Dynamical modeling of pro- and anti-inflammatory cytokines in the early stage of septic shock.

A dynamical model of the pathophysiological behaviors of IL18 and IL10 cytokines with their receptors is tested against data for the case of early sepsis. The proposed approach considers the surroundings (organs and bone marrow) and the different subsystems (cells and cyctokines). The interactions between blood cells, cytokines and the surroundings are described via mass balances. Cytokines are adsorbed onto associated receptors at the cell surface. The adsorption is described by the Langmuir model and gives rise to the production of more cytokines and associated receptors inside the cell. The quantities of pro and anti-inflammatory cytokines present in the body are combined to give global information via an inflammation level function which describes the patient's state. Data for parameter estimation comes from the Sepsis 48 H database. Comparisons between patient data and simulations are presented and are in good agreement. For the IL18/IL10 cytokine pair, 5 key parameters have been found. They are linked to pro-inflammatory IL18 cytokine and show that the early sepsis is driven by components of inflammatory character.

Model of mucociliary clearance in cystic fibrosis lungs.

Mucus clearance is a primary innate defense mechanism in the human airways. Cystic fibrosis (CF) is a genetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CF is characterized by dehydration of airway surface liquid and impaired mucociliary clearance. As a result, microorganisms are not efficiently removed from the airways, and patients experience chronic pulmonary infections and inflammation. We propose a new physiologically based mathematical model of muco-ciliary transport consisting of the two major components of the mucociliary clearance system: (i) periciliary liquid layer (PCL) and (ii) mucus layer. We study mucus clearance under normal conditions and in CF patients. Restoring impaired clearance of airway secretions in one of the major goals of therapy in patients with CF. We consider the action of the aerosolized and inhaled medication dornase alfa, which reduces the viscosity of cystic fibrosis mucus, by selectively cleaving the long DNA strands it contains. The results of the model simulations stress the potential relevance of the location of the drug deposition in the central or peripheral airways. Mucus clearance was increased in case the drug was primarily deposited peripherally, i.e. in the small airways.

Pharmacokinetic/pharmacodynamic model of a methionine starvation based anti-cancer drug.

A new therapeutic approach against cancer is developed by the firm Erytech. This approach is based on starved cancer cells of an amino acid essential to their growth (the L-methionine). The depletion of plasma methionine level can be induced by an enzyme, the methionine-γ-lyase. The new therapeutic formulation is a suspension of erythrocytes encapsulating the activated enzyme. Our work reproduces a preclinical trial of a new anti-cancer drug with a mathematical model and numerical simulations in order to replace animal experiments and to have a deeper insight on the underlying processes. With a combination of a pharmacokinetic/pharmacodynamic model for the enzyme, substrate, and co-factor with a hybrid model for tumor, we develop a "global model" that can be calibrated to simulate different human cancer cell lines. The hybrid model includes a system of ordinary differential equations for the intracellular concentrations, partial differential equations for the concentrations of nutrients and drugs in the extracellular matrix, and individual based model for cancer cells. This model describes cell motion, division, differentiation, and death determined by the intracellular concentrations. The models are developed on the basis of experiments in mice carried out by Erytech. Parameters of the pharmacokinetics model were determined by fitting a part of experimental data on the concentration of methionine in blood. Remaining experimental protocols effectuated by Erytech were used to validate the model. The validated PK model allowed the investigation of pharmacodynamics of cell populations. Numerical simulations with the global model show cell synchronization and proliferation arrest due to treatment similar to the available experiments. Thus, computer modeling confirms a possible effect of treatment based on the decrease of methionine concentration. The main goal of the study is the development of an integrated pharmacokinetic/pharmacodynamic model for encapsulated methioninase and of a mathematical model of tumor growth/regression in order to determine the kinetics of L-methionine depletion after co-administration of Erymet product and Pyridoxine.

Twice- or Once-Daily Dosing of Direct Oral Anticoagulants, a systematic review and meta-analysis.

AIM: The direct oral anticoagulants (DOAC) have similar half-lives, but the dosing regimen varies between once daily (QD) or twice daily (BID). For some prescribers, the QD regimen improves compliance. Others prefer BID regimens to promote better stability of plasma concentrations, particularly in the event of missed doses. Limited level of evidence provides guidance about the best treatment strategy. The purpose of this study was to compare the treatment effect of QD vs. BID administration of DOACs in major orthopedic surgery (MOS), non-valvular atrial fibrillation (NVAF), venous thromboembolism (VTE), and acute coronary syndrome (ACS). METHODS: We conducted a systematic review up to April 2020. We included phase II clinical trials comparing DOAC QD vs BID with same daily dose. We extracted data for the occurrence of major thrombosis (proximal deep vein thrombosis, pulmonary embolism, myocardial infarction, ischemic stroke) and major hemorrhage (ISTH criteria and recommendations of the European Medicines Agency for surgical patients). Relative risks (RR) were combined using a fixed and random effects weighted meta-analysis. RESULTS: Twelve randomized, controlled, phase II trials were included (10,716 patients), representing 24 dosing regimen comparisons of apixaban, darexaban, edoxaban, rivaroxaban, letaxaban, and dabigatran. There was no difference for major thrombotic event (RRBID/QD = 1.06, 95%IC 0.86-1.30) nor for major bleeding (RRBID/QD = 1.02, 95%IC 0.84-1.23) between the BID vs QD regimens, without heterogeneity (I2 = 0%). CONCLUSION: Our study does not support a global difference in term of efficacy and safety of the BID and QD regimens of DOAC in MOS, NVAF, VTE and ACS.

Determination of the optimal dose of ephedrine in the treatment of arterial hypotension due to general anesthesia in neonates and infants below 6 months old: the ephedrine study protocol for a randomized, open-label, controlled, dose escalation trial.

BACKGROUND: Arterial hypotension induced by general anesthesia is commonly identified as a risk factor of morbidity, especially neurological, after cardiac or noncardiac surgery in adults and children. Intraoperative hypotension is observed with sevoflurane anesthesia in children, in particular in neonates, infants younger than 6 months, and preterm babies. Ephedrine is commonly used to treat intraoperative hypotension. It is an attractive therapeutic, due to its dual action on receptors alpha and beta and its possible peripheral intravenous infusion. There are few data in the literature on the use of ephedrine in the context of pediatric anesthesia. The actual recommended dose of ephedrine (0.1 to 0.2 mg/Kg) frequently leads to a therapeutic failure in neonates and infants up to 6 months of age. The use of higher doses would probably lead to a better correction of hypotension in this population. The objective of our project is to determine the optimal dose of ephedrine for the treatment of hypotension after induction of general anesthesia with sevoflurane, in neonates and infants up to 6 months of age. METHODS: The ephedrine study is a prospective, randomized, open-label, controlled, dose-escalation trial. The dose escalation consists of 6 successive cohorts of 20 subjects. The doses studied are 0.6, 0.8, 1, 1.2, and 1.4 mg/kg. The dose chosen as the reference is 0.1 mg/kg, the actual recommended dose. Neonates and infants younger than 6 months, males and females, including preterm babies who undergo a surgery with general anesthesia inducted with sevoflurane were eligible. Parents of the subject were informed. Then, the subjects were randomized if presenting a decrease in mean blood pressure superior to 20% of their initial mean blood pressure (before induction of anesthesia), despite a vascular filling with sodium chloride 0.9%. The primary outcome is the success of the therapy defined as an mBP superior to 80% of the baseline mBP (prior to anesthesia) within 10 min post ephedrine administration. The subjects were followed-up for 3 days postanesthesia. DISCUSSION: This study is the first randomized, controlled trial intending to determine the optimal dose of ephedrine to treat hypotension in neonates and infants below 6 months old. TRIAL REGISTRATION: ClinicalTrials.gov NCT02384876 . Registered on March 2015.

Mathematical model of T-cell lymphoblastic lymphoma: disease, treatment, cure or relapse of a virtual cohort of patients.

T lymphoblastic lymphoma (T-LBL) is a rare type of lymphoma with a good prognosis with a remission rate of 85%. Patients can be completely cured or can relapse during or after a 2-year treatment. Relapses usually occur early after the remission of the acute phase. The median time of relapse is equal to 1 year, after the occurrence of complete remission (range 0.2-5.9 years) (Uyttebroeck et al., 2008). It can be assumed that patients may be treated longer than necessary with undue toxicity.The aim of our model was to investigate whether the duration of the maintenance therapy could be reduced without increasing the risk of relapses and to determine the minimum treatment duration that could be tested in a future clinical trial.We developed a mathematical model of virtual patients with T-LBL in order to obtain a proportion of virtual relapses close to the one observed in the real population of patients from the EuroLB database. Our simulations reproduced a 2-year follow-up required to study the onset of the disease, the treatment of the acute phase and the maintenance treatment phase.

Differential binding of the Bombyx silk gland-specific factor SGFB to its target DNA sequence drives posterior-cell-restricted expression.

The gene encoding the silk protein P25 in Bombyx mori is expressed in the posterior silk gland (PSG) cells and repressed in the middle silk gland (MSG) cells. To identify the factors involved in this transcription-dependent spatial restriction, we examined the P25 chromatin in PSG and MSG nuclei by DNase I-aided ligation-mediated PCR and analyzed the expression of various P25-lacZ constructs in biolistically treated silk glands. P25 promoter activation depends on two cis-acting elements. One coincides with the target sequence of SGFB, a silk gland-specific factor present in all silk gland nuclei, but bound to its target DNA sequence in only PSG cells. The interaction of the other element with a factor that we named PSGF is also exclusive to PSG cells. Placed ahead of a non-P25-related basal promoter, the SGFB and PSGF elements are sufficient to drive posterior-cell transcription. Collectively, our data support the hypothesis that the spatial restriction of P25 expression is driven by the stabilization of SGFB onto its target sequence by the action of PSGF.

Conditions of microvessel occlusion for blood coagulation in flow.

Vessel occlusion is a perturbation of blood flow inside a blood vessel because of the fibrin clot formation. As a result, blood circulation in the vessel can be slowed down or even stopped. This can provoke the risk of cardiovascular events. In order to explore this phenomenon, we used a previously developed mathematical model of blood clotting to describe the concentrations of blood factors with a reaction-diffusion system of equations. The Navier-Stokes equations were used to model blood flow, and we treated the clot as a porous medium. We identify the conditions of partial or complete occlusion in a small vessel depending on various physical and physiological parameters. In particular, we were interested in the conditions on blood flow and diameter of the wounded area. The existence of a critical flow velocity separating the regimes of partial and complete occlusion was demonstrated through the mathematical investigation of a simplified model of thrombin wave propagation in Poiseuille flow. We observed different regimes of vessel occlusion depending on the model parameters both for the numerical simulations and in the theoretical study. Then, we compared the rate of clot growth in flow obtained in the simulations with experimental data. Both of them showed the existence of different regimes of clot growth depending on the velocity of blood flow.

Dynamic changes of depolarizing GABA in a computational model of epileptogenic brain: Insight for Dravet syndrome.

Abnormal reemergence of depolarizing GABAA current during postnatal brain maturation may play a major role in paediatric epilepsies, Dravet syndrome (DS) being among the most severe. To study the impact of depolarizing GABA onto distinct patterns of EEG activity, we extended a neural mass model as follows: one sub-population of pyramidal cells was added as well as two sub-populations of interacting interneurons, perisomatic-projecting interneurons (basket-like) with fast synaptic kinetics GABAA (fast, I1) and dendritic-projecting interneurons with slow synaptic kinetics GABAA (slow, I2). Basket-like cells were interconnected to reproduce mutual inhibition mechanisms (I1➔I1). The firing rate of interneurons was adapted to mimic the genetic alteration of voltage gated sodium channels found in DS patients, SCN1A(+/-). We implemented the "dynamic depolarizing GABAA" mediated post-synaptic potential in the model, as some studies reported that the chloride reversal potential can switch from negative to more positive value depending on interneuron activity. The "shunting inhibition" promoted by GABAA receptor activation was also implemented. We found that increasing the proportion of depolarizing GABAA mediated IPSP (I1➔I1 and I1➔P) only (i.e., other parameters left unchanged) was sufficient to sequentially switch the EEG activity from background to (1) interictal isolated polymorphic epileptic spikes, (2) fast onset activity, (3) seizure like activity and (4) seizure termination. The interictal and ictal EEG patterns observed in 4 DS patients were reproduced by the model via tuning the amount of depolarizing GABAA postsynaptic potential. Finally, we implemented the modes of action of benzodiazepines and stiripentol, two drugs recommended in DS. Both drugs blocked seizure-like activity, partially and dose-dependently when applied separately, completely and with a synergic effect when combined, as has been observed in DS patients. This computational modeling study constitutes an innovative approach to better define the role of depolarizing GABA in infantile onset epilepsy and opens the way for new therapeutic hypotheses, especially in Dravet syndrome.

Comparison of 3 and 6 months of oral anticoagulant therapy after a first episode of proximal deep vein thrombosis or pulmonary embolism and comparison of 6 and 12 weeks of therapy after isolated calf deep vein thrombosis.

BACKGROUND: The optimal duration of oral anticoagulant therapy after a first episode of venous thromboembolism remains controversial. METHODS AND RESULTS: We performed an open-label, randomized trial comparing a short oral anticoagulant course (3 months for proximal deep vein thrombosis [P-DVT] and/or pulmonary embolism [PE]; 6 weeks for isolated calf DVT [C-DVT]) with a long course of therapy (6 months for P-DVT/PE; 12 weeks for C-DVT). The outcome events were recurrences and major, minor, or fatal bleeding complications. A total of 736 patients were enrolled. There were 23 recurrences of venous thromboembolism in the short treatment group (6.4%) and 26 in the long treatment group (7.4%); the 2 treatment regimens had an equivalent effect. For the hemorrhage end point, the difference between the short and the long treatment groups was not significant: 15.5% versus 18.4% for all events (P=0.302), 1.7% versus 2.8% (P=0.291) for major events, and 13.9% versus 15.3% for minor bleeding. Subgroup analysis demonstrated that the rate of recurrence was lower for C-DVT than for P-DVT or PE. CONCLUSIONS: After isolated C-DVT, 6 weeks of oral anticoagulation is sufficient. For P-DVT or PE, we demonstrated an equivalence between 3 and 6 months of anticoagulant therapy. For patients with temporary risk factors who have a low risk of recurrence, 3 months of treatment seems to be sufficient. For patients with idiopathic venous thromboembolism or permanent risk factors who have a high risk of recurrence, other trials are necessary to assess prolonged therapy beyond 6 months.

Revisiting the effect compartment through timing errors in drug administration.

The variations in the pharmacological effects induced by timing errors in drug intake are compared for two drugs, one acting by way of an effect compartment and the other directly from the central compartment. A simulation was performed for two drugs having the same concentration-effect relationship at the receptor site, the same mean effect at equilibrium and identical concentrations in the central compartment. In this article. Patrice Nony, Michel Cucherat and Jean-Pierre Boissel discuss how, for the same variability of concentrations in the central compartment, the variations in mean effects are different. When there is a large variability in the interval separating two consecutive doses, the model that includes an effect compartment dampens the pharmacokinetic variability present in the central compartment. Such an approach may be useful for the prescription recommendations of drugs, especially those with narrow therapeutic indices.

Phosphodiesterase III inhibitors for heart failure.

BACKGROUND: In the treatment of chronic heart failure, vasodilating agents, ACE inhibitors and beta-blockers have shown an increase of life expectancy. Another strategy is to increase the inotropic state of the myocardium : phosphodiesterase inhibitors (PDIs) act by increasing intra-cellular cyclic AMP, thereby increasing the concentration of intracellular calcium, and lead to a positive inotropic effect. OBJECTIVES: This overview on summarised data aims to review the data from all randomised controlled trials of PDIs III versus placebo in symptomatic patients with chronic heart failure. The primary endpoint is total mortality. Secondary endpoints are considered such as cause-specific mortality, worsening of heart failure (requiring intervention), myocardial infarction, arrhythmias and vertigos. We also examine whether the therapeutic effect is consistent in the subgroups based on the use of concomitant vasodilators, the severity of heart failure, and the type of PDI derivative and/or molecule. This overview updates our previous meta-analysis published in 1994. SEARCH STRATEGY: Randomised trials of PDIs versus placebo in heart failure were searched using MEDLINE (1966 to 2004 January), EMBASE (1980 to 2003 December), Cochrane CENTRAL trials (The Cochrane Library Issue 1, 2004) and McMaster CVD trials registries, and through an exhaustive handsearching of international abstracting publications (abstracts published in the last 22 years in the "European Heart Journal", the "Journal of the American College of Cardiology" and "Circulation"). SELECTION CRITERIA: All randomised controlled trials of PDIs versus placebo with a follow-up duration of more than three months. DATA COLLECTION AND ANALYSIS: 21 trials (8408 patients) were eligible for inclusion in the review. 4 specific PDI derivatives and 8 molecules of PDIs have been considered. MAIN RESULTS: As compared with placebo, treatment with PDIs was found to be associated with a significant 17% increased mortality rate (The relative risk was 1.17 (95% confidence interval 1.06 to 1.30; p<0.001). In addition, PDIs significantly increase cardiac death, sudden death, arrhythmias and vertigos. Considering mortality from all causes, the deleterious effect of PDIs appears homogeneous whatever the concomitant use (or non-use) of vasodilating agents, the severity of heart failure, the derivative or the molecule of PDI used. AUTHORS' CONCLUSIONS: Our results confirm that PDIs are responsible for an increase in mortality rate compared with placebo in patients suffering from chronic heart failure. Currently available results do not support the hypothesis that the increased mortality rate is due to additional vasodilator treatment. Consequently, the chronic use of PDIs should be avoided in heart failure patients.

Effects on bone mass of long term treatment with thyroid hormones: a meta-analysis.

Osteoporosis is the main cause of spine and hip fractures. Morbidity, mortality, and costs arising from hip fractures have been well documented. Thyroid hormones (TH) are widely prescribed, mainly in the elderly. Some studies (but not all) found a deleterious effect of suppressive TH therapy on bone mass. These conflicting data raised a controversy as to the safety of current prescribing and follow-up habits, which, in turn, raised major health-care issues. To look for a detrimental effect on bone of TH therapy, we performed a meta-analysis (by pooling standardized differences, using a fixed effect model) of all published controlled cross-sectional studies (41, including about 1250 patients) concerning the impact of TH therapy on bone mineral density (BMD). Studies with women receiving estrogen therapy were excluded a priori, as were studies with a high percentage of patients with postoperative hypoparathyroidism, when no separate data were available. We decided to stratify the data according to anatomical site, menopausal status, and suppressive or replacement TH therapy, resulting in 25 meta-analysis on 138 homogeneous subsets of data. The main sources of heterogensity between studies that we could identify were replacement or suppressive TH therapy, menopausal status, site (lumbar spine, femoral neck, Ward's triangle, greater trochanter, midshaft and distal radius, with various percentages of cortical bone), and history of hyperthyroidism, which has recently been found to impair bone mass in a large epidemiological survey. To improve homogeneity, we excluded a posteriori 102 patients from 3 studies, who had a past history of hyperthyroidism and separate BMD data, thus allowing assessment of the TH effect in almost all 25 subset meta-analyses. However, controls were usually not matched with cases for many factors influencing bone mass, such as body weight, age at menarche and at menopause, calcium dietary intake, smoking habits, alcohol intake, exercise, etc. For lumbar spine and hip (as for all other sites), suppressive TH therapy was associated with significant bone loss in postmenopausal women (but not in premenopausal women), whereas, conversely, replacement therapy was associated with bone loss in premenopausal women (spine and hip), but not in postmenopausal women. The detrimental effect of TH appeared more marked on cortical bone than on trabecular bone. Only a large long term prospective placebo-controlled trial of TH therapy (e.g. in benign nodules) evaluating BMD (and ideally fracture rate) would provide further insight into these issues.

Implication of evidence-based medicine in prescription guidelines taught to French medical students: current status in the cardiovascular field.

OBJECTIVES: To study how satisfactory the contents of introductory courses in cardiovascular therapeutics, given to medical students in France, are with respect to the concepts of evidence-based medicine. METHODS: Medical school lecturers were asked to provide written course material used as part of medical school courses. Best-available evidence was classified as existent (including two therapeutic subclasses: indicated and contraindicated), and nonexistent. Four scores (from 0 to 10) were given, according to conformity with best-available evidence, and citation of randomized clinical trials (RCT), meta-analyses and therapeutic objectives. RESULTS: Thirty-four written documents were obtained from 43 faculties. Although the score (mean +/- SEM) of conformity with best-available evidence was 5.43 +/- 0.28 for the existent best-available evidence class, the corresponding scores for the citation of RCT, meta-analyses, and therapeutic objectives were, respectively, 1 +/- 0.2, 0.16 +/- 0.07, and 2.7 +/- 0.3. The four scores were highest when the best-available evidence belonged to the indicated class, intermediate when best-available evidence was nonexistent, and lowest for the contraindicated class (P < .05). These scores were significantly higher when the printed material was intended for specialists. CONCLUSION: Despite some limitations, the extent of agreement with the best-available evidence is only moderate. Pathophysiologic reasoning is largely preferred to justify the choice of therapeutics recommended to medical students.

Population pharmacokinetics of recombinant factor VIIa in volunteers anticoagulated with acenocoumarol.

This study establishes a population PK model for FVII clotting activity (FVII:C) after injection of recombinant activated factor VII (rFVIIa) to healthy volunteers. Twenty eight volunteers, anticoagulated with acenocoumarol, received one or two rFVIIa injections, with dose ranging from 5 to 320 microg/kg. The FVII:C kinetic was fitted to a 2 compartment model, with continuous "endogenous perfusion" mimicking endogenous activity. Estimated clearance was 2.4 1/h (20% inter-individual variability and 9% inter-period variability). The volume of distribution at steady-state appeared to be significantly dose dependent: 78 ml/kg for doses < or = 20 microg/kg and 88 ml/kg for doses > 20 microg/kg respectively, with 16% inter-individual variability. The dose producing 50% of the maximum drop of INR was estimated to be 2.2 microg/kg. The model will be used to better define the dosage regimen for future clinical developments.

Biomarkers of 3-nitropropionic acid (3-NPA)-induced mitochondrial dysfunction as indicators of neuroprotection.

In humans or animals, symptoms of mitochondrial energy dysfunction may be produced by mutations or inborn errors of the necessary enzymes, as well as by enzyme inhibitors or uncouplers of the oxidative phosphorylation process. 3-Nitropropionic acid (3-NPA) is a toxin that is sometimes produced on moldy crops (sugarcane, peanuts, etc.) in amounts sufficient to cause severe neuromuscular disorders when consumed by humans. In vitro, 3-NPA irreversibly inactivates SDH, a Complex II respiratory enzyme important for mitochondrial energy production. We have been studying biomarkers of 3-NPA exposure in the expectation that such markers may be useful in the screening process to identify neuroprotective agents against neurotoxicity produced by mitochondrial energy dysfunction. Animals were sacrificed at various times after 3-NPA exposure for histochemical visualization of SDH activity and measurement of immediate postmortem rectal temperature. 3-NPA-treated rats experienced progressive hypothermia that reached a loss of 3 degrees C or more in core body temperature by three hours after dosing. The optical density of the SDH stain in brain was reduced, following a similar time course, most prominently in the cerebellum and least sharply in the thalamus. Some rats were given injections of L-carnitine (an enhancer of fatty acid transport) either alone, or as a pretreatment prior to a dose of 3-NPA. Although L-carnitine deficiency by itself can produce mitochondrial dysfunction, pretreatment with L-carnitine was of limited efficacy at overcoming the effects of 3-NPA on either body temperature or quantitative SDH histochemistry. Body temperature and SDH histochemistry may be useful biomarkers for evaluating the efficacy of neuroprotective agents against lower doses of 3-NPA, against other pharmacological models of mitochondrial dysfunction, or even against genetic mitochondrial diseases.

Doxorubicin concentration time course in the myocardium after single administration to the dog. Possible role in the cardiac effects.

Three hours after i.v. administration of doxorubicin, concentrations of the drug in the myocardium are much higher (about 50 times) and decrease much more slowly (drug still detected 21 days later) than those in the plasma, so that storage results from too early readministration, with possible toxic signs.

In vivo measurement of myocardial oxidative metabolism and blood flow does not show changes in cancer patients undergoing doxorubicin therapy.

PURPOSE: The aim was to investigate in patients receiving doxorubicin whether any alteration in myocardial oxidative metabolism or blood flow as assessed by positron emission tomography (PET) could be observed either after the first dose of the drug, or during its chronic administration. METHODS: Six female non-heart-failure cancer patients treated with doxorubicin were included in a longitudinal study. Resting radionuclide cineangiography and PET scanning with carbon-11 acetate were performed the day before the initiation of doxorubicin treatment at a dosage of 50 mg/m2 every 3 weeks, and 3 weeks after the cumulative administration of 300 mg/m2 (chronic toxicity). In addition, PET was performed 24 h after the first administration of doxorubicin (evaluation of acute toxicity). Myocardial oxidative metabolism and blood flow were assessed by PET (acute and chronic toxicity), and left ventricular ejection fraction was measured by radionuclide angiography (chronic toxicity). RESULTS: Using PET for both acute and chronic toxicity evaluations, no significant effect of doxorubicin was observed either on the flux through the tricarboxylic acid (TCA) cycle or on myocardial blood flow. However, systolic left ventricular function showed a small but significant impairment after the administration of 300 mg/m2 of doxorubicin. CONCLUSIONS: Other hypotheses should be explored to better explain the predominant mechanisms of the cardiotoxicity of anthracyclines in humans.

Private hospital and phase I.

Since December 1988. French law has authorized phase I studies and the creation of phase I units within public or private hospitals. The scientific standards regarding private hospitals are not different from those in public hospitals. Practitioners who conduct clinical trials in private hospitals are well aware of good clinical practices and methodological constraints. Phase I units can be structured in private as well as within public hospitals. Finally, the question to be addressed is whether clinical pharmacology and scientific investigations in healthy volunteers should be integrated in the policy of private hospitals.

The place of simultaneous pharmacokinetic pharmacodynamic modeling in new drug development: trends and perspectives.

The potential applications in drug development of pharmacokinetic-pharmacodynamic modeling are numerous: optimal medication regimen, design of galenic forms, identification of specific effects of metabolites and enantiomers. Nevertheless, this methodology is presently under-used, as appears from an analysis of the literature. We examine this point as well as progress in both non-invasive pharmacodynamic measurement and specific experimental design that could lead to a future extension of PK-PD in toxicology and phase I drug development.