and CHF patients, of angiotensinergic and nonangiotensinergic mechanisms in the haemodynamic effects of ACEIs.
  British Journal of Clinical Pharmacology 08/2001; 52(1):25-33. · 2.96 Impact Factor
• Article: Hemodynamic and histomorphometric characteristics of dilated cardiomyopathy of Syrian hamsters (Bio TO-2 strain).

  S Goineau, D Pape, P Guillo, M P Ramée, E Bellissant
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  ABSTRACT: The natural history of the disease of the dilated strain Bio TO-2 of cardiomyopathic hamsters (CMH) is not totally characterized. We investigated its hemodynamic and histomorphometric characteristics at 140, 180, 220, 260, and 300 days of age. Forty CMH and 40 controls were investigated (8 at each stage). Mean arterial pressure (MAP, carotid artery catheter) and cardiac output and femoral blood flow (CO, FBF, transit time method) were measured in anesthetized animals. Systemic (SVR) and femoral (FVR) vascular resistances were calculated. Atria, left and right ventricles (LV, RV), lungs, and liver were weighed. LV cavity area, LV and RV wall thicknesses and collagen densities were determined (computer-assisted image analyzer). Pulmonary and hepatic congestion were assessed (arbitrary scales). Compared with controls, MAP, CO and FBF were significantly lower in CMH throughout the study (on average: -22%, -34%, -33%, respectively), FVR was significantly increased (+15%), but SVR was not significantly modified. Concerning histomorphometric characteristics, differences between groups significantly increased with age for most variables: at 300 days, atria (+292%), RV (+13%), lungs (+44%), and liver (+23%) weights, LV cavity area (+130%), LV (+364%) and RV (+181%) collagen densities were significantly increased in CMH vs controls, whereas LV (-40%) and RV (-23%) wall thicknesses were significantly decreased. At 260 and 300 days, CMH showed significant pulmonary congestion without hepatic alteration. Bio TO-2 CMH progressively develop an alteration of cardiac function leading to decreased MAP and musculo-cutaneous blood flow associated with cardiac remodeling including atria hypertrophy and LV dilation, wall thinning and a rise in collagen density.
  Canadian Journal of Physiology and Pharmacology 05/2001; 79(4):329-37. · 1.95 Impact Factor
• Article: Increased sensitivity of vascular smooth muscle to nitric oxide in dilated cardiomyopathy of Syrian hamsters (Bio TO-2 strain).

  S Goineau, D Pape, P Guillo, M P Ramée, E Bellissant
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  ABSTRACT: We assessed the evolution with time of the responsiveness of three vascular beds in dilated cardiomyopathic hamsters of the Bio TO-2 strain. Eight cardiomyopathic hamsters and 8 control hamsters were investigated at 180 and 300 days of age. Thoracic aorta and mesenteric and renal artery rings were studied in isolated organ baths. Cumulative concentration-response relations to phenylephrine, acetylcholine, sodium nitroprusside, and angiotensin II were established for each ring. Maximum effect (Emax) and concentration inducing 50% of Emax (EC50) were determined from each concentration-response curve and pD2 was calculated as -log(EC50). Compared with control hamsters, in cardiomyopathic hamsters, Emax of phenylephrine was not modified in aorta, whereas it was significantly lower in mesenteric (-6% and -33% at 180 and 300 days, respectively) and renal (-17% and -24%) arteries. Emax of acetylcholine was significantly higher in aorta (+57% and +30%), mesenteric (+42% and +34%), and renal (+168% and +70%) arteries. Emax of sodium nitroprusside was significantly higher in aorta (+26% and +16%) and tended to be higher in mesenteric (+25% and +23%) and renal (+27% and +10%) arteries. Emax of angiotensin II was not modified in aorta and tended to be lower in mesenteric artery at 300 days. The pD2 of phenylephrine was significantly increased in aorta and the pD2 of sodium nitroprusside was significantly increased in aorta and renal artery. In conclusion, in dilated cardiomyopathic hamsters, endothelium-dependent and -independent vasodilations are enhanced early, demonstrating increased sensitivity of vascular smooth muscle to nitric oxide. This abnormality may be involved in the decreased responsiveness to phenylephrine and angiotensin II.
  Journal of Cardiovascular Pharmacology 04/2001; 37(3):290-300. · 2.29 Impact Factor
• Article: Effect of hydrocortisone on phenylephrine--mean arterial pressure dose-response relationship in septic shock.

  E Bellissant, D Annane
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  ABSTRACT: Septic shock is characterized by decreased responsiveness to catecholamines. Because endogenous steroids are known to play a role in the modulation of vasomotor tone, the purpose of our study was to investigate the phenylephrine-mean arterial pressure dose-response relationship in patients with septic shock and the effect of a physiological dose of hydrocortisone on it. Twelve patients meeting usual criteria for septic shock and 12 age-matched control subjects were investigated before and 1 hour after receiving 50 mg intravenous hydrocortisone. Sixteen incremental doses of phenylephrine (microg/kg/min) were infused, and the effects on mean arterial pressure (mm Hg) were recorded. A sigmoid model, E = E0 + [Emax x Dgamma/(ED50gamma + Dgamma)], was fitted to individual data. In this model, E is the predicted effect and D is the dose of phenylephrine infused. E0 represents the basal value of effect (ie, the value of mean arterial pressure without drug), Emax is the maximum theoretical effect, ED50 is the dose of phenylephrine for which an effect of 50% of Emax is observed, and gamma is the Hill coefficient which accounts for the sigmoidicity of the curve. As compared with in control subjects, in patients, E0 was decreased before (58 +/- 8 versus 73 +/- 7 mm Hg) and after (64 +/- 12 versus 82 +/- 10 mm Hg) administration of hydrocortisone (P = .0001 for group), Emax was reduced before (39 +/- 17 versus 84 +/- 18 mm Hg) and after (77 +/- 26 versus 106 +/- 21 mm Hg) administration of hydrocortisone (P = .0001 for group), ED50 was not modified, and gamma was increased before (3.5 +/- 1.8 versus 1.3 +/- 0.3) and after (1.9 +/- 1.1 versus 1.3 +/- 0.3) administration of hydrocortisone (P = .0010 for group). Hydrocortisone similarly increased E0 in both groups (P = .0003 for sequence, P = .2883 for interaction), increased more Emax in patients than in control subjects (P < .0001 for sequence; P = .0280 for interaction), did not change ED50, and decreased y in patients but not in control subjects (P = .0025 for sequence, P = .0025 for interaction). In patients with septic shock, the Emax of phenylephrine is decreased, whereas its ED50 is not modified, both before and after administration of hydrocortisone. A physiological dose of hydrocortisone tends to normalize the relationship.
  Clinical Pharmacology &#38 Therapeutics 09/2000; 68(3):293-303. · 6.04 Impact Factor
• Article: Comparison of four sequential methods allowing for early stopping of comparative clinical trials.

  V Sebille, E Bellissant
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  ABSTRACT: Phase III trials aim to assess whether a new treatment has superior efficacy than a standard treatment. Sequential methods, such as the sequential probability ratio test (SPRT), the triangular test (TT) and so-called one-parameter boundaries (OPB), now allow early stopping of such trials, both in the case of efficacy (alternative hypothesis; H(1)) and in the case of lack of efficacy (null hypothesis; H(0)). We compared the statistical properties of the SPRT and the TT, and of OPB with Pocock (OPB(Delta=0.5)) and O'Brien and Fleming (OPB(Delta=0)) type boundaries, in the setting of one-sided comparative trials with normal response. We studied the type I error (alpha), power (1-beta), average sample number (ASN) and 90th percentile (P90) of the number of patients required to reach a conclusion using simulations. The four tests were also compared with the corresponding single-stage design (SSD). All sequential tests display alpha and 1-beta close to nominal values and, as compared with SSD, allow important decreases in ASN: for example, -48%, -42%, -40% and -31% under H(0) and H(1) for SPRT, TT, OPB(Delta=0.5) and OPB(Delta=0) respectively. For situations between H(0) and H(1), ASNs of all sequential tests were still smaller than the sample size required by SSD, with the TT displaying the largest decrease (-25%). The P90s of the TT and OPB(Delta=0) under H(0) and H(1) were smaller than the P90s of the SPRT and OPB(Delta=0.5), which were similar to the sample size required by SSD. If all sequential tests display approximately similar features, the TT is the most appealing regarding decreases in sample size, especially for situations between H(0) and H(1).
  Clinical Science 06/2000; 98(5):569-78. · 4.61 Impact Factor
• Source

  Available from: Véronique Sébille

  Article: A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin.

  D Annane, V Sébille, G Troché, J C Raphaël, P Gajdos, E Bellissant
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  ABSTRACT: The hypothalamic-pituitary-adrenal axis is a major determinant of the host response to stress. The relationship between its activation and patient outcome is not known. To evaluate the prognostic value of cortisol levels and a short corticotropin stimulation test in patients with septic shock. Prospective inception cohort study conducted between October 1991 and September 1995 in 2 teaching hospital adult intensive care units in France. A total of 189 consecutive patients who met clinical criteria for septic shock. A short corticotropin stimulation test was performed in all patients by intravenously injecting 0.25 mg of tetracosactrin; blood samples were taken immediately before the test (T0) and 30 (T30) and 60 (T60) minutes afterward. Twenty-eight-day mortality as a function of variables collected at the onset of septic shock, including cortisol levels before the corticotropin test and the cortisol response to corticotropin (delta max, defined as the difference between T0 and the highest value between T30 and T60). The 28-day mortality was 58% (95% confidence interval [CI], 51%-65%) and median time to death was 17 days (95% CI, 14-27 days). In multivariate analysis, independent predictors of death (P < or = .001 for all) were McCabe score greater than 0, organ system failure score greater than 2, arterial lactate level greater than 2.8 mmol/L, ratio of PaO2 to fraction of inspired oxygen no more than 160 mm Hg, cortisol level at T0 greater than 34 microg/dL and delta max no more than 9 microg/dL. Three groups of patient prognoses were identified: good (cortisol level at T0 < or = 34 microg/dL and delta max > 9 microg/dL; 28-day mortality rate, 26%), intermediate (cortisol level at T0 34 microg/dL and delta max < or = 9 microg/dL or cortisol level at T0 > 34 microg/dL and delta max > 9 microg/dL; 28-day mortality rate, 67%), and poor (cortisol level at T0 > 34 microg/dL and delta max < or = 9 microg/dL; 28-day mortality rate, 82%). Our data suggest that a short corticotropin test has a good prognostic value and could be helpful in identifying patients with septic shock at high risk for death.
  JAMA The Journal of the American Medical Association 02/2000; 283(8):1038-45. · 30.03 Impact Factor
• Article: Pharmacokinetic-pharmacodynamic model for fantofarone cardiac and brachial haemodynamic effects in healthy volunteers.

  E Bellissant, J F Giudicelli
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  ABSTRACT: To investigate the pharmacokinetics of SR 33671, the main active metabolite of the calcium antagonist fantofarone, and the relationships between its concentrations and pharmacodynamic effects after a single oral administration of two doses (100 and 300 mg) of fantofarone. A placebo-controlled, randomized, double-blind and crossover study was performed in six healthy volunteers. SR 33671 plasma concentrations (C, ng ml-1 ) and effects (E) on heart rate (HR, beats min-1 ), PR interval duration (ms), brachial artery flow (BAF, ml min-1 ) and brachial vascular resistance (BVR, mmHg s ml-1 ) were determined repeatedly after drug intake. Haemodynamic effects were expressed as percent changes from initial values. Bi-exponential (pharmacokinetics), and linear [E=S.C+E0, for cardiac effects] or sigmoid [E=Emax.Cgamma/(CEgamma50+Cgamma ), for haemodynamic effects] models were fitted to individual data. Peak plasma concentrations and areas under the curve up to 24 h were (mean+/-s.d.) 16+/-10 ng ml-1 and 157.50+/-89.13 ng ml-1 h, and 63+/-11 ng ml-1 and 535.50+/-135.11 ng ml-1 h, after 100 and 300 mg, respectively. Terminal half-life was approximately 4 h. For pharmacodynamics, we obtained: S=-0.201+/-0.057 beats min-1/ng ml-1 for HR, S=0.526+/-0.114 ms/ng ml-1 for PR interval duration, Emax=42+/-6%, CE50=8.8+/-7.2 ng ml-1 and gamma=2.2+/-1.5 for BAF, and Emax=-28+/-4%, CE50=5.8+/-5.1 ng ml-1 and gamma=3.4+/-1.8 for BVR. At a SR 33671 concentration of 15 ng ml-1, BVR is decreased by 27% whereas HR is reduced by less than 3 beats min-1 and PR interval duration is increased by less than 8 ms. Fantofarone is able to induce submaximal peripheral vasodilating effects at doses that are devoid of any clinically significant cardiac effect.
  British Journal of Clinical Pharmacology 01/2000; 48(6):801-10. · 2.96 Impact Factor
• Article: Fecal incontinence with normal anal canal pressures: where is the pitfall?

  L Siproudhis, E Bellissant, M Pagenault, M H Mendler, H Allain, J F Bretagne, M Gosselin
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  ABSTRACT: One third of subjects who suffer from fecal incontinence are found to have values within the normal range when anal manometry is performed. For these patients, one hypothesis is that impaired rectal adaptation to distension may occur. The aim of our study was to analyze anorectal responses to rectal isobaric distension in this population. This was a prospective study conducted in 51 consecutive incontinent patients (45 female, six male) divided into two groups according to their functional anal state: absence (19 patients aged 55 +/- 6 yr) or presence of manometric anal weakness (32 patients aged 59 +/- 2 yr). The subjects were submitted to two randomized modes of rectal isobaric distension (tonic, phasic) with an electronic barostat. Anal pressures, perception, and volumes of the rectum were recorded at six different preselected pressures. As compared with those having anal weakness, patients with no anal weakness retained higher mean pressures at both upper (36.9 +/- 2.2 vs 22.9 +/- 1.4 mm Hg; p = 0.01) and lower parts (41.0 +/- 2.0 vs 23.3 +/- 1.4 mm Hg; p = 0.002) of the anal canal, similar perception scores, but much lower rectal volumes (68.5 +/- 5.5 vs 121.8 +/- 7.0 ml; p = 0.008) in response to rectal isobaric distension. A decrease in rectal adaptation could be involved in fecal leakage in patients with no anal manometric weakness.
  The American Journal of Gastroenterology 07/1999; 94(6):1556-63. · 7.28 Impact Factor
• Article: Safety and efficacy of ritonavir and saquinavir in combination with zidovudine and lamivudine.

  C Michelet, E Bellissant, A Ruffault, C Arvieux, J F Delfraissy, F Raffi, C Bazin, I Renard, V Sébille, J P Chauvin, E Dohin, F Cartier
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  ABSTRACT: Ritonavir is a potent inhibitor of cytochrome P4503A4 that strongly increases saquinavir bioavailability. In this study we assessed the safety and antiretroviral efficacy of the combination of these two compounds in patients pretreated and receiving continued treatment with zidovudine and lamivudine who were protease inhibitor naive and who had a CD4 cell counts below 200/mm3. In this 48-week pilot study, all patients received 600 mg ritonavir and 400 mg saquinavir twice daily. Administration of zidovudine and lamivudine was continued without a change in previous doses. Viral load, CD4 cell count, and the emergence of resistance to the two protease inhibitors were evaluated repeatedly up to week 48. Sixteen patients were included in the study. Previous nucleoside analog treatment duration was 48+/-22 months (mean +/- SD). Two patients quit taking both protease inhibitors within 2 weeks. The ritonavir dose had to be reduced in 10 other patients because of side effects. Between inclusion and week 48, plasma viremia varied from 4.87+/-0.43 to 3.00+/-1.29 log10 copies/mL and CD4 cell counts ranged from 98+/-61 to 250+/-139/mm3. Ten patients (63%) had viral loads below 200 copies/mL and 7 (44%) had viral loads below 50 copies/mL. A single key mutation that conferred ritonavir resistance I84V and V82A/V developed in two patients. A mutation at codon 54 developed in another patient. These mutations were associated with repeated cessations of antiretroviral treatment. No lipodystrophy was observed. Ritonavir and saquinavir in combination are quite well tolerated and induce a high and sustained antiretroviral efficacy. A four-drug combination that includes these two protease inhibitors should be considered as a first line of treatment in patients with low CD4 cell counts.
  Clinical Pharmacology &#38 Therapeutics 07/1999; 65(6):661-71. · 6.04 Impact Factor