Population Pharmacokinetics of Posaconazole Tablets and Monte Carlo Simulations To Determine whether All Patients Should Receive the Same Dose.

Posaconazole is extensively used for prophylaxis for invasive fungal infections. The gastro-resistant tablet formulation has allowed the bioavailability issues encountered with the oral suspension to be overcome. However, overexposure is now frequent. This study aimed to (i) describe the pharmacokinetics of posaconazole tablets in a real-life cohort of patients with hematological malignancies and (ii) perform Monte Carlo simulations to assess the possibility that the daily dose can be reduced while keeping a sufficient exposure. Forty-nine consecutive inpatients were prospectively included in the study. Posaconazole trough concentrations (TC) were measured once a week, and biological and demographic data were collected. The concentrations were analyzed by compartmental modeling, and Monte Carlo simulations were performed using estimated parameters to assess the rate of attainment of the target TC after dose reduction. The pharmacokinetics of posaconazole were well described using a one-compartment model with first-order absorption and elimination. The values of the parameters (interindividual variabilities) were as follows: the absorption constant (ka ) was 0.588 h-1 (fixed), the volume of distribution (V/F) was 420 liters (28.2%), and clearance (CL/F) was 7.3 liters/h (24.2%) with 31.9% interoccasion variability. Forty-nine percent of the simulated patients had TC at steady state of ≥1.5 µg/ml and maintained a TC above 1 µg/ml after a reduction of the dose to 200 mg daily. A third of these patients eligible for a dose reduction had TC of ≥1.5 µg/ml as soon as 48 h of treatment. Though posaconazole tablets were less impacted by bioavailability issues than the oral suspension, the pharmacokinetics of posaconazole tablets remain highly variable. Simulations showed that approximately half of the patients would benefit from a reduction of the dose from 300 mg to 200 mg while keeping the TC above the minimal recommended target of 0.7 µg/ml, resulting in a 33% savings in the cost of this very expensive drug.

MR delayed enhancement imaging findings in suspected acute myocarditis.

The purpose of the study was to prospectively assess the clinical impact of routinely performed delayed enhancement imaging in suspected acute myocarditis. A two-centre prospective study was performed in patients with suspected acute myocarditis. The protocol included horizontal long axis, vertical long axis and short axis ciné MR and delayed enhancement imaging after Gd-DTPA infusion (0.2 mmol/kg). Sixty consecutive patients were enrolled (aged 49.4 +/- 17.8 years). MRI demonstrated delayed enhancement sparing the subendocardicardial layer in 51.6% of patients, concordant with the diagnosis of acute myocarditis; 16.7% of patients exhibited delayed enhancement involving the subendocardial layer with irregular margins, concordant with the diagnosis of acute myocardial infarction; 31.7% of patients had delayed enhancement imaging that was considered normal. Routine imaging to identify delayed enhancement provided crucial information in suspected acute myocarditis by reinforcing the diagnosis in 51.6% of patients and correcting a misdiagnosed acute myocardial infarction in 16.7% of patients.

[Troponin dosage in a patient with asymptomatic myocarditis due to trichinellosis]. / Myocardite asymptomatique au cours d''un cas de trichinellose: intérêt du dosage de la troponine.

Human trichinellosis is a potentially severe parasitic disease occurring after ingestion of undercooked meat infected with Trichinella sp. larvae. We report the case of a patient who ate an undercooked bear meat hunted in Canada; he presented with the usual symptoms of trichinellosis (i.e, facial oedema, myalgias and fever) complicated with an asymptomatic myocarditis. Myocarditis is a rare, but potentially lethal complication of trichinellosis. Myocarditis should be screened systematically even when specific symptoms are missing; dosage of troponin serum is a simple and reliable mean for such screening.

Safety study and therapeutic drug monitoring of the oral tablet formulation of posaconazole in patients with haematological malignancies.

PURPOSE: Posaconazole is a triazole antifungal widely used for prophylaxis of invasive fungal disease (IFI). Posaconazole tablets allow reaching higher plasma levels than the oral suspension, but safety data with this formulation in real life are scarce. This study aimed at evaluating the safety profile, the pharmacokinetic variability, and the concentration-toxicity relationship of posaconazole tablets in patients with haematological malignancies. METHODS: Sixty neutropenic patients treated with posaconazole tablets for prophylaxis of IFI were prospectively included in the study. Adverse drug reactions (ADR) were recorded and analyzed by the Regional Pharmacovigilance Centre to assess posaconazole implication. Blood samples were drawn once a week and plasma trough concentrations (C min) were assayed by LC-MS/MS. The rates of ADR by quartile of C min were compared. RESULTS: Eighteen patients (30%) experienced at least one ADR attributed to posaconazole. Liver function test (LFT) abnormalities were encountered in 20% of patients and resulted in four (6.7%) treatment discontinuations. Posaconazole median (range) C min was 1.36 (< 0.1-3.44) µg/mL (inter-patient CV = 43.9%). During follow-up, 28.6% of patients had at least one concentration < 0.7 µg/mL, and 35.7% had at least one concentration > 2 µg/mL. Rates of ADR by quartile of C min were not different. CONCLUSIONS: Posaconazole was well tolerated; however, LFT abnormalities were frequent. ADR occurrence was not linked to posaconazole exposure. Because posaconazole concentrations were highly variable, TDM can be helpful to avoid underexposure to the drug and increase its efficacy in preventing IFI. Conversely, a large proportion of patients was overexposed and might have benefited of a dose reduction.

[Revascularisation of unprotected left main coronary artery disease: an update]. / Revascularisation du tronc commun coronaire gauche non protégé.

Coronary bypass grafting is the reference treatment of unprotected left main coronary disease. Nevertheless, the experience of invasive cardiologists and the introduction of active stents make angioplasty possible in selected cases. Only the results of controlled clinical trials (SYNTAX trial currently under way) will enable physicians to choose the most appropriate method of revascularisation for their patients.

[Aortic bioprosthesis implanted percutaneously: three year follow up]. / Bioprothèse aortique implantée par voie percutanée: suivi à trois ans.

Percutaneous implantation of a bioprosthesis for the treatment of degenerative aortic stenosis ushered in a new era for interventional cardiology, and now represents the best therapeutic option for a growing number of patients for whom surgical aortic replacement would be too risky. This is the case in about a third of symptomatic patients affected. Between 2003 and 2005, we performed initial feasibility studies (I-REVIVE and RECAST) in Rouen, on non-operable patients in a critical state, included for purely compassionate reasons. The valve used was a pericardial bioprosthesis mounted in an expandable balloon stent. The mean age of the patients was 80 years, all had multiple co-morbidity and had been turned down by the cardiac surgeons. In 33 of the 36 included patients, the technique was attempted by the anterograde trans-septal approach (n=27, success rate 80%) or by the retrograde arterial route (n=7, success rate 57%). Echocardiography following implantation revealed a final aortic surface area of 1.70 cm2 and a transvalvular gradient of 9 mmHg. A significant paravalvular aortic leak was noted in 5 cases. There were 6 deaths by 1 month, related to the procedure, and 10 deaths by 6 months, from non-cardiac causes and not related to the procedure. There was no occurrence of coronary occlusion, secondary displacement or dysfunction of the prosthesis. In December 2006, 8 patients reached 2 years of follow up, and two others reached 3 years, symptom free and still with an unchanged valvular function. Significant technological improvements have made the technique simpler, quicker and safer, with very much improved short and long term results. The new trans-apical approach is under evaluation with some promising initial results. More than 280 patients have been implanted to date. Other implantable prostheses are under evaluation. This therapeutic modality looks likely to develop rapidly, and in the near future it should offer a new and optimal solution for all high surgical risk or non-operable patients.

[Intra-stent restenosis following implantation of a bare endoprosthesis]. / Resténose intra-stent après implantalion d'une endoprothèse nue.

The aim of this retrospective study was to evaluate the immediate and long-term results of various treatments for patients with a primary lesion of intra-stent restenosis (ISR). The study included 214 patients (233 endoprostheses, site of a primary ISR), with an average age of 61+/-11 years. These patients had received one of the following treatments: balloon angioplasty alone (101 patients), implantation of a second endoprosthesis (32 patients), medical treatment (65 patients), or revascularisation surgery with aorto-coronary bypass (16 patients). After retrospective analysis of the initial data, clinical follow-up was studied for all patients, and severe cardiac events were recorded. The immediate treatment of the ISR with angioplasty or bypass had an initial success rate of 100%. At the end of follow up (26+/-1.8 months) for the series as a whole, 9 patients (4.1%) had died, 7 (3.2%) had suffered a myocardial infarction, and 22 (10.3%) had had to undergo a secondary revascularisation procedure. 111 (52%) patients had angiographic follow up. A second ISR was noted in 43 cases (39%). The type of treatment provided was not a predictive factor for the occurrence of a severe cardiac event. In conclusion, whatever treatment of ISR is used, the immediate result is satisfactory. The rate of severe cardiac events is acceptable and in 10.3% of cases necessitates a secondary revascularisation procedure within 2 years. The very promising recent development of new active endoprostheses could alter the management of coronary patients in the years to come.

[Balloon aortic valvuloplasty in the adult. Immediate results and in-hospital complications in the latest series of 141 consecutive patients at the University Hospital of Rouen (2002-2005)]. / Valvuloplastie aortique par ballonnet chez l'adulte. Résultats immédiats et complications intrahospitalières dans la dernière série de 141 patients consécutifs au CHU de Rouen (2002-2005).

UNLABELLED: With the aging population, elderly patients with degenerative, severely calcified, and symptomatic aortic stenosis are becoming a frequent problem in medical decision making, particularly because many are declined for surgical valve replacement. For these patients, balloon aortic dilatation could be a palliative treatment. PATIENTS AND METHODS: we analyzed retrospectively our techniques and complications during hospitalization for percutaneous aortic balloon dilatation in 141 consecutive patients (45% women, mean age 83 +/- 10 y) from January 2002 to April 2005. The Parsonnet's score was 41 +/- 8 and the Euroscore was 10 +/- 2. We excluded the patients enrolled for percutaneous aortic valve implantation. This technique was performed under local anesthesia, from retrograde or antegrade approach. Rapid pacing stimulation (220/bpm) with a pacing-lead placed in the right ventricle was performed during balloon inflation. RESULTS: the aortic valve area was increased from 0.59 +/- 0.19 to 1.02 +/- 0.34 cm2 (p < 0.001) and the transvalvular mean gradient decreased from 49.3 +/- 21.2 to 22.2 +/- 11.8 mmHg (p < 0.001). Six patients (4%) died (3 during aortic valve dilatation) and 9 patients (6%) had non fatal complications: 2 transitory strokes, 8 non surgical vascular complications and 5 episodes of atrio-ventricular complete block (these complication were non exclusive). The patients were discharged at 5, 6 +/- 3 days. CONCLUSION: In the hands of skilled operators, aortic percutaneous balloon dilatation has become a simple technique, associated with a low risk of complications despite a very ill patient population. This technique remains a good option for a number of patients before the onset of percutaneous aortic valve implantation.

[Myocarditis versus myocardial infarction in diabetic patients: a new role for non invasive imaging]. / Myocardite ou infarctus chez le diabétique: un nouveau rôle pour l'imagerie non invasive.

A young diabetic patient was referred to our institution for clinical symptoms of myopericarditis. Cardiac MRI and MDCT of the coronary arteries were performed successively. They demonstrated an acute myocardial infarction related to a left circumflex coronary artery occlusion which was treated by stent angioplasty. This case suggests that cardiac MR and possibly cardiac MDCT could be proposed in patients with a suspected myopericarditis, especially if diabetes mellitus is associated.

[Immediate results and clinical follow-up of patients treated with drug eluting stents implantation in routine clinical practice]. / Résultats immédiats et suivi clinique des patients traités par implantation de stents actifs en pratique courante.

Multiple recent randomized studies have demonstrated the superiority of drug eluting stents (DES) compared to bare stents for reduction of restenosis rates after angioplasty. We sought to study if the results obtained in these studies with highly selected patients could be translated to patients treated in routine clinical practice. To this end, we retrospectively reviewed hospital charts of 134 consecutive patients treated in our center with 202 DES implantation between November 2002 and January 2004. Thirty nine % of patients had diabetes and 59% had multivessel disease. Coronary lesions were often complex (type B2: 24%, type C: 35%). Mean percent diameter stenosis was 68 +/- 13% with a reference artery diameter of 2.62 +/- 0.5 mm. One patient (0.75%) died in-hospital from cardiogenic shock. At a mean follow-up of 12 +/- 2.6 months, 7 patients (5.3%) died, including 2 extracardiac deaths. Recurrent chest pain occurred in 16 patients (12%), with only 3 (2.3%) in-stent restenosis. Major adverse cardiac event rate was 8.2%. This study confirms that in a non-selected population, the rate of subsequent revascularization after DES implantation is very low. It can be hoped that the indications of implantations will progressively spread with a lowered cost of these DES.

Increased inhibition of cytochrome P450 3A4 with the tablet formulation of posaconazole.

Being a substrate of the cytochrome P450 3A4 (CYP3A4) isoenzyme, sirolimus metabolism is decreased when posaconazole is administered concomitantly. However, because of the poor bioavailability of the oral suspension of posaconazole with which low plasma concentrations are obtained, CYP3A4 inhibition is weak and a 50-75% dose reduction of sirolimus is sufficient to avoid sirolimus overdosage. The new tablet formulation allows reaching posaconazole concentrations 3-4 fold higher than those obtained with the oral suspension. Based on a case of sirolimus overdosage following posaconazole tablets administration, we modelled the inhibition of sirolimus clearance by posaconazole, and then simulated several dosage regimens of sirolimus taken together with posaconazole tablets. We were able to describe well the interaction, and found a value of IC50 of posaconazole towards sirolimus clearance of 0.68 µg/mL. The simulations showed that even a 80% decrease of the daily dose of sirolimus is unsuitable in many cases with trough concentrations of posaconazole of 2 µg/mL. A decrease of 40% of the dose with spacing administrations of 3 days may be considered. The clinicians and pharmacologists must be warned that the use of posaconazole tablets may result in an inhibition of CYP3A4 of greater magnitude than with the oral suspension.

Balloon angioplasty for the treatment of coronary in-stent restenosis: immediate results and 6-month angiographic recurrent restenosis rate.

OBJECTIVES: The purpose of this prospective study was to evaluate the immediate results and the 6-month angiographic recurrent restenosis rate after balloon angioplasty for in-stent restenosis. BACKGROUND: Despite excellent immediate and mid-term results, 20% to 30% of patients with coronary stent implantation will present an angiographic restenosis and may require additional treatment. The optimal treatment for in-stent restenosis is still unclear. METHODS: Quantitative coronary angiography (QCA) analyses were performed before and after stent implantation, before and after balloon angioplasty for in-stent restenosis and on a 6-month systematic coronary angiogram to assess the recurrent angiographic restenosis rate. RESULTS: Balloon angioplasty was performed in 52 patients presenting in-stent restenosis. In-stent restenosis was either diffuse (> or =10 mm) inside the stent (71%) or focal (29%). Mean stent length was 16+/-7 mm. Balloon diameter of 2.98+/-0.37 mm and maximal inflation pressure of 10+/-3 atm were used for balloon angioplasty. Angiographic success rate was 100% without any complication. Acute gain was lower after balloon angioplasty for in-stent restenosis than after stent implantation: 1.19+/-0.60 mm vs. 1.75+/-0.68 mm (p=0.0002). At 6-month follow-up, 60% of patients were asymptomatic and no patient died. Eighteen patients (35%) had repeat target vessel revascularization. Angiographic restenosis rate was 54%. Recurrent restenosis rate was higher when in-stent restenosis was diffuse: 63% vs. 31% when focal, p=0.046. CONCLUSIONS: Although balloon angioplasty for in-stent restenosis can be safely and successfully performed, it leads to less immediate stenosis improvement than at time of stent implantation and carries a high recurrent angiographic restenosis rate at 6 months, in particular in diffuse in-stent restenosis lesions.

The French Randomized Optimal Stenting Trial: a prospective evaluation of provisional stenting guided by coronary velocity reserve and quantitative coronary angiography. F.R.O.S.T. Study Group.

OBJECTIVES: We sought to make a prospective comparison of systematic stenting with provisional stenting guided by Doppler measurements of coronary velocity reserve and quantitative coronary angiography. BACKGROUND: Despite the increasing use of stents during percutaneous transluminal coronary angioplasty, it is unclear whether systematic stenting is superior to a strategy of provisional stenting in which stents are placed only in patients with unsatisfactory results or as a bail-out procedure. METHODS: Two hundred fifty-one patients undergoing elective coronary angioplasty were randomly assigned either to provisional stenting (group 1, in which stenting was performed if postangioplasty coronary velocity reserve was <2.2 and/or residual stenosis > or =35% or as bail-out) or to systematic stenting (group 2). The primary end point was the six-month angiographic minimal lumen diameter (MLD). Major adverse cardiac events were secondary end points (death, acute myocardial infarction and target lesion revascularization). RESULTS: Stenting was performed in 48.4% of patients in group 1 and 100% of patients in group 2 (p<0.01). Six months after angioplasty, the MLD did not differ between groups (1.90+/-0.79 mm vs. 1.99+/-0.70 mm, p = 0.39), as was the rate of binary restenosis (27.1% vs. 21.4%, p = 0.37). Among patients with restenosis, 13/32 (40.6%) in group 1 but 100% (25/25) in group 2 had in-stent restenosis (p<0.01). Target lesion revascularization (15.1% vs. 14.4% in groups 1 and 2 respectively, p = 0.89) and major adverse cardiac events (15.1% vs. 16.0%, p = 0.85) were not significantly different. CONCLUSIONS: Systematic stenting does not provide superior angiographic results at six months as compared with provisional stenting.

[Treatment of acute myocardial infarction due to embolism by a thromboaspiration catheter]. / Traitement d'un infarctus du myocarde aigu d'origine embolique par catheter de thrombo-aspiration.

Although rare, coronary embolism poses a therapeutic problem. Thromboaspiration is an elegant alternative to implantation of a stent. The place of stenting in acute myocardial infarction depends on the results of randomised trials. The authors report the case of a 69 year old woman who presented with an apico-lateral infarction probably due to a coronary embolism after postoperative thrombosis of a mechanical mitral valve prosthesis. The authors performed a percutaneous revascularisation by thromboaspiration with a good result.

[Macromolecular complex of cardiac troponin I: differences of reactivity with DPC and Dade-Behring assays]. / Complexe macromoléculaire de troponine I cardiaque: différence de réactivité des trousses de dosage DPC et Dade-Behring.

We have recently identified a macromolecular 440-kDa cardiac troponin I (cTnI) complex after successful percutaneous transluminal coronary angioplasty (PTCA) (Clin Chem 2003; 49: 505-7). The aim of the work was to confirm the existence of such a complex by using another cTnI assay (Dimension RXL, Dade-Behring). We have first studied the correlation between the two assays by using heparinized samples [cTnI(Immulite) = 2.00 cTnI(Dimension) - 0.01 (n = 176; r = 0,987)]. Then, cTnI taken 120 minutes after PTCA for two patients was measured with the two assays after fractionation by FPLC. The obtained results confirmed the existence of the 440-kDa cTnI complex and showed that the reactivity between the assays (DPC/Dade-Behring ratio) depended on the nature of the complex: the ratio increased from 0.7 (440-kDa cTnI complex) to 3 (80-kDa cTnI complex) therefore suggesting caution in the comparison between the different cTnI assays in the context of reperfusion therapy.

Ischaemic preconditioning is not mediated by oxygen derived free radicals in rats.

OBJECTIVE: Although several studies have shown that ischaemic preconditioning greatly limits myocardial infarct size in the rat, the mechanisms of the beneficial effect of preconditioning in this species are not known. Experiments in dogs and rabbits have suggested that this effect could be related in part to the production of oxygen derived free radicals, as free radical scavengers partially prevent the limitation of infarct size induced by preconditioning. This study was designed to assess the contribution of oxygen derived free radicals in the infarct size limiting effects of preconditioning in rats, using the cell diffusible free radical scavenger N-2-mercaptopropionyl glycine (MPG). METHODS: Open chest rats underwent 20 minutes of coronary occlusion followed by one hour of reperfusion. Preconditioning was elicited by three cycles of five minutes ischaemia and five minutes reperfusion. MPG (20 mg.kg-1) was infused for 60 minutes starting 30 minutes before preconditioning. Control hearts (with or without MPG) were treated identically but without ischaemic preconditioning. Area at risk and infarct size were determined by India ink injection and triphenyltetrazolium chloride stain, with computerised analysis of enlarged sections after colour video acquisition. RESULTS: During preconditioning, reperfusion after the first episode of ischaemia was associated with a high occurrence of severe ventricular arrhythmias, and this was reduced by MPG. Preconditioning, however, reduced arrhythmias and mortality during subsequent episodes of ischaemia and reperfusion. In the absence of MPG, preconditioning greatly limited infarct size (from (mean (SEM)) 59.8(3.9)% to 1.2(0.6)% of the area at risk; p < 0.01). MPG alone did not affect infarct size (60.5(6.1)%), and did not modify the infarct size limiting effect of preconditioning (infarct size: preconditioning 1.2(0.6)%; preconditioning + MPG 2.9(1.2)%. CONCLUSIONS: Preconditioning greatly reduced infarct size, and this was not affected by MPG. These experiments suggest that production of oxygen derived free radicals does not contribute to preconditioning in the rat heart.

Comparison of quantitative angiographically derived and measured translesion pressure and flow velocity in coronary artery disease.

Although quantitative coronary angiography (QCA) has been used to determine lesion severity, angiographically derived parameters of translesional physiology have not been compared with those directly measured in the same patients. Thus, the aim of this study was to correlate QCA-derived translesional pressure and flow data with directly measured data in patients. QCA (DCI-ACA program), translesional pressure gradient (2.2Fr fluid-filled tracking catheter), and intracoronary Doppler flow velocity (0.018-inch FloWire) measurements were simultaneously performed in 28 arteries (25 patients). Mean diameter stenosis was 51 +/- 2.3% (range 29 to 73). No patient had left ventricular hypertrophy or valvular heart disease. The arteries studied were left anterior descending in 14, circumflex in 8, and right coronary in 6 patients. Stenotic flow reserve and baseline and maximal gradients were calculated by the DCI program. Coronary flow reserve and baseline and maximal hyperemic gradients were also directly measured distal to the stenosis after administration of intracoronary adenosine (12 to 18 micrograms). QCA-derived pressure gradients did not correlate with the measured gradients at baseline (r2 = 0.005; p = 0.73) or at maximal hyperemia (r2 = 0.1; p = 0.13). No correlation was found between the QCA-predicted flow reserve and the coronary flow reserve measured distal to the stenosis (r2 = 0.02; p = 0.46). Furthermore, stenotic flow reserve and measured gradient were not significantly correlated (r2 = 0.1; p = 0.16). In this range of stenoses of intermediate severity, there was no correlation between the measured pressure gradient or coronary flow reserve and lesion diameter or cross-sectional area by QCA.(ABSTRACT TRUNCATED AT 400 WORDS)