En dépit d’épidémies répétées, il n’existe pas à ce jour de thérapeutique ayant démontré son efficacité dans la maladie à virus Ebola. Sur la base d’expérimentations réalisées chez la souris et le macaque dans le cadre du consortium Reaction!, l’objectif de cette thèse visait à caractériser l’effet d’une molécule antivirale, le favipiravir, via l’implémentation de modèles mathématiques mécanistiques de l’infection et de la réponse immunitaire associée. L’approche utilisée pour construire ces modèles et en estimer les paramètres reposait sur les modèles non linéaires à effets mixtes. Un premier travail a permis d’explorer la relation concentration-effet sur la charge virale plasmatique chez la souris. Le second projet a conduit à caractériser la pharmacocinétique non linéaire dose et temps dépendante du favipiravir chez le macaque, en vue d’identifier les schémas posologiques pertinents pour la réalisation des études d’efficacité chez l’animal infecté. Au décours de leur réalisation, l’intégration des données virologiques et immunitaires générées au sein d’un modèle conjoint a permis de caractériser un effet modéré du favipiravir sur la réplication virale, mais suffisant pour limiter le développement d’une réaction inflammatoire délétère, et ainsi améliorer le taux de survie des animaux traités. Les simulations réalisées avec ce modèle ont pu souligner l’impact déterminant du délai d’initiation du traitement sur la survie. Ces résultats incitent à la poursuite de l’évaluation clinique du favipiravir, en favorisant des essais de prophylaxie ou post exposition. Enfin, un dernier travail a démontré l’absence de potentialisation du favipiravir par la ribavirine dans Ebola. / In spite of recurrent outbreaks, no therapeutics with demonstrated clinical efficacy are available in Ebola virus disease. Based on experimentations performed by Reaction! Consortium in mice and macaques, this thesis aimed to characterize the effect of an antiviral drug, favipiravir, using mechanistic mathematical models of the infection and associated immune response. The approach to build models and estimate parameters relied on nonlinear mixed effect models. The first project of this thesis explored the concentration-effect relationship on the viremia in mice. Then, a second project allowed to characterize the pharmacokinetics of favipiravir in macaques, underlying dose and time non linearity, and to identify relevant dosing regimen for efficacy experiments in infected animals. Once these experiments completed, the integration of the virological and immunological data into a mechanistic joint model shed light on the effect of favipiravir. The moderate inhibition of the viral replication resulting from the favipiravir plasma concentrations was enough to limit the development of a deleterious inflammatory response, and thus improve the survival rate of treated macaques. Simulations performed with this model underlined the crucial impact of the treatment initiation delay on survival. These results encourage the pursuit of the clinical evaluation of favipiravir in prophylaxis or post exposure trials. Finally, a last project demonstrated the lack of benefit of ribavirin addition to favipiravir in Ebola virus disease.

京都大学 / 0048 / 新制・論文博士 / 博士(薬科学) / 乙第13334号 / 論薬科博第3号 / 新制||薬科||13(附属図書館) / (主査)教授 松原 和夫, 教授 山下 富義, 教授 髙倉 喜信 / 学位規則第4条第2項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

Dans le monde entier l’antibiorésistance des entérobactérales communautaires, notamment par production de ß-lactamase à spectre étendu (E-BLSE), conduit à une consommation préoccupante d’antibiotique de dernier recours tels les carbapénèmes. Dérivé de la ticarcilline la témocilline pourrait représentée une alternative y compris sur certaines entérobactérales productrices de carbapénèmase (EPC). Néanmoins, il existe une incertitude concernant les concentrations critiques distinguant les entérobactérales sensibles des résistantes avec trois valeurs selon les pays utilisateurs de témocilline (8 mg/L, 16 mg/L ou 32 mg/L) tandis qu’une harmonisation internationale reste en attente. En ce contexte trois travaux originaux ont été poursuivi ainsi qu’une revue de la littérature. Il fut d’abord étudié in vitro la sensibilité à la témocilline de 762 entérobactérales responsables d’infection urinaire communautaire. Dans un contexte de prévalence faible des E-BLSE (5%) et nulle des EPC, les trois méthodes de routine (disque, automate, Etest) se sont révélées très fiables, la borne épidémiologique pour la témocilline s’établissant à 8 mg/L. Ensuite, l’efficacité de la témocilline vis-à-vis d’entérobactérales productrices ou non de ßlactamases (E-BLSE ou EPC) a été évaluée dans deux modèles murins complémentaires. Il a été montré l’efficacité de la témocilline à un schéma reproduisant la posologie humaine de 2 g toutes 12 h vis-à-vis d’entérobactérales pour lesquels la CMI de la témocilline était de 8 mg/L. L’efficacité de ce schéma posologique, bien que significative, était moindre vis-à-vis des isolats pour lesquels la CMI de la témocilline était de 16 mg/L. Par contre, il ne fut pas observé d’efficacité significative de la témocilline vis-à-vis des isolats avec une CMI à 32 mg/L quelques soit le schéma posologique (2 g toutes les 8 ou 12 h). L’ensemble de ces résultats, ainsi qu’une revue exhaustive des données de la littérature, conduisent à proposer une concentration critique de 8 mg/L pour le schéma posologique de 2 g toutes les 12 h, et de 16 mg/L pour celui de 2 g toutes les 8h. Cette dernière proposition correspondrait au « sensible à forte exposition », nouvelle définition de la catégorisation « intermédiaire » selon les dernières recommandations de l’EUCAST. / Worldwide spread of antimicrobial resistance among community-acquired enterobacterales, especially ESBL, leads to a worrying consumption of last resort antibiotics like carbapenem. Derivative of ticarcillin, temocillin may be an attractive carbapenem-sparing agent including against some carbapenemase-producing enterobacterales (CPE). Nevertheless, there is still uncertainty regarding clinical breakpoints with 3 different values depending on countries (8 mg/L, 16 mg/L, 32 mg/L), moreover international consensus about this issue is awaited. In this context, three original studies were conducted along with a literature review. First, in vitro susceptibility to temocillin of 762 enterobacterales from community-acquired urinary tract infection was studied. In this area of low prevalence of ESBL and no CPE, the three routine susceptibility methods (disk diffusion, automate, Etest) were very accurate, epidemiological cut-off was set to 8 mg/L. Then, temocillin efficacy against enterobacterales producing or not producing ß-lactamase (ESBL or CPE) was assessed by two complementary murine models. We demonstrated that temocillin exposure reproducing 2 g q12h regimen showed efficacy against strains with temocillin MIC of 8 mg/L. This regimen exhibited a lower, even though significant, efficacy against strain with temocillin MIC of 16 mg/L. On the over hand, it was not observed significant efficacy against strain with temocillin MIC of 32 mg/L whatever the regimen used (2 g q12h or q8h). All together this results and the literature review support a clinical breakpoints of 8 mg/L for2 g q12h regimen, and 16 mg/L for 2 g q8h regimen. This last proposition correspond to the new susceptibility category : “Intermediate – Susceptible, increase exposure” from the last EUCAST recommendations.

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No description available.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by consistently high blood glucose, resulting from a combination of insulin resistance and reduced capacity of β-cells to secret insulin. While the exact causes of T2DM is yet unknown, obesity is known to be a major risk factor as well as co-morbidity for T2DM. As the global prevalence of obesity continues to increase, the association between obesity and T2DM warrants further study. Traditionally, mathematical models to study T2DM were mostly empirical and thus fail to capture the dynamic relationship between glucose and insulin. More recently, mechanism-based population models to describe glucose-insulin homeostasis with a physiological basis were proposed and offered a substantial improvement over existing empirical models in terms of predictive ability. The primary objectives of this thesis are (i) examining the predictive usefulness of semi-mechanistic models in T2DM by applying an existing population model to clinical data, and (ii) exploring the relationship between obesity and T2DM and describe it mathematically in a novel semi-mechanistic model to explain changes to the glucose-insulin homeostasis and disease progression of T2DM. Through the use of non-linear mixed effects modelling, the primary mechanism of action of an antidiabetic drug has been correctly identified using the integrated glucose-insulin model, reinforcing the predictive potential of semi-mechanistic models in T2DM. A novel semi-mechanistic model has been developed that incorporated a relationship between weight change and insulin sensitivity to describe glucose, insulin and glycated hemoglobin simultaneously in a clinical setting. This model was also successfully adapted in a pre-clinical setting and was able to describe the pathogenesis of T2DM in rats, transitioning from healthy to severely diabetic. This work has shown that a previously unutilized biomarker was found to be significant in affecting glucose homeostasis and disease progression in T2DM, and that pharmacometric models accounting for the effects of obesity in T2DM would offer a more complete physiological understanding of the disease.

Tuberculosis is an ancient infectious disease and a leading cause of death globally. Preclinical research is important for defining drugs and regimens which should be carried forward to human studies. This thesis aims to characterize the population pharmacokinetics and exposure-response relationships of anti-tubercular drugs alone and in combinations, and to suggest experimental designs for preclinical settings. The population pharmacokinetics of rifampicin, isoniazid, ethambutol and pyrazinamide were described for the first time in two mouse models. This allowed for linking the population pharmacokinetic model to the Multistate Tuberculosis Pharmacometric (MTP) model for biomarker response, which was used to characterize exposure-response relationships in monotherapy. Pharmacodynamic interactions in combination therapies were quantitatively described by linking the MTP model to the General Pharmacodynamic Interaction (GPDI) model, which provided estimates of single drug effects together with a quantitative model-based evaluation framework for evaluation of pharmacodynamic interactions among drugs in combinations. Synergism (more than expected additivity) was characterized between rifampicin and ethambutol, while antagonism (less than expected additivity) was characterized between rifampicin and isoniazid in combination therapies. The new single-dose pharmacokinetic design with enrichened individual sampling was more informative than the original design, in which only one sample was taken from each mouse in the pharmacokinetic studies. The new oral zipper design allows for informative pharmacokinetic sampling in a multiple-dose administration scenario for characterizing pharmacokinetic-pharmacodynamic relationships, with similar or lower bias and imprecision in parameter estimates and with a decreased total number of animals required by up to 7-fold compared to the original design. The optimized design for assessing pharmacodynamic interactions in the combination therapies, which was based on EC20, EC50 and EC80 of the single drug, provided lower bias and imprecision than a conventional reduced four-by-four microdilution checkerboard design at the same total number of samples required, which followed the 3Rs of animal welfare. In summary, in this thesis the population pharmacokinetic-pharmacodynamic models of first-line drugs in mice were characterized through linking each population pharmacokinetic model to the MTP model. Pharmacodynamic interactions were quantitatively illustrated by the MTP-GPDI model. Lastly, experimental designs were optimized and recommended to both pharmacokinetic and pharmacodynamic studies for preclinical settings.

La diminution des doses administrées ou même la cessation complète d'un traitement chimiothérapeutique est souvent la conséquence de la réduction du nombre de neutrophiles, qui sont les globules blancs les plus fréquents dans le sang. Cette réduction dans le nombre absolu des neutrophiles, aussi connue sous le nom de myélosuppression, est précipitée par les effets létaux non spécifiques des médicaments anti-cancéreux, qui, parallèlement à leur effet thérapeutique, produisent aussi des effets toxiques sur les cellules saines. Dans le but d'atténuer cet impact myélosuppresseur, on administre aux patients un facteur de stimulation des colonies de granulocytes recombinant humain (rhG-CSF), une forme exogène du G-CSF, l'hormone responsable de la stimulation de la production des neutrophiles et de leurs libération dans la circulation sanguine. Bien que les bienfaits d'un traitement prophylactique avec le G-CSF pendant la chimiothérapie soient bien établis, les protocoles d'administration demeurent mal définis et sont fréquemment déterminés ad libitum par les cliniciens. Avec l'optique d'améliorer le dosage thérapeutique et rationaliser l'utilisation du rhG-CSF pendant le traitement chimiothérapeutique, nous avons développé un modèle physiologique du processus de granulopoïèse, qui incorpore les connaissances actuelles de pointe relatives à la production des neutrophiles des cellules souches hématopoïétiques dans la moelle osseuse. À ce modèle physiologique, nous avons intégré des modèles pharmacocinétiques/pharmacodynamiques (PK/PD) de deux médicaments: le PM00104 (Zalypsis®), un médicament anti-cancéreux, et le rhG-CSF (filgrastim). En se servant des principes fondamentaux sous-jacents à la physiologie, nous avons estimé les paramètres de manière exhaustive sans devoir recourir à l'ajustement des données, ce qui nous a permis de prédire des données cliniques provenant de 172 patients soumis au protocol CHOP14 (6 cycles de chimiothérapie avec une période de 14 jours où l'administration du rhG-CSF se fait du jour 4 au jour 13 post-chimiothérapie). En utilisant ce modèle physio-PK/PD, nous avons démontré que le nombre d'administrations du rhG-CSF pourrait être réduit de dix (pratique actuelle) à quatre ou même trois administrations, à condition de retarder le début du traitement prophylactique par le rhG-CSF. Dans un souci d'applicabilité clinique de notre approche de modélisation, nous avons investigué l'impact de la variabilité PK présente dans une population de patients, sur les prédictions du modèle, en intégrant des modèles PK de population (Pop-PK) des deux médicaments. En considérant des cohortes de 500 patients in silico pour chacun des cinq scénarios de variabilité plausibles et en utilisant trois marqueurs cliniques, soient le temps au nadir des neutrophiles, la valeur du nadir, ainsi que l'aire sous la courbe concentration-effet, nous avons établi qu'il n'y avait aucune différence significative dans les prédictions du modèle entre le patient-type et la population. Ceci démontre la robustesse de l'approche que nous avons développée et qui s'apparente à une approche de pharmacologie quantitative des systèmes (QSP). Motivés par l'utilisation du rhG-CSF dans le traitement d'autres maladies, comme des pathologies périodiques telles que la neutropénie cyclique, nous avons ensuite soumis l'étude du modèle au contexte des maladies dynamiques. En mettant en évidence la non validité du paradigme de la rétroaction des cytokines pour l'administration exogène des mimétiques du G-CSF, nous avons développé un modèle physiologique PK/PD novateur comprenant les concentrations libres et liées du G-CSF. Ce nouveau modèle PK a aussi nécessité des changements dans le modèle PD puisqu’il nous a permis de retracer les concentrations du G-CSF lié aux neutrophiles. Nous avons démontré que l'hypothèse sous-jacente de l'équilibre entre la concentration libre et liée, selon la loi d'action de masse, n'est plus valide pour le G-CSF aux concentrations endogènes et mènerait en fait à la surestimation de la clairance rénale du médicament. En procédant ainsi, nous avons réussi à reproduire des données cliniques obtenues dans diverses conditions (l'administration exogène du G-CSF, l'administration du PM00104, CHOP14). Nous avons aussi fourni une explication logique des mécanismes responsables de la réponse physiologique aux deux médicaments. Finalement, afin de mettre en exergue l’approche intégrative en pharmacologie adoptée dans cette thèse, nous avons démontré sa valeur inestimable pour la mise en lumière et la reconstruction des systèmes vivants complexes, en faisant le parallèle avec d’autres disciplines scientifiques telles que la paléontologie et la forensique, où une approche semblable a largement fait ses preuves. Nous avons aussi discuté du potentiel de la pharmacologie quantitative des systèmes appliquées au développement du médicament et à la médecine translationnelle, en se servant du modèle physio-PK/PD que nous avons mis au point. / Dose-limitation or interruption of chemotherapeutic treatment is most often prompted by a decrease in circulating neutrophils, the most abundant white blood cell in the human body. Myelosuppression, or a reduction in absolute neutrophil counts (ANCs) by anti-cancer treatments, is precipitated by the nonspecific killing effect of chemotherapeutic drugs which have toxic effects on noncancerous cells. To mitigate this myelosuppressive effect, patients are frequently administered recombinant human granulocyte colony-stimulating factor (rhG-CSF), an exogenous form of the cytokine G-CSF, which stimulates neutrophil production and release into the blood stream. While the benefits of adjuvant treatment rhG-CSF during chemotherapy are well recognised, the protocols with which it is administered are not well defined and are frequently determined ad libitum by clinicians. To quantify and address the optimisation of the administration of rhG-CSF during chemotherapeutic treatment, we developed a physiological model of granulopoiesis which incorporates the contemporary understanding of the production of neutrophils from the hematopoietic stem cells in the bone marrow. To this physiological model, we incorporated mechanistic pharmacokinetic/pharmacodynamic (PK/PD) models of two drugs, PM00104 (Zalypsis), a chemotherapeutic drug, and rhG-CSF (filgrastim). Through exhaustive parameter estimation using first principles and no data fitting, we successfully predicted clinical data from 172 patients for an average patient undergoing the CHOP14 protocol (6 cycles of 14-day periodic chemotherapy with rhG-CSF administered on days 4-13 post-chemotherapy). We then demonstrated that delaying the administration of rhG-CSF to 6 or 7 days post-chemotherapy allowed for a reduction in the number of filgrastim administrations from ten to four or even three while maintaining or improving the neutrophil nadir. We also investigated the effects of PK variability on the model's predictions by incorporating population PK (PopPK) models of both drugs. Using five different variability scenarios and cohorts of 500 in silico patients per scenario, we established that there are no statistically significant differences between a typical patient and the population in the model's predictions with respect to three crucial clinical endpoints, namely the time to ANC nadir, the ANC nadir, and the area under the concentration-effect curve. The model's robustness to PK variability allows for the scaling up from the individual to population level. Motivated by the use of rhG-CSF in other disease-states, namely periodic pathologies like cyclical neutropenia, we next endeavoured to contextualise the model within dynamic diseases. By bringing to light that the cytokine paradigm is broken when exogenous cytokine mimetics are administered, we developed a novel physiological PK model for G-CSF incorporating both unbound and bound concentrations. The updated PK model prompted changes to the PD model since we could now track the concentrations of bound G-CSF. We showed that the mass-action equilibrium hypopthesis for bound and unbound drugs is not valid and led to overestimations of the renal clearance of G-CSF. We also successfully reproduced clinical data in a variety of settings (exogenous G-CSF alone, PM00104 alone, CHOP14 protocol) and clarified the mechanisms underlying the body's response to both drugs. Lastly, we discussed the potential of quantitative systems pharmacology in both drug development and translational medicine by using the physiological PK/PD model we developed.

With approximately nine million new cases and the attributable cause of death of an estimated two millions people every year there is an urgent need for new and effective drugs and treatment regimens targeting tuberculosis. The tuberculosis drug development pathway is however not ideal, containing non-predictive model systems and unanswered questions that may increase the risk of failure during late-phase drug development. The aim of this thesis was hence to develop pharmacometric tools in order to optimize the development of new anti-tuberculosis drugs and treatment regimens. The General Pulmonary Distribution model was developed allowing for prediction of both rate and extent of distribution from plasma to pulmonary tissue. A distribution characterization that is of high importance as most current used anti-tuberculosis drugs were introduced into clinical use without considering the pharmacokinetic properties influencing drug distribution to the site of action. The developed optimized bronchoalveolar lavage sampling design provides a simplistic but informative approach to gathering of the data needed to allow for a model based characterization of both rate and extent of pulmonary distribution using as little as one sample per subject. The developed Multistate Tuberculosis Pharmacometric model provides predictions over time for a fast-, slow- and non-multiplying bacterial state with and without drug effect. The Multistate Tuberculosis Pharmacometric model was further used to quantify the in vitro growth of different strains of Mycobacterium tuberculosis and the exposure-response relationships of three first line anti-tuberculosis drugs. The General Pharmacodynamic Interaction model was successfully used to characterize the pharmacodynamic interactions of three first line anti-tuberculosis drugs, showing the possibility of distinguishing drug A’s interaction with drug B from drug B’s interaction with drug A. The successful separation of all three drugs effect on each other is a necessity for future work focusing on optimizing the selection of anti-tuberculosis combination regimens. With a focus on pharmacokinetics and pharmacodynamics, the work included in this thesis provides multiple new methods and approaches that individually, but maybe more important the combination of, has the potential to inform development of new but also to provide additional information of the existing anti-tuberculosis drugs and drug regimen.

O carvedilol é um fármaco utilizado na terapêutica da hipertensão e da insuficiência cardíaca congestiva. É disponível para uso clínico como racemato e seus enantiômeros apresentam atividade semelhante sobre os receptores 1-adrenérgicos, sendo que o enantiômero S-(-) é mais ativo como antagonista dos receptores adrenérgicos. O presente estudo visa investigar a influência do Diabetes mellitus (DM) tipo 2 e da insuficiência renal crônica (IRC) em pacientes em diálise peritoneal ambulatorial contínua (DPAC) na farmacocinética enantiosseletiva e na farmacodinâmica do carvedilol em pacientes hipertensos. Os pacientes hipertensos investigados divididos nos grupos controle (n=8), DM tipo 2 (n=8) e IRC em DPAC (n=6) receberam dose única p.o. de 25 mg de carvedilol racêmico. Os enantiômeros do carvedilol e metabólitos 4-hidroxifenil e O-desmetilcarvedilol foram analisados no sistema LC-MS/MS empregando coluna quiral e fase móvel constituída por mistura de metanol: ácido acético: dietilamina. O método foi linear no intervalo de concentrações de 0,1-100 ng de cada enantiômero do carvedilol/mL de líquido de diálise, 0,2-200 ng de cada enantiômero do carvedilol/mL de plasma, 2,5-2500 ng de cada enantiômero do carvedilol, 4-hidroxifenil e O-desmetilcarvedilol/mL de urina. Os parâmetros farmacocinéticos foram calculados empregando o programa WinNonlin. O teste de Wilcoxon foi usado para avaliar as razões enantioméricas dentro dos grupos e o teste de Mann-Whitney foi utilizado para avaliar as diferença dos parâmetros farmacocinéticos entre os grupos. Na investigação do fenótipo oxidativo tipo metoprolol todos os pacientes incluídos no estudo foram fenotipados como metabolizadores extensivos. Os pacientes investigados com DM tipo 2 comparados com o grupo controle não apresentaram alterações na farmacocinética e farmacodinâmica (PK-PD) do carvedilol. Os pacientes com IRC em DPAC apresentaram valores de clearance (CL/F) dos enantiômeros R-(+) - e S-(-)-carvedilol de 25,17 e 27,89 L/h, respectivamente, sendo significativamente inferiores aos obtidos para os pacientes do grupo controle (76,76 e 142,0 L/h). As razões de AUCR/S foram de 2,27 para os pacientes do grupo controle e de 0,97 para os pacientes com IRC em DPAC. Os pacientes com IRC em DPAC não mostraram enantiosseletividade na farmacocinética do carvedilol em razão do acúmulo plasmático preferencial do enantiômero com atividade -bloqueadora S-(-)-carvedilol. / Carvedilol is used for the treatment of hypertension and congestive heart failure. The drug is available for clinical use as the racemate and its enantiomers exert similar activity on 1-adrenergic receptors, whereas the S-(-) enantiomer is more active as a -adrenergic receptor antagonist. The aim of the present study was to investigate the influence of type 2 Diabetes mellitus (DM) and chronic renal failure (CRF) on patients receiving continuous ambulatory peritoneal dialysis (CAPD) on the enantioselective pharmacokinetics and pharmacodynamics of carvedilol in hypertensive patients. The hypertensive patients were divided into a control (n=8), type 2 DM (n=8) and CRF on CAPD (n=6) group and received a single oral dose of 25 mg racemic carvedilol. The enantiomers of carvedilol and of the metabolites 4-hydroxyphenyl and O-desmethylcarvedilol were analyzed by LC-MS/MS using a chiral column and a mobile phase consisting of a mixture of methanol:acetic acid-diethylamine. The method was linear within the following concentration ranges: 0.1-100 ng of each carvedilol enantiomer/mL dialysis fluid, 0.2-200 ng of each carvedilol enantiomer/mL plasma, and 2.5-2500 ng of each enantiomer of carvedilol, 4-hydroxyphenyl carvedilol and O-desmethyl carvedilol/mL urine. The pharmacokinetic parameters were calculated using the WinNonlin program. Enantiomer ratios within groups were evaluated by the Wilcoxon test and the Mann-Whitney test was used to determine differences in the pharmacokinetic parameters between groups. Determination of the metoprolol type oxidation phenotype showed that all patients included in the study were extensive metabolizers. Patients with type 2 DM presented no changes in the pharmacokinetics or pharmacodynamics of carvedilol when compared to the control group. Clearance (CL/F) of the R-(+)- and S-(-)-carvedilol enantiomers was significantly lower in patients with CRF on CAPD (25.17 and 27.89 L/h, respectively) compared to the control group (76.76 and 142.0 L/h). The AUCR/S ratios were 2.27 for control patients and 0.97 for patients with CRF on CAPD. Patients with CRF on CAPD showed no enantioselectivity in the pharmacokinetics of carvedilol due to the preferential plasma accumulation of the enantiomer with -blocker activity, S-(-)-carvedilol.