Jean-Pierre Kantelip

Mesenchymal Progenitor Cells Differentiate into an Endothelial Phenotype, Enhance Vascular Density, and Improve Heart Function in a Rat Cellular Cardiomyoplasty Model

Background—Cellular cardiomyoplasty is a promising approach to improve postinfarcted cardiac function. The differentiation pathways of engrafted mesenchymal progenitor cells (MPCs) and their effects on the left ventricular function in a rat myocardial infarct heart model were analyzed. Methods and Results—A ligation model of left coronary artery of Lewis rats was used. MPCs were isolated by bone marrow cell adherence. Seven days after ligation, MPCs labeled with 4′,6-diamidino-2′-phenylindole were injected into the infarcted myocardium (n=8). Culture medium was injected in the infarcted myocardium of control animals (n=8). Thirty days after implantation, immunofluorescence studies revealed some engrafted cells expressing a smooth muscle phenotype (&agr; SM actin+), as similarly observed in culture. Other engrafted cells lost their smooth muscle phenotype and acquired an endothelial phenotype (CD31+). Furthermore, vessel density was augmented in the MPC group in comparison with the control group. After 30 days, echocardiography showed an improvement on left ventricular performance in the MPCs compared with the control group. Conclusions—In vivo administration of syngenic MPCs into a rat model of myocardial infarcted heart was safety demonstrated. Some engrafted cells appeared to differentiate into endothelial cells and loss their smooth muscle phenotype. MPC engraftment might to contribute to the improvement on the cardiac function in such a setting.

Interindividual Variability of Methadone Response Impact of Genetic Polymorphism

Methadone, an opioid analgesic, is used clinically in pain therapy as well as for substitution therapy in opioid addiction. It has a large interindividual variability in response and a narrow therapeutic index. Genetic polymorphisms in genes coding for methadone-metabolizing enzymes, transporter proteins (p-glycoprotein; P-gp), and μ-opioid receptors may explain part of the observed interindividual variation in the pharmacokinetics and pharmacodynamics of methadone. Cytochrome P450 (CYP) 3A4 and 2B6 have been identified as the main CYP isoforms involved in methadone metabolism. Methadone is a P-gp substrate, and, although there are inconsistent reports, ABCB1 genetic polymorphisms also contribute slightly to the interindividual variability of methadone kinetics and influence dose requirements. Genetic polymorphism is the cause of high interindividual variability of methadone blood concentrations for a given dose; for example, in order to obtain methadone plasma concentrations of 250 ng/mL, doses of racemic methadone as low as 55 mg/day or as high as 921 mg/day can be required in a 70-kg patient without any co-medication.The clinician must be aware of the pharmacokinetic properties and pharmacological interactions of methadone in order to personalize methadone administration. In the future, pharmacogenetics, at a limited level, can also be expected to facilitate individualized methadone therapy.

Findings on ambulatory electrocardiographic monitoring in subjects older than 80 years.

Twenty-four-hour electrocardiograms were recorded in 50 subjects (44 women, 6 men) older than 80 years without cardiovascular disease and with normal standard electrocardiographic responses. During waking and sleeping periods, the mean sinus rates were, respectively, 78 +/- 3 and 64 +/- 1 beats/min; heart rate ranged from 43 to 180 beats/min over 24 hours. Supraventricular tachycardia (SVT) was present in 28% of the subjects. Nocturnal sinus arrhythmia was only noted in 12% of the patients; it was accompanied by sinus pauses of 1.8 to 2 seconds, and 1 woman had a transient pattern compatible with atrioventricular dissociation. Supraventricular ectopic contractions (SVECs) were present in all cases. The frequency was less than 1 per hour in 25% and more than 20 per hour in 65%. Serious supraventricular tachyarrhythmias included an episode of ectopic atrial tachycardia (1 subject), a short run of atrial fibrillation (1 subject) and of flutter (1 subject), and several episodes of supraventricular tachycardia (2 subjects), all accompanied by more than 50 SVECs per hour. The number of ventricular premature contractions (VPCs) exceeded 10 per hour in 32% and were multifocal in 18%. There were couplets in 8% and a run of 6 VPCs in 1 subject (2%). In conclusion, sinus pause and atrioventricular block are unusual in people older than 80 years without apparent heart disease. In contrast, frequent SVECs and VPCs are more common. This study stresses the difficulty of evaluating the normality of the electrocardiogram with portable monitoring in the older population.

Role of β1- and β2-adrenoceptor Subtypes in Preconditioning Against Myocardial Dysfunction after Ischemia and Reperfusion

Abstract:Using an isolated nonworking rat heart model, this study investigated the role of β-adrenergic preconditioning (β-PC) to attenuate myocardial dysfunction after an ischemia/reperfusion injury. After a 20-min stabilization period, the noradrenaline depleted hearts were perfused for 5 min with

Pharmacokinetic Modelling and Development of Bayesian Estimators for Therapeutic Drug Monitoring of Mycophenolate Mofetil in Reduced-Intensity Haematopoietic Stem Cell Transplantation

BackgroundMycophenolate mofetil, a prodrug of mycophenolic acid (MPA), is used during nonmyeloablative and reduced-intensity conditioning haematopoetic stem cell transplantation (HCT) to improve engraftment and reduce graft-versus-host disease (GVHD). However, information about MPA pharmacokinetics is sparse in this context and its use is still empirical.ObjectivesTo perform a pilot pharmacokinetic study and to develop maximum a posteriori Bayesian estimators (MAP-BEs) for the estimation of MPA exposure in HCT.Patients and MethodsFourteen patients administered oral mycophenolate mofetil 15 g/kg three times daily were included. Two consecutive 8-hour pharmacokinetic profiles were performed on the same day, 3 days before and 4 days after the HCT. One 8-hour pharmacokinetic profile was performed on day 27 after transplantation. For these 8-hour pharmacokinetic profiles, blood samples were collected predose and 20, 40, 60, 90 minutes and 2, 4, 6 and 8 hours post-dose.Using the iterative two-stage (ITS) method, two different one-compartment open pharmacokinetic models with first-order elimination were developed to describe the data: one with two gamma laws and one with three gamma laws to describe the absorption phase. For each pharmacokinetic profile, the Akaike information criterion (AIC) was calculated to evaluate model fitting. On the basis of the population pharmacokinetic parameters, MAP-BEs were developed for the estimation of MPA pharmacokinetics and area under the plasma concentration-time curve (AUC) from 0 to 8 hours at the different studied periods using a limited-sampling strategy. These MAP-BEs were then validated using a data-splitting method. Results: The ITS approach allowed the development of MAP-BEs based either on ‘double-gamma’ or ‘triplegamma’ models, the combination of which allowed correct estimation of MPA pharmacokinetics and AUC on the basis of a 20 minute-90 minute-240 minute sampling schedule. The mean bias of the Bayesian versus reference (trapezoidal) AUCs was s<5% with <16% of the patients with absolute bias on AUC >20%. AIC was systematically calculated for the choice of the most appropriate model fitting the data.ConclusionPharmacokinetic models and MAP-BEs for mycophenolate mofetil when administered to HCT patients have been developed. In the studied population, they allowed the estimation of MPA exposure based on three blood samples, which could be helpful in conducting clinical trials for the optimization of MPA in reduced-intensity HCT. However, prior studies will be needed to validate them in larger populations.

Effects of bepridil, a new antianginal agent, on ambulatory electrocardiography in human volunteers.

Summary We studied the effects of bepridil, a new antianginal agent, on the ambulatory electrocardiogram in seven human volunteers. The drug was administered in three sequential periods of 12 days separated by 24 days without treatment. Heart rate was not significantly altered at 200 mg/day, but fell from day 3 at 300 mg/day and from day 1 at 600 mg/day. Average fall in heart rate was approximately 8% at 300 mg/day and 11% at 600 mg/day (day 7). At 200 mg/day the peak plasma level was reached after 11 days of treatment (0.28 ± 0.4 μg/ml). At 300 mg/day, a plateau was reached on day 7 (0.44 ± 0.04 μg/ml) and at 600 mg/day from day 8 (0.97 ± 14 μg/ml). We found a highly significant relationship between blood concentration of bepridil and mean RR interval lengths over 24 h. The QTc interval was lengthened at all doses, but there was no significant correlation between plasma level and increase in QTc interval length.

A neutropenia suggesting an interaction between valacyclovir and mycophenolate mofetil

Mycophenolate mofetil (MMF) is a drug which decreases the frequency of renal transplantation rejection. However, cytomegalovirus infections are a common feature of this treatment leading the physicians to prescribe antiviral prophylactic drugs like valacyclovir. During this association, neutropenia occur and the cause of this adverse effect is difficult to define. This report presents a case of neutropenia in a woman treated with MMF and valacyclovir. As the duration of the valacyclovir treatment exactly corresponds to the neutropenia duration, and the mycophenolate trough levels increased with the neutrophil count, the responsibility of this neutropenia was ascribed to valacyclovir. However, an examination of the literature for cases of neutropenia led to the suspicion of an interaction between MMF and valacyclovir. Mycophenolate may increase intracellular concentrations of valacyclovir up to haematotoxic levels. This mechanism may explain the interaction and further research is needed to confirm this interaction.

INFLUENCE OF CHLORALOSE AND PENTOBARBITONE SODIUM ON ATRIOVENTRICULAR CONDUCTION IN DOGS

1 Atrial pacing at progressively increasing frequencies was performed on unanaesthetized dogs through electrodes placed aseptically in the wall of the right atrium and exteriorized in the neck region. 2 Heart rate and two atrioventricular conduction (AVC) parameters, namely the Wenckebach Point (one or two systole block at the end of expiration)‐and the maximum atrioventricular conduction frequency (the frequency of pacing for which ventricles do not follow any auricular stimulation) were measured by electrocardiography. 3 Chloralose (0.08 g/kg i.v.) did not affect either heart rate or AVC but significantly reduced the effect of atropine (0.1 mg/kg i.v.) on all three parameters measured. The effect of isoprenaline (0.25 μg kg−1 min−1) remained unchanged. 4 Pentobarbitone Na (25 mg/kg i.v.) increased heart rate and usually caused the Wenckebach Point to disappear. It reduced the effects of atropine but did not modify those of isoprenaline. 5 In view of these results we suggest that pentobarbitone Na be avoided as an anaesthetic agent in AVC studies. It is possible to dispense with an anaesthetic agent if the technique described here is used.

Pharmacokinetics of mycophenolic acid administered 3 times daily after hematopoietic stem cell transplantation with reduced-intensity regimen.

Mycophenolate mofetil (MMF) is an immunosuppressive drug used as a prophylactic agent to prevent acute graft-versus-host disease (aGVHD) after hematopoietic stem cell transplantation (HSCT). After reduced-intensity conditioning (RIC) regimen, administration of MMF orally 3 times a day (tid) seems to be more beneficial than twice a day (bid). However, information regarding the pharmacokinetic (PK) parameters of mycophenolic acid (MPA), the active metabolite of MMF, administered in this regimen are very limited. We performed a prospective study in 15 patients for whom 3 sets of sampling were performed: at the beginning of the treatment, after 1 week, and after 1 month. Two consecutive 8-hour sets of sampling were performed at day 0 (D0) and D7. Plasma concentrations of MPA were quantified and areas under the curve for 8hours (AUC(0-8)), and maximal and through concentrations were calculated. The results show that AUC(0-8) increases between the beginning of treatment and the end of the first week, but remains stable thereafter. Moreover, a trend to lower AUC(0-8) was observed for the patients who experienced GVHD > or =2 compared to those patients who did not. The other PK parameters are not associated with pharmacodynamic events. A limited sampling strategy with Bayesian estimators is currently under investigation to confirm these data and the role of D7 AUC(0-8) as a potential target of therapeutic drug monitoring (TDM).

Intraperitoneal clearance as a potential biomarker of cisplatin after intraperitoneal perioperative chemotherapy: a population pharmacokinetic study

Background:Intraperitoneal (IP) perioperative chemotherapy with cisplatin is an interesting option in ovarian cancer treatment. A combination of cisplatin with IP epinephrine (already shown to improve IP and decrease systemic platinum (Pt) exposure) was evaluated using a population pharmacokinetic analysis.Methods:Data from 55 patients treated with cisplatin-based IP perioperative chemotherapy with (n=26) or without (n=29) epinephrine were analysed using NONMEM.Results:Epinephrine halves clearance between peritoneum and serum (IPCL) and increases the Pt central volume of distribution, IP exposure and penetration in tissue. IPCL has a better predictive value than any other parameter with respect to renal toxicity.Conclusion:This confirms that IPCL could be useful in assessing renal toxicity. As IPCL is also linked to tissue penetration and IP exposure, it may be proposed as biomarker. In addition to a Bayesian estimation, we propose a single-sample calculation-way to assess it. Prospective studies are needed to validate IPCL as a biomarker in this context.