Mathieu Molimard

Poor adherence is the main reason for loss of CCyR and imatinib failure for chronic myeloid leukemia patients on long-term therapy.

We studied the relation between adherence to imatinib measured with microelectronic monitoring systems and the probabilities of losing a complete cytogenetic response (CCyR) and of imatinib failure in 87 CCyR chronic myeloid leukemia patients receiving long-term therapy. We included in our analysis the most relevant prognostic factors described to date. On multivariate analysis, the adherence rate and having failed to achieve a major molecular response were the only independent predictors for loss of CCyR and discontinuation of imatinib therapy. The 23 patients with an adherence rate less than or equal to 85% had a higher probability of losing their CCyR at 2 years (26.8% vs 1.5%, P = .0002) and a lower probability of remaining on imatinib (64.5% vs 90.6%, P = .006) than the 64 patients with an adherence rate more than 85%. In summary, we have shown that poor adherence is the principal factor contributing to the loss of cytogenetic responses and treatment failure in patients on long-term therapy.

Multidrug resistance gene (MDR1) polymorphisms are associated with major molecular responses to standard-dose imatinib in chronic myeloid leukemia.

Despite the excellent efficacy of imatinib in chronic myeloid leukemia (CML), the response in patients is heterogeneous, which may in part be caused by pharmacogenetic variability. Imatinib has been reported to be a substrate of the P-glycoprotein pump. In the current study, we focused on the ABCB1 (MDR1) genotype. We analyzed the 3 most relevant single nucleotide polymorphisms of MDR1 in 90 CML patients treated with imatinib. Among the patients homozygous for allele 1236T, 85% achieved a major molecular response versus 47.7% for the other genotypes (P = .003). For the 2677G>T/A polymorphism, the presence of G allele was associated with worse response (77.8%, TT/TA; vs 47.1%, GG/GA/GT; P = .018). Patients with 1236TT genotype had higher imatinib concentrations. One of the haplotypes (1236C-2677G-3435C) was statistically linked to less frequent major molecular response (70% vs 44.6%; P = .021). Hence, we demonstrated the usefulness of these single nucleotide polymorphisms in the identification of CML who may or may not respond optimally to imatinib.

The scientific rationale for combining long-acting β2-agonists and muscarinic antagonists in COPD

Bronchodilators are the cornerstone of pharmacological management of COPD. For patients whose conditions are not sufficiently controlled by monotherapy, combining bronchodilators of different classes, in particular an inhaled muscarinic antagonist with an inhaled beta(2)-agonist, seems a convenient way of delivering treatment and obtaining superior results. When administered as combination therapy, short-acting bronchodilators provide superior bronchodilation compared with individual agents given alone. More recently, long-acting beta(2)-agonists (LABAs) and muscarinic antagonists (LAMAs) have been introduced, and current guidelines recommend regular use of these agents alone or as concurrent therapy in COPD to maximize bronchodilation. In particular, the combination of a LABA plus LAMA seems to play an important role. This article illustrates the scientific rationale for combining LABAs and LAMAs in COPD, reviews the clinical evidence to support these agents given in combination, and discusses their potential role in the management of patients with COPD.

Comparison of pharmacokinetics and metabolism of desloratadine, fexofenadine, levocetirizine and mizolastine in humans

Absorption, distribution, metabolism and excretion of desloratadine, fexofenadine, levocetirizine, and mizolastine in humans have been compared. The time required to reach peak plasma levels (tmax) is shortest for levocetirizine (0.9 h) and longest for desloratadine (≥3 h). Steady‐state plasma levels are attained after about 6 days for desloratadine, 3 days for fexofenadine, 2–3 days for mizolastine and by the second day for levocetirizine. The apparent volume of distribution is limited for levocetirizine (0.4 L/kg) and mizolastine (1–1.2 L/kg), larger for fexofenadine (5.4–5.8 L/kg) and particularly large for desloratadine (≈ 49 l/kg). Fexofenadine and levocetirizine appear to be very poorly metabolized (≈ 5 and 14% of the total oral dose, respectively). Desloratadine and mizolastine are extensively metabolized. After administration of 14C‐levocetirizine to healthy volunteers, 85 and 13% of the radioactivity are recovered in urine and faeces, respectively. In contrast, faeces are the preferential route of excretion for 14C‐fexofenadine (80% vs. 11% of the radioactive dose in urine). The corresponding values are 41% (urine) and 47% (faeces) for 14C‐desloratadine, 84–95% (faeces) and 8–15% (urine) for 14C‐mizolastine. The absolute bioavailability is 50–65% for mizolastine; it is high for levocetirizine as the percentage of the drug eliminated unchanged in the 48 h urine is 77% of the oral dose; the estimation for fexofenadine is at least 33%; no estimation was found for desloratadine. Fexofenadine is a P‐glycoprotein (P‐gp) substrate and P‐gp is certainly involved both in the poor brain penetration by the compound and, at least partially, in a number of observed drug interactions. An interaction of desloratadine with P‐gp has been suggested in mice, whereas the information on mizolastine is very poor. The fact that levocetirizine is a substrate of P‐gp, although weak in an in vitro model, could contribute to prevent drug penetration into the brain, whereas it is unlikely to be of any clinical relevance for P‐gp‐mediated drug interactions.

Effect of indacaterol, a novel long-acting β2-agonist, on isolated human bronchi

Indacaterol is a novel β2-adrenoceptor agonist in development for the once-daily treatment of asthma and chronic obstructive pulmonary disease. The present study evaluated the relaxant effect of indacaterol on isolated human bronchi obtained from lungs of patients undergoing surgery for lung carcinoma. Potency (-logEC50), maximal relaxant effect (Emax) and onset of action were determined at resting tone. Duration of action was determined against cholinergic neural contraction induced by electrical field stimulation (EFS). At resting tone, -logEC50 and Emax values were 8.82±0.41 and 77±5% for indacaterol, 9.84±0.22 and 94±1% for formoterol, 8.36±0.16 and 74±4% for salmeterol, and 8.43±0.22 and 84±4% for salbutamol, respectively. In contrast to salmeterol, indacaterol did not antagonise the isoprenaline response. Indacaterols onset of action (7.8±0.7 min) was not significantly different from that of formoterol (5.8±0.7 min) or salbutamol (11.0±4.0 min), but it was significantly faster than that of salmeterol (19.4±4.3 min). EFS-induced contractions were inhibited with -logIC50 values of 6.96±0.13 (indacaterol), 8.96±0.18 (formoterol), 7.18±0.34 (salmeterol) and 6.39±0.26 (salbutamol). Duration of action was >12 h for indacaterol and salmeterol, and 35.3±8.8 and 14.6±3.7 min for formoterol and salbutamol, respectively. In isolated human bronchi, indacaterol behaved as a long-acting β2-adrenoceptor agonist with high intrinsic efficacy and fast onset of action.

Pharmacokinetic/pharmacodynamic correlation and blood-level testing in imatinib therapy for chronic myeloid leukemia

Imatinib is the current standard of care in the treatment of chronic myeloid leukemia (CML), inducing durable responses and prolonged progression-free survival. However, plasma exposure to the drug from a given dosing regimen can vary widely among patients. Reasons for this may include incomplete adherence, intrinsic variations in the metabolism of imatinib, and drug–drug interactions. Data from two recent studies have shown a correlation between imatinib trough plasma concentration and clinical response, leading to suggestions that maintaining imatinib blood concentrations above ∼1000 ng/ml might be associated with improved outcomes. In patients who do not respond as well as expected to initial imatinib treatment, measurement of trough plasma concentration could assist with decisions about whether to increase the dose. Blood-level testing may also be helpful in other clinical scenarios: for example, when poor adherence is suspected, adverse reactions are unusually severe, or there is a possible drug–drug interaction. Further work is required to confirm prospectively the link between imatinib plasma concentrations and response, and to define effective trough concentrations in different patient populations. However, based on the current data, imatinib blood-level testing seems to be a useful aid when making clinical decisions in CML.

High-performance liquid chromatographic method with diode array detection to identify and quantify atypical antipsychotics and haloperidol in plasma after overdose

For toxicological purposes, an HPLC assay was developed for the simultaneous determination of haloperidol and atypical antipsychotics (risperidone, 9-hydroxyrisperidone, olanzapine, clozapine) in human plasma. After a double-step liquid-liquid extraction, compounds were separated on a C(8) column eluted with a gradient of acetonitrile and phosphate buffer 50 mM pH 3.8. A sequential ultraviolet detection was used (260, 280 and 240 nm). Calibration curves were linear in the range 10-1000 ng/ml. The limits of quantification were 5 ng/ml for all drugs. Average accuracy at four concentrations ranged from 93 to 109%. Both inter- and intra-day variation coefficients were lower than 11% for all drugs. This simple and rapid method (run time<15 min) is currently used for poison management.

Impact of patient-related factors on asthma control.

Background. Patient-related factors are a significant component in the serious public health problem of poor asthma control, yet they have not been extensively studied. Aims. To gauge the impact of baseline patient characteristics, compliance and inhaler device manipulation on Asthma Control Score (ACS). Methods. ACS (between 0 and 9) was calculated from data recorded in a routine consultation in 4,362 patients with persistent asthma using a maintenance treatment with only inhaled corticosteroid and correlated with patient characteristics, compliance (using 2 methods) and critical errors in inhaler handling. Results. Mean ASC was 2.95 (95%CI: 2.88–3.02) and asthma control was unsatisfactory (i.e., ACS ≥ 4) in 41.1% of subjects, with higher proportions in smokers, non-compliant patients, and those misusing their device. Mean ACS tended to rise with age, and was higher in smokers than in non-smokers (+0.83 point) and ex-smokers (+0.49 point). More than 20% of all subjects were using their inhaler device incorrectly (Turbuhaler 37.1%; Metered-dose inhaler 28.1%; Diskus 21.3%; Aerolizer 7.4%) and this was associated with a 0.84-point increase in ACS. Mean ACS was lower in the most compliant patients (−0.74 points in the 13.4% with a perfect score on a compliance questionnaire) and much lower than in the least compliant (−1.84 points in the 6.6% who reported missing 4 or more doses per week). Conclusion. Patient-related factors including smoking, poor compliance and critical errors in device manipulation, have significant negative impact on asthma control. This could be addressed by patient education.

Prolonged Moderate Hyperoxia Induces Hyperresponsiveness and Airway Inflammation in Newborn Rats

Bronchopulmonary dysplasia is the most common cause of chronic pulmonary disease in premature infants. Airway inflammation appears to play a major pathogenetic role together with barotrauma and oxygen toxicity. The aim of the present study was to determine the effect of a 15-d exposure to moderate hyperoxia (Fio2, 50%) on airway reactivity and inflammatory response in neonatal and adult rats. We studied in isolated tracheal rings the 1) isometric contraction to cumulative concentrations of carbachol (10−8 to 10−3 M);2) epithelial, submucosal, smooth muscle, and connective tissue surface area; and 3) distribution of inflammatory cells (mastocytes, granulocytes, macrophages) by using MAb. Reactivity to carbachol was significantly increased in the hyperoxic pups, in which a 13% increase in tracheal smooth muscle surface area was observed. Type-I mast cells and macrophages (submucosa and connective tissue) and granulocytes (connective tissue) were increased in the neonatal hyperoxic group. Hyperoxia did not influence functional, morphometric, or cellular data in adult rats. In conclusion, exposure of newborn rats to moderate hyperoxia induces airway hyperresponsiveness and histologic changes similar to those reported in bronchopulmonary dysplasia. Hyperresponsiveness may be ascribed to an increase in smooth muscle related to the release of yet undetermined mediators by inflammatory cells infiltrating the airways. Lung immaturity definitely plays a role because similar alterations are not observed in adult rats.

Muscarinic Stimulation of Airway Smooth Muscle Cells

1. Acetylcholine, the principal neurotransmitter of the parasympathetic nervous system, is released at both ganglionic synapses and postganglionic neuroeffector junctions and acts by activation of nicotinic and muscarinic cholinoceptors. This review focuses on the effects of postjunctional muscarinic stimulation of airway smooth muscle. 2. On pharmacological criteria, four distinct subtypes of muscarinic cholinoceptor, denoted M1, M2, M3 and M4 receptors, have been identified by use of selective antagonists. Cloned muscarinic cholinoceptors are members of the family of GTP-binding protein-coupled receptors, which are characterized by seven transmembrane (TM) regions connected by intra- and extracellular loops. Between the fifth and the sixth TM regions, muscarinic receptors possess a large intracytoplasmic loop that is considered to be responsible for G-protein-coupling selectivity and exhibits high divergence between the different subtypes. 3. At the site of the smooth muscle itself, both binding and Northern blot studies have demonstrated, in a variety of species, that muscarinic receptor subtypes present are M2 and M3. M2 receptors are coupled to Gi proteins and adenylyl cyclase inhibition and thus to cAMP signaling. M3 receptors are coupled to Gq/11 protein and phosphoinositide hydrolysis and thus to calcium signaling. 4. Muscarinic-induced contraction of airway smooth muscle is mediated by M3 receptors. M2-mediated inhibition of adenylyl cyclase contributes to the prevention of bronchodilation. Cross-talk between muscarinic and beta2 adrenoceptors is likely to be present in airway smooth muscle. The pathophysiological role of this cross-talk requires further investigation.