Eliane M. Billaud

Noninvasive Measurement of Medium-Sized Artery Intima-Media Thickness in Humans: In vitro Validation

Recent research in ultrasound technology has led to the development of a high-resolution echo-tracking device. The present study was performed to evaluate the accuracy in the measurement of human radial artery intima-media thickness with this new device. We determined the correlation between histological and ultrasonic measurements of intima-media thickness in 15 radial artery segments obtained from the distal end of the wrist-elbow harvest for coronary bypass grafting in patients with coronary heart disease. For arterial intima-media thickness, a positive correlation was observed between ultrasonic and histological measurements (r = 0.618; p < 0.014), and the difference between ultrasound and histology measurements was 41 +/- 66 microns, with the higher measurements found by the ultrasonic device. In a subgroup of 11 patients, we determined the correlation between in vivo ultrasonic measurements of radial artery intima-media thickness at the preoperative stage and in vitro ultrasonic measurements of intima-media thickness obtained postoperatively in the same arterial segments. Internal diameter was larger in vivo than in vitro, and intima-media thickness was smaller in vivo than in vitro. The cross-sectional area of the arterial wall was calculated from internal diameter and intima-media thickness. In vitro wall cross-sectional area was correlated with in vivo wall cross-sectional area (r = 0.929; p < 0.0001). Repeatability of in vivo intima-media thickness measurements was investigated in 10 subjects through the calculation of the repeatability coefficient as defined by the British Standards Institution.(ABSTRACT TRUNCATED AT 250 WORDS)

Voriconazole pharmacokinetic variability in cystic fibrosis lung transplant patients.

Background. Aspergillosis is a high‐risk complication in cystic fibrosis (CF) lung transplant patients. Azole antifungal drugs inhibit CYP3A4, resulting in significant metabolic drug–drug interactions. Voriconazole (VRZ) was marketed without therapeutic drug monitoring (TDM) recommendations, consistent with favorable pharmacokinetics, but regular determinations of plasma VRZ concentration were introduced in our center to manage interactions with calcineurin inhibitors and to document the achievement of therapeutic levels.

A universal formula based on cystatin C to perform individual dosing of carboplatin in normal weight, underweight, and obese patients.

Purpose: It has recently been shown that it is possible to improve the prediction of carboplatin clearance by adding plasma cystatin C level (cysC), an endogenous marker of glomerular filtration rate, to the other patient characteristics routinely used for carboplatin individual dosing, namely serum creatinine (Scr), actual body weight (ABW), age, and sex. This multicenter pharmacokinetic study was done to evaluate prospectively the benefit of using cysC for carboplatin individual dosing. Experimental Design: The 357 patients included in the study were receiving carboplatin as part of established protocols. A population pharmacokinetic analysis was done using NONMEM program. Seven covariates studied were as follows: Scr, cysC, age, sex, ABW, ideal body weight, and lean body mass. Results: The best covariate equation was as follows: carboplatin clearance (mL/min) = 117.8. (Scr/75)−0.450. (cysC/1,00)−0.385. (ABW/65)+0.504. (age/56)−0.366. 0.847sex, with Scr in μmol/L, cysC in mg/L, ABW in kilograms, age in years, and sex = 0 for male. Using an alternative weight descriptor (ideal body weight or lean body mass) did not improve the prediction. This final covariate model was validated by bootstrap analysis. The bias (mean percentage error) and imprecision (mean absolute percentage error) were +1% and 15%, respectively, on the total population, and were of a similar magnitude in each of the three subgroups of patients defined according to their body mass index. Conclusion: For the first time, a unique formula is proposed for carboplatin individual dosing to patients, which is shown to be equally valid for underweight, normal weight, and obese patients.

The 2015 International Society for Heart and Lung Transplantation Guidelines for the management of fungal infections in mechanical circulatory support and cardiothoracic organ transplant recipients: Executive summary.

Shahid Husain, MD, MS, Amparo Sole, MD, PhD, Barbara D. Alexander, MD, MHS, Saima Aslam, MD, MS, Robin Avery, MD, Christian Benden, MD, Eliane M. Billaud, PharmD, PhD, Daniel Chambers, MBBS, MD, Lara Danziger-Isakov, MD, Savitri Fedson, MD, Kate Gould, MD, Aric Gregson, MD, Paolo Grossi, MD, PhD, Denis Hadjiliadis, MD, Peter Hopkins, MD, Me-Linh Luong, MD, Debbie J.E. Marriott, MD, Victor Monforte, MD, Patricia Munoz, MD, PhD, Alessandro C. Pasqualotto, MD, PhD, Antonio Roman, MD, Fernanda P. Silveira, MD, Jeffrey Teuteberg, MD, MS, Stephen Weigt, MD, Aimee K. Zaas, MD, MHS, Andreas Zuckerman, MD, and Orla Morrissey, MD, PhD

Pharmacological considerations for azole antifungal drug management in cystic fibrosis lung transplant patients

This paper aims to present our experience in the pharmacological approach of the management of azole antifungal drugs in cystic fibrosis lung transplant patients. Cystic fibrosis (CF) lung transplantation is associated with multi-factorial care management, because of immunosuppressive requirements, risk of infections, frequency of gastro-oesophageal reflux disease, hepatic alterations and CF pharmacokinetics (PK) specificities that result in important PK variability. CF is associated with frequent colonization of the airways by filamentous fungi, especially by Aspergillus species. Today the antifungal therapeutic arsenal offers several possibilities for long-term oral therapy including azole drugs (itraconazole, voriconazole and posaconazole). Therefore, nephrotoxic amphotericin B should be avoided. The liver is important in the pharmacological profile of azole drugs, due to metabolic elimination, hepatotoxicity and PK drug-drug interaction (DDI) involving CYP3A4 metabolic inhibition. Targets for such DDI are numerous, but immunosuppressive drugs are of major concern, justifying combined therapeutic drug monitoring (TDM) of both azoles (inhibitors) and immunosuppressants (targets) on an individualized patient basis to adjust the coprescription quantitatively. The risk of long under-dosed periods, frequently addressed in this population, could justify, on a PK basis, the need for combination with an exclusive parenteral antifungal while waiting for azole relevant drug level. High PK variability, the risk of low exposure, therapeutic issues and DDI management in this complex underlying disease justify close monitoring with systematic combined TDM of azole and immunosuppressants, in case of coprescription.

Management of Metabolic Cytochrome P450 3A4 Drug-Drug Interaction between Everolimus and Azole Antifungals in a Renal Transplant Patient

We report a case of a 54-year-old male renal transplant patient who received antifungal azole treatment in combination with the recently introduced immunosuppressant agent everolimus to prevent post-transplantation aspergillosis reactivation. Voriconazole was withdrawn after 1 month because of elevated concentrations (5 mg/L trough plasma determination) and hepatotoxicity, and substituted by several months of treatment with posaconazole (observed concentration range 1–2 mg/L). We observed pharmacokinetic drug interactions between both voriconazole and posaconazole, and everolimus cytochrome P450 3A4 metabolism, resulting in 7.5- and 3.8-fold increase, respectively, in everolimus blood trough concentrations. Combined therapeutic drug monitoring (TDM) of both everolimus and azole inhibitors allowed for safe and convenient modification of everolimus dosage, which was tapered to maintain a target range of 5–15 ng/mL during and after antifungal treatments. While significant in their effects, these drug interactions were able to be managed safely through a careful approach to management and use of individual TDM.

Interaction Between Roxithromycin and Cyclosporin in Heart Transplant Patients

SummaryCyclosporin is an immunosuppressive agent commonly used in transplant patients. It is actively metabolised by the cytochrome P450 system and interactions with drugs metabolised by the same system are predictable. This is particularly relevant since cyclosporin has a low therapeutic index and its renal toxicity is concentration-related.Roxithromycin, a new, well-tolerated macrolide with a weak interactive profile, uses the same isoenzyme of the P450 system as cyclosporin. To evaluate its interaction potential in clinical practice, 8 heart transplant recipients treated with cyclosporin for at least 1 month received roxithromycin for 11 days (150mg twice daily). Bi-weekly controls of plasma cyclosporin concentrations and creatinine levels were carried out before, during and after roxithromycin treatment. A slight nonsignificant rise in cyclosporin concentrations was observed, but creatinine levels remained stable during roxithromycin treatment. Values of cyclosporin concentrations diminished after withdrawal of roxithromycin. Cyclosporin dosage adjustment was not necessary. There was a minor pharmacokinetic interaction, which can be considered safe for the usual therapeutic dosage of roxithromycin used.

Safe Management of Tacrolimus Together With Posaconazole in Lung Transplant Patients With Cystic Fibrosis

Oral posaconazole (PSZ), an azole antifungal drug, was recently introduced for the treatment of invasive fungal infections. The prescription of PSZ together with the immunosuppressant tacrolimus (TRL) was evaluated in 14 lung transplant patients with cystic fibrosis. PSZ inhibited CYP3A4 TRL metabolism, resulting in a decrease of TRL dose by a factor of 3, with tapering to a mean of 2 mg/d. Previous studies with itraconazole and voriconazole showed that TRL dose could be decreased by factors of 5 and 4, respectively. Joint therapeutic drug monitoring of TRL and PSZ was carried out to investigate the high risk of interindividual variability associated with this coprescription in such patients.

Effects of clonidine on plasma catecholamines and neuropeptide Y in hypertensive patients at rest and during stress

Neuropeptide Y (NPY), a potent vasoconstrictor agent reported to be released, in addition to norepinephrine (NE), by sympathetic nerve endings during stress, may contribute to the pressor response to various stimuli. The objectives of this study were to determine (a) whether plasma NPY concentrations are altered during different types of stress (cold pressor test, mental stress, and active orthostatism) and (b) whether clonidine, via its central sympatholytic effect, affects the stress-induced blood pressure, NPY, and/or catecholamine changes. Eighteen untreated patients with mild essential or borderline hypertension participated in an acute randomized, double-blind, parallel study. The blood pressure and heart rate were recorded during three control periods, each followed by either a cold pressor test (CPT), a mental stress test (MS: mental arithmetic), or active orthostatism (AO), performed in a random order. Venous blood samples for catecholamines and NPY determination were taken at the end of each control and test period. This entire procedure was repeated after oral clonidine (150 (μg) or placebo. Before treatment, a CPT, MS, or AO increased the blood pressure to the same extent. The stress-induced increase in plasma NE was greater during AO (+ 99 ± 23%) than during CPT (+ 35 ± 8%) and MS (+ 55 ± 12%). The stress-induced increase in plasma epinephrine was only significant during MS (+ 142 ± 69%). A small but significant increase in NPY (p < 0.05) was observed during AO only (+ 10 ± 7%). Compared to placebo, clonidine significantly decreased the basal blood pressure and the pressor response to CPT, but did not change the pressor response to MS and AO. Clonidine decreased the baseline plasma NE but did not change the plasma NPY. Clonidines differential effect of clonidine on basal plasma NE and NPY levels was also observed during stress: clonidine attenuated the AO-induced increase in plasma NE, but did not change the AO-induced increase in plasma NPY. To the extent that plasma NE and NPY concentrations reflect NE and NPY release, respectively, these results suggest that clonidine may affect NE and NPY release by sympathetic nerve endings differentially, both at rest and during stress.

Drug adherence in hypertension: from methodological issues to cardiovascular outcomes

: Adherence to treatment is now well recognized as a crucial key in the effectiveness of antihypertensive drugs; however, it is often overlooked in the management of hypertension because methodology to assess it is partly unreliable and limits its use in clinical practice. The available evidence suggests that nonadherence is highly prevalent in a chronic asymptomatic condition such as hypertension. It may undermine benefits expected from antihypertensive agents and therefore, may negatively impact cardiovascular, cerebrovascular and renal outcomes. In this review, we discuss the methodological issues related to the measurement of drug adherence in a research setting and clinical practice, the prevalence and the impact of drug nonadherence on blood pressure control and thus in apparent resistant hypertension, and on cardiovascular, cerebrovascular and renal outcomes.