Philippe Collart

In vitro inhibition of human liver drug metabolizing enzymes by second generation antihistamines

Cetirizine, terfenadine, loratadine, astemizole and mizolastine were compared for their ability to inhibit marker activities for CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and for some glucuronidation isoenzymes in human liver microsomes. The most pronounced effects were observed with terfenadine, astemizole and loratadine which inhibited CYP3A4-mediated testosterone 6beta-hydroxylation (IC50 of 23, 21 and 32 microM, respectively) and CYP2D6-mediated dextromethorphan O-demethylation (IC50 of 18, 36 and 15 microM, respectively). In addition, loratadine markedly inhibited the CYP2C19 marker activity, (S)-mephenytoin 4-hydroxylation (Ki of 0.17 microM). Furthermore, loratadine activated the CYP2C9-catalyzed tolbutamide hydroxylation (ca. 3-fold increase at 30 microM) and inhibited some glucuronidation enzymes. Mizolastine appeared to be a relatively weak and unspecific inhibitor of CYP2E1, CYP2C9, CYP2D6 and CYP3A4 (IC50Ss in the 100 micromolar range). Cetirizine demonstrated no effect on the investigated activities. A comparison of the inhibitory potencies of cetirizine, terfenadine, loratidine, astemizole and mizolastine with their corresponding plasma concentrations in humans suggests that these antihistamines are not likely to interfere with the metabolic clearance of coadministered drugs, with the exception of loratidine, which appears to inhibit CYP2C19 with sufficient potency to warrant additional investigation.

Gender differences in acute myocardial infarction, twenty-five years registration.

BACKGROUND/OBJECTIVES The French-speaking Community of Belgium has set up a register of ischaemic cardiopathies (1983-2007). The aim consists in analyzing the evolution of fatal and non-fatal acute coronary events rates as well as the 28 days case fatality on a 25-year period and examine sex differences in lethality. METHODS This register assures a standardized procedure according to the MONICA criteria. For each period, we present attack rates and trends analysis. Hospital lethality takes again in-patients and community lethality is calculated starting from all the cases. RESULTS The total attack rate is rather stable between 1983 and 2007 for women (from 12 to 19 per 10,000 residents). For men, there is a distinct decline of the total attack rate since 1991 till 1993 (63 to 43 per 10,000 residents). We systematically observe a reduction in risk between men and women according to the age. For each 5-year period, this risk decreases significantly with age and this difference is strongest during the periods 1993-1997 and 1998-2002. The analysis shows also a significant decline in lethality between the 1983-1987 and 1993-1997 periods. Among women, lethality is systematically higher than in men in spite of the presence or the absence of antecedents of myocardial infarction. CONCLUSIONS Favourable evolutions in the attack rates of acute coronary events in the study population appear clearly on the 25-year period of observation. The whole lethality rates decreased during the first 15 years of the register; after that, it stabilized.

4-Benzyl-1H-imidazoles with Oxazoline Termini as Histamine H3 Receptor Agonists

Research on the therapeutic applications of the histamine H3 receptor (H3R) has traditionally focused on antagonists/inverse agonists. In contrast, H3R agonists have received less attention despite their potential use in several disease areas. The lower availability of H3R agonists not only hampers their full therapeutic exploration, it also prevents an unequivocal understanding of the structural requirements for H3R activation. In the light of these important issues, we present our findings on 4-benzyl-1H-imidazole-based H3R agonists. Starting from two high throughput screen hits (10 and 11), the benzyl side chain was altered with lipophilic groups using combinatorial and classical chemical approaches (compounds 12-31). Alkyne- or oxazolino-substituents gave excellent affinities and agonist activities up to the single digit nM range. Our findings further substantiate the growing notion that basic ligand sidechains are not necessary for H 3R activation and reveal the oxazolino group as a hitherto unexplored functional group in H3R research.

Air pollution and ST-elevation myocardial infarction: A case-crossover study of the Belgian STEMI registry 2009–2013

BACKGROUND Previous studies have shown that air pollution particulate matter (PM) is associated with an increased risk for myocardial infarction. The effects of air pollution on the risk of ST-elevation myocardial infarction (STEMI), in particular the role of gaseous air pollutants such as NO2 and O3 and the susceptibility of specific populations, are still under debate. METHODS All patients entered in the Belgian prospective STEMI registry between 2009 and 2013 were included. Based on a validated spatial interpolation model from the Belgian Environment Agency, a national index was used to address the background level of air pollution exposure of Belgian population. A time-stratified and temperature-matched case-crossover analysis of the risk of STEMI was performed. RESULTS A total of 11,428 STEMI patients were included in the study. Each 10μg/m3 increase in PM10, PM2.5 and NO2 was associated with an increased odds ratio (ORs) of STEMI of 1.026 (CI 95%: 1.005-1.048), 1.028 (CI 95%: 1.003-1.054) and 1.051 (CI 95%: 1.018-1.084), respectively. No effect of O3 was found. STEMI was associated with PM10 exposure in patients ≥75y.o. (OR: 1.046, CI 95%: 1.002-1.092) and with NO2 in patients ≤54y.o. (OR: 1.071, CI 95%: 1.010-1.136). No effect of air pollution on cardiac arrest or in-hospital STEMI mortality was found. CONCLUSION PM2.5 and NO2 exposures incrementally increase the risk of STEMI. The risk related to PM appears to be greater in the elderly, while younger patients appear to be more susceptible to NO2 exposure.

Discovery of a new class of non-imidazole oxazoline-based histamine H(3) receptor (H(3)R) inverse agonists

H3R inverse agonists based on an aminopropoxy‐phenyloxazoline framework constitute highly valuable druglike lead compounds that display efficacy in a mouse model of recognition memory.

Day-of-the-week variations in myocardial infarction onset over a 27-year period: the importance of age and other risk factors.

INTRODUCTION The aim of this study was to analyze the day-of-the-week variations of acute myocardial infarction (AMI) over a 27-year period. The effects of sex, age, history of AMI, hypertension, fatality, and temporal changes over the 27-year period were also investigated. METHODS The Charleroi register of ischemic cardiopathies is the oldest register of infarctions in the French-speaking community of Belgium and is one of the very rare registers that can track trends over 27 years. The analyses presented in our study relate only to patients in the 25- to 69-year age range over time from 1983 to 2009. The χ2 test for goodness of fit was used to test the difference among the frequencies of AMI events over 7 days during the week. RESULTS Data from 9732 cases of AMI were analyzed. Overall, there was a significant day-of-the-week variation (P<.001), with an excess of AMI observed on Mondays (n=1495) and a minimum on Saturdays (n=1259), corresponding to a relative increase in AMI of 18.2% over the 2 days. The Monday peak is more pronounced for the 35- to 44-year (P=.045) age bracket than for the 45- to 54-year (P=.27) and the 55- to 64-year (P=.032) brackets. The cases with (n=2713) and without (n=4931) arterial hypertension exhibited the same day-of-the-week variation. In contrast, the cases with antecedent AMI (n=1888) exhibited a less pronounced excess of MI incidence on Mondays compared with the cases without antecedent (n=5970). CONCLUSIONS The present study demonstrates that there is a marked incidence peak in AMI on Mondays. This peak is similar for men and women but varies according to age. The Monday peak is not observed in subjects previously admitted for AMI or in fatal cases. The organization of the emergency medical services could take into account the day-of-the-week pattern of AMI to adapt emergency medical service capacity to needs.

Comparison of four case-crossover study designs to analyze the association between air pollution exposure and acute myocardial infarction

The case-crossover design is frequently used for analyzing the acute health effects of air pollution. Nevertheless, only a few studies compared different methods for selecting control periods. In this study, the bidirectional method and three time-stratified methods were used to estimate the association between air pollution and acute myocardial infarction (AMI) in Charleroi, Belgium, during 1999–2008. The strongest associations between air pollution and AMI were observed for PM10 and NO2 during the warm period, OR = 1.095 (95 % CI: 1.003–1.169) and OR = 1.120 (95 % CI: 1.001–1.255), respectively. The results of this study reinforce the evidence of the acute effects of air pollution on AMI, especially during the warm season. This study suggests that the different methods of case-crossover study design are suitable to studying the association between acute events and air pollution. The temperature-stratified design is useful to exclude temperature as a potential confounder.

Trends in acute myocardial infarction treatment between 1998 and 2007 in a Belgian area (Charleroi)

Background/objectives: To describe the evolution of the therapeutic practices over 10 years of follow-up of acute myocardial infarction (AMI) in Charleroi and to analyse the factors influencing the choice of treatments and the mortality of these patients. Methods: The Charleroi register of ischaemic cardiopathies is the oldest register of infarctions in the French-speaking community of Belgium and is one of the very rare registers that allows identifying tendencies over 25 years. Analyses presented hereafter relate only patients in the 25–69-year age range over time from 1998 to 2007. The data were analysed in five periods of 2 years. Treatment evolutions over time were analysed using chi-squared tests for trend and logistic regression analyses identify factors influencing the type of treatment. Results: The present study shows a marked increase in the utilization of percutaneous transluminal coronary angioplasty (PTCA) between 1998–1999 and 2006–2007. The use of thrombolytic agents on approximately one-third of the patients treated remained fairly stable between 1998 and 2007. A lower proportion of patients with a history of AMI received thrombolytic agents. Thrombolysis seems beneficial for men and without effect for women. The use of β-blockers continued to increase until the 2000–2001 period and remained fairly stable for the two following periods. 42% of patients were administered three medications (angiotensin-converting enzyme inhibitors, antiplatelet drugs, and β-blockers). Association of PTCA with antiplatelet drugs, β-blockers, and thrombolysis was observed for 58.7, 50.6, and 25.7%, respectively. These associations were still observed after adjustment for gender, age, and comorbidity. The factors associated with fatality were specifically old-aged patients, antecedents of diabetes, hypercholesterolaemia and oral antiplatelet drugs, and β-blockers therapies and PTCA. Conclusions: The evolution of the therapeutic data on AMI in this register confirms the use and the efficacy of thrombolytic therapy. PTCA becomes the main coronary reperfusion treatment with less risk of bleeding. Angiotensin-converting enzyme inhibitors were without effect on mortality.

Effets de la pollution particulaire sur le risque de maladies cardiovasculaires

The effects of air pollution on health are quite well-documented and the influence of particulate pollution on morbidity and mortality from myocardial infarction and stroke is increasingly evident. The objective of this literature review is to identify and synthesize articles on the impact of air pollution by PM10 and PM2.5 of myocardial infarction and stroke. A total of 14 studies were reported on the effects of PM10 and five on the effects of PM2.5. Nine out of 14 studies for PM10 and two studies of five for PM2.5 have found a significant association with myocardial infarction and/or stroke. Particle composition according to location, study period and population must be considered in interpreting the results on the health effects of air pollution. The integration of these elements is important for decision making in tune with social and economic conditions specific to each environment.

Discovery of selective alpha(2C) adrenergic receptor agonists.

Neuropathic pain has recently been defined by the International Association for the Study of Pain (IASP) as “pain caused by a lesion or disease of the somatosensory system”. Neuropathic pain is chronic and may involve the central nervous system (CNS) (e. g. , stroke-related pain), as well as the peripheral nervous system (e. g. , trauma, resection, infection or progressive degeneration of a peripheral nerve). Examples of neuropathic pain include diabetic painful neuropathy, post-herpetic neuralgia, trigeminal neuralgia, cancerand HIV-related neuropathic pain, and iatrogenic neuropathic pain, associated with postsurgical neuropathy and neuropathies induced by cancer chemotherapy or antiretroviral drugs. Currently marketed drugs treating neuropathic pain are not optimal since they alleviate pain in only about 50 % of patients, making the treatment of neuropathic pain an unmet medical need. 4] Anti-epileptic drugs, such as gabapentin (Neurontin) and pregabalin (Lyrica), are the most commonly prescribed treatment. Delineating the specific role of different neurotransmitter–receptor systems in conducting pain messages has been the subject of intense research efforts. In particular, monoaminergic neurotransmitters, including serotonin, dopamine and noradrenaline (NA), are considered as mechanistic targets for pain. For instance, Tanabe and co-workers have provided evidence that gabapentin is characterized by a supraspinal site of action, in which central NA is involved. Their results indicate that gabapentin acts on supraspinal structures to activate the descending noradrenergic system. This terminates in the lumbar spinal cord, where NA interacts with a2 adrenergic receptors (ARs) to reduce the transmission of nociceptive information. The role of the noradrenergic system in pain mechanisms was confirmed when the drug clonidine (1), an a2-AR agonist and initially designed to reduce blood pressure in patients with essential hypertension, demonstrated marked anesthetic and analgesic properties. Clonidine became the first drug to be approved by the US Food and Drug Administration (FDA) for the treatment of cancer-related neuropathic pain as a substitute for opioids in patients suffering from excessive tolerance-related side effects. However, clonidine produces clinically relevant, dose-limiting adverse effects, such as arterial hypotension and sedation, that negatively impact its use, which, in cancer neuropathy, is limited to spinal infusion. The neurotransmitter NA acts through several ARs, including a2-ARs belonging to the seven-transmembrane G protein-coupled receptors (GPCRs). The a2-ARs are subdivided into a2A/D, a2B and a2C subtypes, [9–11] where a2A/D-AR is a global nomenclature for the human a2Aand murine a2D-AR orthologues. [12]