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Glucocorticoids probably improve outcomes in patients hospitalised for community acquired pneumonia (CAP). In this a priori planned exploratory subgroup analysis of the phase 3 randomised controlled Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHSS) trial, we aimed to investigate responses to hydrocortisone plus fludrocortisone between CAP and non-CAP related septic shock.

•The median voriconazole concentration in urine was 1.7 mg/L (range: 0.3–12.6).•Measures of voriconazole concentrations in plasma and urine were highly correlated.•Voriconazole shows promise as an alternative treatment for fluconazole-resistant urinary candidiasis.

Les troubles de la perception des sons font partie des effets indésirables peu connus observés sous antiépileptiques, affectant majoritairement les patients traités par carbamazépine (CBZ). Nous décrivons ici un cas original français de trouble de la perception de la hauteur tonale sous CBZ se traduisant par une perte de l’oreille absolue. Nous proposons également une revue de la littérature et des bases française (base nationale de pharmacovigilance [BNPV]) et mondiale (Vigibase®) de pharmacovigilance. Le cas clinique concerne un patient de 22 ans à l’oreille absolue présentant une épilepsie partielle non traitée. Suite à un épisode convulsif généralisé, l’introduction de CBZ LP (200mg matin et soir) est décidée. Dès l’introduction du traitement, le patient constate une modification de la perception des sons. Cet effet indésirable a persisté malgré une diminution progressive des doses. Le patient rapportait une récupération totale de son oreille absolue lors de l’arrêt total de la CBZ 11 ans plus tard. Dans la BNPV, un seul autre cas de trouble de la perception de la hauteur tonale sous CBZ a été identifié (aucun cas n’étant retrouvé sous oxcarbazépine, lacosamide, valproate de sodium, lamotrigine, lévétiracétam, phénobarbital, phénytoïne, primidone, éthosuximide, vigabatrine, felbamate, gabapentine, tiagabine et topiramate). Dans la littérature, 27 cas de troubles de la perception des sons ont été publiés sous CBZ, 1 cas sous oxcarbazépine et 1 cas sous lacosamide. Cet effet indésirable très rare est essentiellement identifié dans la littérature dans la population japonaise, chez des musiciens expérimentés. D’apparition rapide après l’introduction du traitement, une résolution complète des symptômes, majoritairement à l’arrêt du traitement, est observée sans qu’aucune séquelle ne semble rapportée. Du fait de l’impact sur la qualité de vie, notamment chez les patients dont la profession a un rapport avec la musique, la connaissance de cet effet indésirable semble importante pour évoquer ce diagnostic.

Les bonnes pratiques cliniques (BPC) sont un ensemble d’exigences de qualité devant être respectées lors de la réalisation d’un essai clinique. Avant le démarrage d’un essai, les investigateurs s’engagent à réaliser la recherche conformément aux BPC, aux dispositions réglementaires en vigueur et au protocole. Le promoteur est responsable de la sélection des investigateurs et du contrôle de leurs compétences. En France, si les promoteurs industriels demandent aux investigateurs une certification aux BPC de façon systématique, les promoteurs académiques semblent moins exigeants. Nous avons réalisé une double enquête, entre avril et juin 2018 : (1) nationale auprès des 40 délégations à la recherche clinique et à l’innovation des promoteurs académiques, afin de déterminer leurs exigences concernant la certification aux BPC des investigateurs des recherches qu’elles promeuvent et (2) régionale auprès des médecins des centres hospitaliers du réseau « Bretagne recherche clinique hospitalière » : Rennes, Saint-Malo, Saint-Brieuc, Vannes, Lorient et Pontivy, afin de déterminer leur taux de certification aux BPC et leurs souhaits en termes de formation à la recherche clinique. Parmi les 28 (70 %) délégations à la recherche ayant répondu à l’enquête, 18 (64 %) exigeaient systématiquement la certification aux BPC des investigateurs en cas d’études interventionnelles de catégorie 1. Ce taux diminuait à 50 % et 18 % pour les études de catégorie 2 et 3, respectivement. Un total de 345 médecins a répondu à la deuxième enquête, parmi lesquels 263 (76 %) avaient déjà participé ou participaient à une recherche clinique. Seuls 29 % des médecins ayant répondu et, parmi ceux-ci, 54 % des médecins ayant déjà eu la qualification d’investigateur principal, possédaient une certification aux BPC. Ces résultats soulignent l’importance de mettre en place des actions de formation aux BPC dans les établissements publics de santé.

Au-delà de l’application des exigences réglementaires, la recherche clinique nécessite une démarche permanente de contrôle qualité. Les centres d’investigation clinique (CICs) sont des structures de recherche clinique académiques labellisées par l’Institut national de la santé et de la recherche médicale (Inserm) dont le fonctionnement s’appuie sur des recommandations de bonnes pratiques. Il est important d’accompagner cette standardisation des pratiques par la mise en place d’un système de management de la qualité. Cet article présente la démarche qui a permis au CIC de Rennes d’être certifié ISO 9001 par l’association française de normalisation (Afnor certification) en mai 2016. L’application des principes fondamentaux de la norme ISO 9001 au domaine de la recherche clinique est abordée. Les problématiques du choix du périmètre de la certification et de la cartographie des processus qui en découle sont exposées. Les activités de méthodologie, gestion et analyse d’études cliniques ont été choisies pour la certification initiale du CIC de Rennes. Les perspectives d’extension du périmètre de certification sont abordées en fin d’article.

The authors of this retrospective study assessed the association between high intrapatient tacrolimus variability during the first postoperative month and liver transplant outcome measures, including graft survival and tacrolimus-related toxicities.

Background We aimed to determine the impact of inosine triphosphatase (ITPA) deficiency on ribavirin (RBV)-induced anaemia in HIV–HCV-coinfected patients receiving a triple therapy including the haematotoxic direct-acting antiviral agent boceprevir (BOC).Methods Patients of the ANRS HC27 BocepreVIH study were genotyped for two ITPA single nucleotide polymorphisms involved in ITPA deficiency. RBV trough concentration (Ctrough) was determined at week (W)4 and W8. Impact of ITPA deficiency on anaemia, RBV Ctrough, response and haematotoxicity (grade 3/4 anaemia, erythropoietin [EPO] use, RBV dose reduction or transfusion between day [D]0 and W8) was evaluated. Impact of RBV Ctroughon anaemia was also studied.Results Among the 63 genotyped patients, 33% had a predicted ITPA deficiency. ITPA deficiency was associated with a lower haemoglobin (Hb) decline both at W4 (-1.0 g/dl versus -2.1 g/dl; P=0.02) and W8 (-2.7 g/dl versus -4.1 g/dl; P=0.05). None of the patients with ITPA deficiency received EPO between D0–W8 versus 26% of patients without ITPA deficiency (P=0.01). RBV Ctroughwas associated with Hb decrease both at W4 and W8 and an RBV Ctroughcutoff value of 2 µg/ml was significantly associated with a W4 Hb decline >2 g/dl. Haematotoxicity was significantly associated with a lower W4 Hb level (P=0.017), absence of ITPA deficiency (P=0.018) and higher RBV Ctrough(P=0.012). ITPA deficiency, W4 RBV Ctroughand gender were independent predictors of anaemia at W4. ITPA deficiency was not associated with virological response.Conclusions ITPA deficiency and RBV Ctroughare still predictive of RBV-induced anaemia in HIV–HCV-coinfected patients treated with RBV combined with a first-generation direct antiviral agent.

Background: Melatonin synchronizes central but also peripheral oscillators (fetal adrenal gland, pancreas, liver, kidney, heart, lung, fat, gut, etc.), allowing temporal organization of biological functions through circadian rhythms (24-hour cycles) in relation to periodic environmental changes and therefore adaptation of the individual to his/her internal and external environment. Measures of melatonin are considered the best peripheral indices of human circadian timing based on an internal 24-hour clock. Methods: First, the pharmacology of melatonin (biosynthesis and circadian rhythms, pharmacokinetics and mechanisms of action) is described, allowing a better understanding of the short and long term effects of melatonin following its immediate or prolonged release. Then, research related to the physiological effects of melatonin is reviewed. Results: The physiological effects of melatonin are various and include detoxification of free radicals and antioxidant actions, bone formation and protection, reproduction, and cardiovascular, immune or body mass regulation. Also, protective and therapeutic effects of melatonin are reported, especially with regard to brain or gastrointestinal protection, psychiatric disorders, cardiovascular diseases and oncostatic effects. Conclusion: This review highlights the high number and diversity of major melatonin effects and opens important perspectives for measuring melatonin as a biomarker (biomarker of early identification of certain disorders and also biomarker of their follow-up) and using melatonin with clinical preventive and therapeutic applications in newborns, children and adults based on its physiological regulatory effects.

Using Fibroscan to evaluate liver quality (controlled attenuation and liver stiffness) before procurement in 23 DBDs and comparing results to liver biopsy, the authors show excellent predictive value of this non-invasive method.

Stimuler la notification des effets indésirables et améliorer l’information sur la sécurité du médicament dans le territoire du centre régional de pharmacovigilance de Rennes.

Hydrocortisone enhances the pressor response to catecholamines in healthy volunteers and septic shock patients. Similar data do not exist for fludrocortisone. We assessed the effects of single administrations of fludrocortisone and hydrocortisone on systolic blood pressure until 2 hours after treatments injection and on in vitro vascular contraction of mesenteric artery rings to phenylephrine at 3 hours, in normal and endotoxemic rats. Intravenous fludrocortisone (5 and 20 gkg) and hydrocortisone (4 and 20 mgkg) were administered in 16 groups (8 without and 8 with lipopolysaccharide-induced endotoxemic shock) of 10 Wistar rats according to four 2 × 2-factorial designs. Fludrocortisone and hydrocortisone similarly increased systolic blood pressure (P< 0.001 for both) but more in endotoxemic than in normal animals. Fludrocortisone and hydrocortisone significantly modified contractile response to phenylephrine (P= 0.039 and P= 0.007, respectively). At dose 1, fludrocortisone had no effect and hydrocortisone decreased contraction, whereas, at dose 2, both fludrocortisone and hydrocortisone increased contraction, especially in endotoxemic rats and with additive effect. Our results show that single intravenous administrations of fludrocortisone and hydrocortisone increase blood pressure and contractile response of mesenteric arteries to phenylephrine. The magnitude of these effects depends on dose and pathophysiological conditions and is higher in endotoxemic than in normal rats.

Objective.To compare an interventional protocol with a standard protocol for preventing the acquisition of methicillin-resistant Staphylococcus aureus(MRSA) in the intensive care unit (ICU).Design.Prospective, randomized, controlled, parallel-group, nonblinded clinical trial.Setting.Medical ICUs of 2 French university hospitals.Participants.Five hundred adults with an expected length of stay in the ICU greater than 48 hours.Interventions.For the intervention group, the protocol required repeated MRSA screening, contact and droplet isolation precautions for patients at risk for MRSA at ICU admission and for MRSA-positive patients, and decontamination with nasal mupirocin and chlorhexidine body wash for MRSA-positive patients. For the standard group, the standard precautions protocol was used, and the results of repeated MRSA screening in the standard group were not communicated to investigators.Main Outcome Measure.MRSA acquisition rate in the ICU. An audit was conducted to assess compliance with hygiene and isolation precautions.Results.In the intent-to-treat analysis (n= 488), the MRSA acquisition rate in the ICU was similar in the standard (13 [5.3%] of 243) and intervention (16 [6.5%] of 245) groups (P=.58). The audit showed that the overall compliance rate was 85.5% in the standard group and 84.1% in the intervention group (P=.63), although compliance was higher when isolation precautions were absent than when they were in place (88.2% vs 79.1%; P<.001). MRSA incidence rates were higher without isolation precautions (7.57‰) than with isolation precautions (2.36‰; P=.01).Conclusions.Individual allocation to MRSA screening, isolation precautions, and decontamination do not provide individual benefit in reducing MRSA acquisition, compared with standard precautions, although the collective risk was lower during the periods of isolation.Trial Registration.Clinicaltrials.gov identifier: NCT00151606.

Background: Atazanavir (ATV) is a potent and safe protease inhibitor (PI) initially approved in adult HIV-1 infected patients in combination with other antiretroviral drugs with once daily administration. In combination with nucleoside reverse transcriptase inhibitors (NRTIs) and boosted with ritonavir, it has been established as the preferred initial regimen in published guidelines. Objective: This article reviews relevant pharmacodynamic, pharmacokinetic, efficacy and safety data of ATV, administered boosted with ritonavir or unboosted, in comparison with other PIs and/or non-NRTIs, with special focus on recent studies. Methods: Review articles, recent primary literature and scientific meeting reports were analyzed. Results: Compared to most PIs with similar efficacy, the advantages of ATV are a once daily administration with only 100 mg ritonavir when boosted, a good gastrointestinal tolerance with limited diarrhea, a neutral effect on cholesterol and triglycerides, and a favorable resistance profile. However, highly frequent hyperbilirubinemia is observed resulting in some cases in clinical jaundice. Unboosted ATV must be cautiously used because increased resistances have been described. Conclusion: The combination of a similar efficacy, a better tolerance and a low pill burden, as compared to other PIs, makes boosted ATV one of the best options, in combination with NRTIs, in PI-naive HIV-1 infected patients.

International guidelines for management of septic shock recommend that dopamine or norepinephrine are preferable to epinephrine. However, no large comparative trial has yet been done. We aimed to compare the efficacy and safety of norepinephrine plus dobutamine (whenever needed) with those of epinephrine alone in septic shock.

Background: The efficacy of corticosteroids in reducing the incidence of postextubation laryngeal oedema is controversial. We aimed to test our hypothesis that methylprednisolone started 12 h before a planned extubation could prevent postextubation laryngeal oedema. Methods: We did a placebo-controlled, double-blind multicentre trial in 761 adults in intensive-care units. Patients who were ventilated for more than 36 h and underwent a planned extubation received intravenous 20 mg methylprednisolone (n=380) or placebo (381) 12 h before extubation and every 4 h until tube removal. The primary endpoint was occurrence of laryngeal oedema within 24 h of extubation. Laryngeal oedema was clinically diagnosed and deemed serious if tracheal reintubation was needed. Analyses were done on a per protocol and intention-to-treat basis. This trial is registered at ClinicalTrials.gov, number NCT00199576. Findings: 63 patients could not be assessed, mainly because of self-extubation (n=16) or cancelled extubation (44) between randomisation and planned extubation. 698 patients were analysed (343 in placebo group, 355 in methylprednisolone group). Methylprednisolone significantly reduced the incidence of postextubation laryngeal oedema (11 of 355, 3%vs 76 of 343, 22%, p<0.0001), the global incidence of reintubations (13 of 355, 4%vs 26 of 343, 8%, p=0.02), and the proportion of reintubations secondary to laryngeal oedema (one of 13, 8 %vs 14 of 26, 54%, p=0.005). One patient in each group died after extubation, and atelectasia occurred in one patient given methylprednisolone. Interpretation: Methylprednisolone started 12 h before a planned extubation substantially reduced the incidence of postextubation laryngeal oedema and reintubation. Such pretreatment should be considered in adult patients before a planned extubation that follows a tracheal intubation of more than 36 h.

Septic shock, the most severe complication of sepsis, is a deadly disease. In recent years, exciting advances have been made in the understanding of its pathophysiology and treatment. Pathogens, via their microbial-associated molecular patterns, trigger sequential intracellular events in immune cells, epithelium, endothelium, and the neuroendocrine system. Proinflammatory mediators that contribute to eradication of invading microorganisms are produced, and anti-inflammatory mediators control this response. The inflammatory response leads to damage to host tissue, and the anti-inflammatory response causes leucocyte reprogramming and changes in immune status. The time-window for interventions is short, and treatment must promptly control the source of infection and restore haemodynamic homoeostasis. Further research is needed to establish which fluids and vasopressors are best. Some patients with septic shock might benefit from drugs such as corticosteroids or activated protein C. Other therapeutic strategies are under investigation, including those that target late proinflammatory mediators, endothelium, or the neuroendocrine system.

Chronic angiotensin I–converting enzyme inhibition can be associated with aldosterone escape. We investigated the effects of enalapril, spironolactone, and their combination on hemodynamics and cardiac remodeling in cardiomyopathic hamsters to determine whether these drugs could exert additive effects. Cardiomyopathic hamsters, Bio TO-2 dilated strain, were orally treated with enalapril (20 mg · kg−1· day−1) and/or spironolactone (20 mg · kg−1· day−1) according to a 2 × 2 factorial design from 120 days of age. Animals were investigated at 180 (10 animals per group) and 240 (16 animals per group) days of age. Compared with corresponding untreated groups, enalapril significantly decreased mean blood pressure (−18); enalapril and spironolactone significantly increased cardiac output (28, 11) and femoral blood flow (10, 12) and significantly decreased systemic (−38, −17) and femoral (−26, −13) vascular resistances. Enalapril and spironolactone significantly decreased left ventricle cavity area (−21, −26) and left (−34, −47) and right (−37, −48) ventricle collagen density. Spironolactone significantly increased left ventricle wall thickness (4). There were significant enalapril × spironolactone interactions for most variables (compared with control group, 52, 36, 45 for cardiac output; 26, 28, 26 for femoral blood flow; −50, −30, −45 for systemic vascular resistance; −33, −20, −35 for femoral vascular resistance; −27, −31, −40 for left ventricle cavity area; and −46, −58, −60 for left and −39, −50, −66 for right ventricle collagen density in enalapril, spironolactone, and enalapril spironolactone groups, respectively). In cardiomyopathic hamsters, enalapril and spironolactone in combination did not improve hemodynamics more than enalapril alone but induced stronger effects than each drug alone on cardiac remodeling.

The use of -blockers reduces angiotensin II levels, but could not adequately suppress aldosterone production. Thus, the combination of a -blocker with an aldosterone receptor antagonist could exert additive effects. The effects of metoprolol and spironolactone and their combination on hemodynamics and cardiac remodeling in cardiomyopathic hamsters (CMH) were investigated. The Bio TO-2 dilated strain of CMH was treated orally with metoprolol (10 mg/kg/day), spironolactone (20 mg/kg/day), or both according to a 2 × 2 factorial design (24 animals per group) from 120 days of age and during 120 days. As compared to corresponding untreated groups, metoprolol significantly decreased mean blood pressure (−7), and metoprolol and spironolactone significantly increased cardiac output (18 and 19, respectively), mesenteric blood flow (11 and 14), and femoral blood flow (13 and 17), and significantly decreased systemic (−24 and −15), mesenteric (−14 and −13) and femoral (−19 and −10) vascular resistances. Metoprolol significantly increased renal blood flow (22) and significantly decreased renal vascular resistance (−23). Metoprolol and spironolactone significantly decreased the cavity area of the left ventricle (−21 and −32, respectively) and the collagen density of the left (−36 and −39) and right (−38 and −43) ventricles. Although the combination did not induce stronger effects than each drug alone on the systemic and most regional hemodynamic variables, it did have a stronger effect on the cardiac remodeling (compared to control group −24, −34, and −46 for the left ventricle cavity area, −33, −35, and −62 for collagen density in the left ventricle, and −52, −57, and −59 for collagen density in the right ventricle, respectively, in the metoprolol, spironolactone, and metoprolol spironolactone groups). In CMH, metoprolol and spironolactone combined did not improve hemodynamics more than each drug alone, but did exert additive effects on cardiac remodeling.

The effects of the selective angiotensin II type 1 receptor antagonist candesartan on cardiac, systemic, and regional hemodynamics and on cardiac, pulmonary, and hepatic histomorphometry were investigated in cardiomyopathic hamsters (CMHs), Bio TO-2 dilated strain, with advanced congestive heart failure (CHF). Two groups were treated orally with candesartan cilexetil at 22 or 50 mg/kg/d from 190 days of age and compared with a control group (38 animals/group). Investigations were performed at 225, 255, and 285 days of age. Left ventricle (LV) and systemic blood pressures and cardiac output and mesenteric and femoral blood flows were measured in anesthetized animals. LV cavity area, LV and right ventricle (RV) wall thickness and collagen density, and pulmonary and hepatic congestion were assessed. Compared with the control group, candesartan did not modify cardiac hemodynamics but significantly and dose-dependently decreased systemic vascular resistances (on average −23 and −32 after 22 and 50 mg/kg, respectively) and increased stroke volume (32 and 42) and cardiac output (27 and 34). Candesartan did not modify mesenteric vascular resistances and blood flow but significantly and dose-dependently decreased femoral vascular resistances (−19 and −33) and increased femoral blood flow (33 and 43). Candesartan significantly decreased LV cavity area (−14 and −8) and LV (−15 and −31) and RV (−16 and −24) collagen density but did not modify LV and RV wall thickness. Candesartan decreased pulmonary congestion at 255 and 285 days of age but did not modify hepatic congestion. In CMHs with advanced CHF, candesartan cilexetil improves systemic and femoral hemodynamics, partly reverses cardiac remodeling, and decreases pulmonary congestion.

We investigated the effects of the 1-2-1-blocker, labetalol, in the congestive heart failure (CHF) model induced by aortic constriction in the guinea pig. One hundred days after aortic constriction, 52 animals were given either placebo, labetalol 2 mg/kg/d, or labetalol 20 mg/kg/d for 60 days. Eighteen sham-operated animals were used as controls. Investigations were performed at the end of the treatment period. Compared with sham-operated animals, banded animals receiving placebo showed signs of overt CHF with cardiac, systemic and regional (mesenteric and femoral) hemodynamic dysfunction, and pulmonary and hepatic congestion. An increase in whole heart, atria, and left and right ventricle weights associated with left ventricular cavity enlargement and left and right ventricular wall thickening indicated a remodeling process. Compared with placebo, labetalol did not significantly modify cardiac, systemic, or regional hemodynamic variables but significantly decreased pulmonary and hepatic congestion. Labetalol significantly reduced left ventricular cavity area (−10 and −20 after 2 and 20 mg/kg, respectively) and left ventricular (−4 and −16) and right ventricular (−4 and −19) wall thickness. In conclusion, labetalol induced partial regression of cardiac remodeling before hemodynamic improvement. This early anti-remodeling effect could play a role in the favorable effects observed with 1-2-1-blockers in humans.

In septic shock, the alteration of the gut barrier contributes to the development of multiple organ failure. The aim of the study was to compare epinephrine with the combination of dobutamine and norepinephrine on gastric perfusion in patients with septic shock. In a prospective randomized study on 2 parallel groups, systemic and pulmonary hemodynamics (arterial and Swan‐Ganz catheters), gastric mucosal blood flow (laser Doppler flowmetry technique), hepatic function (indocyanine green clearance), and blood gases were evaluated just before catecholamine infusion and when mean arterial pressure reached 70 to 80 mm Hg. Epinephrine or norepinephrine were titrated (from 0.1 μg/kg per minute, with 0.2 μg/kg per minute increases every 5 minutes). Dobutamine was continuously infused at 5 μg/kg per minute. Twenty‐two patients were included (11 in each group). At randomization there was no significant difference between groups. At the time of evaluation, mean arterial pressure was 78 ± 3 and 77 ± 5 mm Hg in the epinephrine and dobutamine‐norepinephrine groups, respectively. There was no significant difference between groups regardless of the systemic and pulmonary hemodynamic or blood gas variable considered. Nevertheless, compared with dobutamine‐norepinephrine, epinephrine tended to induce greater values for cardiac index (5.0 ± 1.6 versus 4.2 ± 1.5 L/min per square meter; P= .078) and oxygen transport (617 ± 166 versus 481 ± 229 mL/min per square meter; P= .068). Epinephrine also induced significantly greater values of gastricmucosal blood flow (662 ± 210 versus 546 ± 200 units; P= .011) but did not modify indocyaninegreen clearance. In patients with septic shock, at doses that induced the same mean arterial pressure, epinephrine enhanced more gastric mucosal blood flow than the combination of dobutamine at 5 μg/kg per minute and norepinephrine. This effect was probably a result of higher cardiac index. Clinical Pharmacology & Therapeutics(2002) 71, 381–388; doi: 10.1067/mcp.2002.122471

ABSTRACTThe 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 log10copies/ml, and CD4 cell counts were 236 ± 126 and 234 ± 125/mm3in the ritonavir and ritonavir-saquinavir groups, respectively. At week 24, viral loads were 2.81 ± 1.48 and 2.08 ± 1.14 log10copies/ml (P= 0.04) and CD4 cell counts were 330 ± 151 and 364 ± 185/mm3(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.

Septic shock remains one of the leading causes of death in intensive care units. Although our understanding of the mechanisms of inflammation has progressed during the last two decades, the drugs developed toward the specific targets of the cytokine cascade have failed to improve patients’ survival. Corticosteroids were the first antiinflammatory drugs tested in randomized controlled trials. Administered during short courses and at high doses, they did not induce any beneficial effect. However, recent findings on the mechanisms of action of steroids and on the mechanisms of host response to septic insult have led to a reappraisal of the use of these drugs in septic shock. Several randomized controlled trials have evaluated the efficacy and safety of prolonged treatments with low doses of hydrocortisone in severe sepsis. These trials strongly suggest that this new strategy of administration of corticosteroids reduces the morbidity of septic shock and may favorably affect survival.

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 pD2was calculated as −log(EC50). Compared with control hamsters, in cardiomyopathic hamsters, Emaxof 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. Emaxof acetylcholine was significantly higher in aorta (+57% and +30%), mesenteric (+42% and +34%), and renal (+168% and +70%) arteries. Emaxof 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. Emaxof angiotensin II was not modified in aorta and tended to be lower in mesenteric artery at 300 days. The pD2of phenylephrine was significantly increased in aorta and the pD2of 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.

Background: 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.Methods: 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 (μg/kg/min) were infused, and the effects on mean arterial pressure (mm Hg) were recorded. A sigmoid model, E = E0+ [Emax· Dγ/(ED50γ + Dγ)], was fitted to individual data. In this model, E is the predicted effect and D is the dose of phenylephrine infused. E0represents the basal value of effect (ie, the value of mean arterial pressure without drug), Emaxis the maximum theoretical effect, ED50is the dose of phenylephrine for which an effect of 50% of Emaxis observed, and γ is the Hill coefficient which accounts for the sigmoidicity of the curve.Results: As compared with in control subjects, in patients, E0was 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), Emaxwas 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), ED50was not modified, and γ 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 E0in both groups (P = .0003 for sequence, P = .2883 for interaction), increased more Emaxin patients than in control subjects (P < .0001 for sequence; P = .0280 for interaction), did not change ED50, and decreased γ in patients but not in control subjects (P = .0025 for sequence, P = .0025 for interaction).Conclusions: In patients with septic shock, the Emaxof phenylephrine is decreased, whereas its ED50is not modified, both before and after administration of hydrocortisone. A physiological dose of hydrocortisone tends to normalize the relationship.Clinical Pharmacology & Therapeutics (2000) 68, 293–303; doi: 10.1067/mcp.2000.109354

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; H1) and in the case of lack of efficacy (null hypothesis; H0). We compared the statistical properties of the SPRT and the TT, and of OPB with Pocock (OPBΔ = 0.5) and O'Brien and Fleming (OPBΔ = 0) type boundaries, in the setting of one-sided comparative trials with normal response. We studied the type I error (α), power (1-β), 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 α and 1-β close to nominal values and, as compared with SSD, allow important decreases in ASN: for example, -48%, -42%, -40% and -31% under H0 and H1 for SPRT, TT, OPBΔ = 0.5 and OPBΔ = 0 respectively. For situations between H0 and H1, 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 OPBΔ = 0 under H0 and H1 were smaller than the P90s of the SPRT and OPBΔ = 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 H0 and H1.

Background: 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.Methods: 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.Results: 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 log10copies/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.Conclusion: 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.

Abstract—The aims of this study were to investigate whether angiotensin II and/or endothelin could contribute to the hypoxic contractile response of isolated rat pulmonary artery. Experiments were performed for 1 h on noradrenaline precontracted arterial rings in hypoxic conditions (95% N2and 5% CO2). Nicardipine, lisinopril, losartan, phosphoramidon, FR139317 and bosentan were used to block Ca2+channels, angiotensin I‐converting enzyme, AT1receptors, endothelin‐converting enzyme, ETAreceptors, and ETA/ETBreceptors, respectively. The profile of the hypoxic contractile response was biphasic, displaying, after a short relaxation, a weak and transient contraction (from 2–4 min) and then, before complete relaxation, a slowly developed but sustained contraction (from 14–60 min). Endothelium removal abolished the transient contraction and reduced (–59%) the sustained contraction. Nicardipine did not modify the transient contraction, but concentration‐dependently decreased (from –35% to –100%) the sustained contraction (P= 0.024). Lisinopril and losartan did not affect the response (P= 0.418 and P= 0.973, respectively). Bosentan did not modify the transient contraction, but concentration‐dependently decreased (from –14% to –71%) the sustained contraction (P= 0.016), whereas phosphoramidon and FR139317 did not affect the response (P= 0.830 and P= 0.806, respectively). Conclusions: in rat, (i) both phases of the hypoxic contractile response are endothelium‐dependent and independent of angiotensin II; (ii) the transient contraction does not depend on endothelin; (iii) the sustained contraction, which involves calcium influx, appears partly dependent on mature endothelin released from storage granules by stimulating ETBreceptors.

The effect of repeated transient global ischemia and microdialysis on changes in aminergic neurotransmitter release was investigated using the rat four-vessel occlusion model of global ischemia. To examine the possible transient or permanent changes in neurotransmitter release, ischemia was induced at varying time points in 5 groups of rats. The first ischemia occurred either 24h (groups I, II, IV, V) or 96h (group III) following vertebral artery electro-coagulation and guide probe implantation(s), and the second ischemia was induced either 48h (groups I, IV, V) or 72h (group II) following the first ischemia. To assess the consequence of repeated microdialysis on the results, one group of rats (group IV) was not dialysed during the first ischemia and another group (group V) was bilaterally dialysed during the second ischemia. Finally, amphetamine-induced neurotransmitter release was also studied in rats submitted to ischemia and compared with that in normal rats. In each case, dopamine, serotonin and their main metabolites were measured by HPLC with electrochemical detection. Monoamine release was inhibited during the second episode of transient ischemia; this non-release was linked to the repeated microdialysis and not to the repeated ischemia. Although the results of chronic studies using brain microdialysis have been widely recognized as valid, the findings presented here indicate that combined with ischemia, probe reinsertion modifies the level of neurotransmitter release.

The effects of single oral doses of lisinopril (5 and 20 mg) on systemic and regional hemodynamics were investigated noninvasively in a placebo-controlled, randomized, double-blind, cross-over study of 6 healthy male volunteers. Lisinopril induced a dose-dependent (significant after 20 mg) and long-lasting (8 h) decrease in mean arterial pressure (MAP, 11 after 20 mg) that was related to a decrease in total peripheral resistance (TPR), because simultaneously heart rate (HR) and cardiac output (CO) were unchanged. Brachial artery flow ( + 42 and +47 after 5 and 20 mg, respectively) and diameter ( + 8 and + 9) increased significantly, whereas brachial vascular resistance (- 31 and - 38) decreased significantly from 2 to 8 h after drug intake. Common carotid artery flow ( + 20 and + 24) also increased significantly, whereas corresponding resistance (-18 and −26) decreased significantly during the same period. Finally, CO was significantly redistributed toward the brachial and, to a lesser extent, the carotid vascular beds after both doses of lisinopril. We conclude that in healthy subjects lisinopril, at non- or slightly hypotensive doses, dilates both arterioles and large arteries and that this va- sodilation is not homogeneous, affecting preferentially the brachial rather than the carotid vascular bed.

In a previous placebo-controlled, randomized, double-blind, cross-over study performed in 6 healthy volunteers, we investigated the pharmacokinetics and pharmacodynamics of a single oral administration of two doses (5 and 20 mg) of the angiotensin-converting enzyme inhibitor (ACEI), lisinopril. The purpose of the present study was to investigate the relation between lisinopril plasma concentrations (C, ng/ml), and lisinopril-induced effects on plasma converting enzyme activity (PCEA, nmol/ml/min), brachial artery flow (BAF, ml/min), and brachial vascular resistance (BVR, mm Hg · s/ml). PCEA and BVR were expressed in percent changes from initial values and BAF was expressed in absolute values. Effects (E) were related to Cby the Hill model: E= Emax· Cγ/CE50γ+ Cγ). For PCEA, the model was fitted to the data of both doses simultaneously. Emaxwas fixed at - 100%, and we obtained (mean ± SD) CE50= 1.4 ± 0.6 ng/ml and γ = 0.6 ± 0.1. For BAF and BVR, the model was fitted to the data of the 20-mg dose for 5 subjects and to those of the 5-mg dose for 1 subject. We obtained Emax= 45 ± 20 ml/min, CE50= 24.0 ± 12.4 ng/ml, and γ = 3.2 ± 1.3 for BAF, and Emax= -45 ± 15%, CE50= 22.0 ± 10.2 ng/ml, and γ = 3.1 ± 1.1 for BVR. Therefore, the concentration-effect relations for BVR (or BAF) and PCEA display quite different shapes (CE50, γ), which emphasizes the necessity of performing pharmacokinetic-pharmacodynamic (PK-PD) modeling on hemodynamic parameters to determine the optimal dosages of ACEIs.

The oxygen consumption (Vo2)/oxygen delivery (Do2relationship was analyzed in ten patients with severe congestive heart failure (CHF) and normal blood lactate levels. First dobutamine and then enoximone, after a washout period, were administered to each patient to increase cardiac output by at least 15 percent. Similar increases in Do2were obtained with both drugs: from 285 ± 46 to 393 ± 87 ml/min/m2for dobutamine, and from 285 ± 54 to 392 ± 99 ml/min/m2for enoximone. However, while Vo2did not change (132 ± 24 vs 132 ± 21 ml/min/m2) (Vo2/Do2independency) with a dobutamine infusion (mean dose of 10 ± 2 μg/kg/min), a significant increase in Vo2from 134 ± 22 to 157 ± 21 ml/min/m2was observed with a bolus infusion of enoximone (mean dose of 1.7 ± 0.5 mg/kg). These results, observed in patients with CHF without patent oxygen debt, suggest that an artefactual Vo2/ Do2dependency might be induced by the cardiovascular drug used to elevate Do2, probably because of a drug-induced oxygen demand increase.

Somatostatin is localized in the intestinal and pelvic nerves of the anorectum and it seems to act as an important neurotransmitter. However, previous analyses of octreotide (a somatostatin analog) effects on anal function showed conflicting results. By use of a dynamic model in healthy subjects, with comparison to the myogenic effect of glucagon, the aim of our study was to further investigate the pharmacologic targets of octreotide. This was a placebo‐controlled, randomized, double‐blinded crossover study performed in 12 healthy volunteers who received octreotide, glucagon, or placebo intravenously on separate days. During each sequence, several pressure steps in 3 different protocols of rectal isobaric distension were applied with an electronic barostat. Manometric responses of the anal canal, adaptative volumes, and perception scores of the rectum were recorded. During both phasic and stepwise distensions, a significant drug effect was encountered at the anal level. Compared with placebo, octreotide significantly increased pressures at both upper and lower levels of the anal canal. In contrast, glucagon decreased pressures at the upper part of the anal canal. Octreotide significantly decreased rectal volumes to phasic distension, but glucagon did not induce any change on rectal adaptation. In addition, neither drug modified perception scores. This study suggests that octreotide acts on reflex arcs and rectal myenteric neurons rather than on anal myogenic targets that respond to glucagon. Clinical Pharmacology & Therapeutics(1998) 64, 424–432; doi:

Background: Sequential methods are particularly interesting when recruitment is difficult because they may allow a study to be stopped early while maintaining type I and II error rates.Methods: This placebo-controlled, randomized double-blind study was aimed at assessing the efficacy of metoclopramide (0.2 mg/kg three times daily during 14 days) on gastroesophageal reflux in infancy. The main end point was the relative variation of the percentage of time at pH <4 between inclusion (day 0) and evaluation (day 14) assessed on two 24-hour esophageal pH recordings. Statistical analysis was performed with use of a sequential method, the triangular test.Results: The study was stopped after the seventh analysis (39 infants evaluated: 20 placebo and 19 metoclopramide) without showing the expected benefit. Improvement on the main end point was 30% ± 48% (mean ± SD). Corresponding unbiased median estimates were 22% for placebo and 39% for metoclopramide (p = 0.28, sequential analysis). On day 14, the percentage of time at pH <4 was 8.1% ± 11.7% for placebo and 6.7% ± 9.2% for metoclopramide (p = 0.68, t test), and the number of reflux episodes >5 minutes was 3.0 ± 3.5 for placebo and 1.9 ± 3.0 for metoclopramide (p = 0.33, t test).Conclusion: If a tendency for a superior improvement with metoclopramide than with placebo was observed on the main end point, it was lower than expected and the difference was not significant. Compared with the corresponding single-stage design, the triangular test allowed to stop the study with a 15% reduction in sample size.

The effects of two oral doses of zabicipril, a new angiotensin converting enzyme inhibitor, on systemic (arterial pressure, heart rate, and cardiac output) hemodynamic parameters and regional (brachial, carotid and femoral arteries' diameters and flows) hemodynamic parameters and on biologic (plasma-converting enzyme and renin activities, catecholamines, and atrial natriuretic factor) parameters were noninvasively investigated and compared with those of a placebo in a double-blind crossover study performed in six healthy male volunteers. Although it did not affect the systemic hemodynamic parameters, zabicipril induced a strong peripheral vasodilation, significantly reducing brachial, carotid, and femoral resistances and increasing the corresponding blood flows from 3 or 4½ hours to 9 hours. This vasodilation affected only the arterioles, not the large arteries, and resulted in a redistribution of cardiac output toward the three regional vascular beds. Zabicipril induced an early, potent, and long-lasting converting enzyme inhibition. Furthermore, zabicipril did not affect plasma catecholamines and atrial natriuretic factor.

The aim of this study was to investigate the relations between the plasma concentrations of spiraprilat (the active metabolite of the angiotensin-converting enzyme inhibitor spirapril) and its effects on plasma converting enzyme activity (PCEA), pulmonary capillary wedge pressure (PCWP), and brachial blood flow (BBF), after a single oral administration of 6 mg of spirapril in eight patients with severe congestive heart failure (CHF). Concentrations and effects were determined before and repeatedly during 48 h after drug intake. A sigmoid model was fitted to individual observations. Maximal effects, concentrations inducing half-maximal effects, and Hill coefficients were −99 ± 2%, 3.9 ± 1.9 ng/ml, and 2.4 ± 0.7 for PCEA inhibition, −15 ± 8 mm Hg, 11.8 ± 9.2 ng/ml, and 2.6 ± 1.3 for PCWP decrease, and 36 ± 19 ml/min, 13.8 ± 7.6 ng/ml, and 3.3 ± 1.0 for BBF increase. In severe CHF, although a 14 ng/ml plasma concentration of spiraprilat may induce a 95% inhibition of PCEA, a 30 ng/ml plasma concentration is mandatory to normalize PCWP and BBF. This concentration corresponds to the peak achieved after a 6-mg oral dose of spirapril.

This case-report describes a massive voriconazole (VRZ) intoxication in a patient with a poor metabolizer profile, highlighted by low plasma main metabolite concentrations (N-oxide voriconazole), despite an extensive genetic profile for CYP2C19and CYP2C9. The patient was treated with a therapeutic dose of VRZ but developed a neurotoxicity leading to hallucinations and coma while the plasma concentration of VRZ reached an exceptional level (20.0 μg/mL on day 10 of the treatment). Since neurological disorders diminished in parallel with the decrease of VRZ plasma concentrations, the coma was likely due to VRZ. The VRZ half-life, calculated to 58 h in this patient, was by far higher than the values reported in the literature. While VRZ concentrations slowly decreased, the N-oxide voriconazole concentrations slowly increased from day 15. Hypotheses for this lack of metabolization of VRZ are an inhibition of the metabolism by esomeprazole, a saturation of the metabolism or an enzymatic auto-inhibition of VRZ metabolism but none of these hypotheses have yet been explored. This case-report of unpredictable accumulation of VRZ in a patient without any genetic risk factor is an advocacy for systematic therapeutic drug monitoring of VRZ.

Introduction

Houot: Bristol Myers Squibb: Honoraria; Merck Sharp Dohme: Honoraria. Gyan:Pfizer: Honoraria. Feugier:janssen: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau; gilead: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau.