Médicaments et allaitement: quelques éléments à considérer avant de les juger incompatibles [Drugs and breastfeeding: some facts to consider before deciding they are incompatible]

Breastfeeding is considered the ideal way of providing young infants with the required nutrients for healthy growth and development. An increase in the prevalence and duration of breastfeeding has been observed over the last years in response to promotion campaigns. When a medicamentous treatment is started, discontinuation of breastfeeding is often proposed, for fear of harmful consequences for the infant. Nevertheless such a decision is not unimportant, and it appears that many drugs can actually be used during breastfeeding without significant risk. An assessment of the real risk incurred by exposed children makes it possible to avoid unnecessary discontinuations of breastfeeding. This article aims to review the facts needed to assess amount of drug exposure to the child and to list the few drugs associated with significant effects on the nursing infant.

Reactions and enzymes in the metabolism of drugs and other xenobiotics.

In this article, we offer an overview of the compared quantitative importance of biotransformation reactions in the metabolism of drugs and other xenobiotics, based on a meta-analysis of current research interests. Also, we assess the relative significance the enzyme (super)families or categories catalysing these reactions. We put the facts unveiled by the analysis into a drug discovery context and draw some implications. The results confirm the primary role of cytochrome P450-catalysed oxidations and UDP-glucuronosyl-catalysed glucuronidations, but they also document the marked significance of several other reactions. Thus, there is a need for several drug discovery scientists to better grasp the variety of drug metabolism reactions and enzymes and their consequences.

On-line desorption of dried blood spots coupled to hydrophilic interaction/reversed-phase LC/MS/MS system for the simultaneous analysis of drugs and their polar metabolites.

An assay for the simultaneous analysis of pharmaceutical compounds and their metabolites from micro-whole blood samples (i.e. 5 microL) was developed using an on-line dried blood spot (on-line DBS) device coupled with hydrophilic interaction/reversed-phase (HILIC/RP) LC/MS/MS. Filter paper is directly integrated to the LC device using a homemade inox desorption cell. Without any sample pretreatment, analytes are desorbed from the paper towards an automated system of valves linking a zwitterionic-HILIC column to an RP C18 column. In the same run, the polar fraction is separated by the zwitterionic-HILIC column while the non-polar fraction is eluted on the RP C18. Both fractions are detected by IT-MS operating in full scan mode for the survey scan and in product ion mode for the dependant scan using an ESI source. The procedure was evaluated by the simultaneous qualitative analysis of four probes and their relative phase I and II metabolites spiked in whole blood. In addition, the method was successfully applied to the in vivo monitoring of buprenorphine metabolism after the administration of an intraperitoneal injection of 30 mg/kg on adult female Wistar rat.

New drugs and combinations for malignant glioma.

A new chemotherapy agent and a method for local delivery of carmustine have recently been approved for the treatment of malignant glioma. However, the increase in survival remains modest at best with only a very select patients currently benefiting truly of these treatments. Combination regimen of different alkylating agents or prior O6-alkyltransferase depletion by O6-benzylguanine or continuous temozolomide administration schedules have shown some indication for increased activity. There is preclinical rational for combining temozolomide with radiotherapy and the initial results of a phase II clinical trial were promising. Several new cytotoxic agents are currently in clinical trials in patients with recurrent glioma. More importantly, targeted therapy and antiangiogenic agents have entered the clinical development phase also for patients with glioblastoma and anaplastic astrocytoma. The optimal timing of administration of non-cytotoxic substances and their integration into the currently available treatments remains a challenge. Novel study designs and identification of surrogate markers are necessary in order to make rapid and clinically meaningful progress. This review summarises the currently available evidence of activity of the recently approved drugs against malignant glioma and mentions also agents which have failed to demonstrate a significant antitumour activity. Study endpoints are critically discussed. Combination regimens with other agents and radiation therapy are reviewed. The rational for using antiangiogenic drugs in selected ongoing trials is discussed.

Forensic intelligence framework-Part I: induction of a transversal model by comparing illicit drugs and false identity documents monitoring

Forensic intelligence is a distinct dimension of forensic science. Forensic intelligence processes have mostly been developed to address either a specific type of trace or a specific problem. Even though these empirical developments have led to successes, they are trace-specific in nature and contribute to the generation of silos which hamper the establishment of a more general and transversal model. Forensic intelligence has shown some important perspectives but more general developments are required to address persistent challenges. This will ensure the progress of the discipline as well as its widespread implementation in the future. This paper demonstrates that the description of forensic intelligence processes, their architectures, and the methods for building them can, at a certain level, be abstracted from the type of traces considered. A comparative analysis is made between two forensic intelligence approaches developed independently in Australia and in Europe regarding the monitoring of apparently very different kind of problems: illicit drugs and false identity documents. An inductive effort is pursued to identify similarities and to outline a general model. Besides breaking barriers between apparently separate fields of study in forensic science and intelligence, this transversal model would assist in defining forensic intelligence, its role and place in policing, and in identifying its contributions and limitations. The model will facilitate the paradigm shift from the current case-by-case reactive attitude towards a proactive approach by serving as a guideline for the use of forensic case data in an intelligence-led perspective. A follow-up article will specifically address issues related to comparison processes, decision points and organisational issues regarding forensic intelligence (part II).

Effects of antibacterial agents and drugs monitored by atomic force microscopy.

Originally invented for topographic imaging, atomic force microscopy (AFM) has evolved into a multifunctional biological toolkit, enabling to measure structural and functional details of cells and molecules. Its versatility and the large scope of information it can yield make it an invaluable tool in any biologically oriented laboratory, where researchers need to perform characterizations of living samples as well as single molecules in quasi-physiological conditions and with nanoscale resolution. In the last 20 years, AFM has revolutionized the characterization of microbial cells by allowing a better understanding of their cell wall and of the mechanism of action of drugs and by becoming itself a powerful diagnostic tool to study bacteria. Indeed, AFM is much more than a high-resolution microscopy technique. It can reconstruct force maps that can be used to explore the nanomechanical properties of microorganisms and probe at the same time the morphological and mechanical modifications induced by external stimuli. Furthermore it can be used to map chemical species or specific receptors with nanometric resolution directly on the membranes of living organisms. In summary, AFM offers new capabilities and a more in-depth insight in the structure and mechanics of biological specimens with an unrivaled spatial and force resolution. Its application to the study of bacteria is extremely significant since it has already delivered important information on the metabolism of these small microorganisms and, through new and exciting technical developments, will shed more light on the real-time interaction of antimicrobial agents and bacteria.

Differential involvement of peroxisome-proliferator-activated receptors alpha and delta in fibrate and fatty-acid-mediated inductions of the gene encoding liver fatty-acid-binding protein in the liver and the small intestine.

Liver fatty-acid-binding protein (L-FABP) is a cytoplasmic polypeptide that binds with strong affinity especially to long-chain fatty acids (LCFAs). It is highly expressed in both the liver and small intestine, where it is thought to have an essential role in the control of the cellular fatty acid (FA) flux. Because expression of the gene encoding L-FABP is increased by both fibrate hypolipidaemic drugs and LCFAs, it seems to be under the control of transcription factors, termed peroxisome-proliferator-activated receptors (PPARs), activated by fibrate or FAs. However, the precise molecular mechanism by which these regulations take place remain to be fully substantiated. Using transfection assays, we found that the different PPAR subtypes (alpha, gamma and delta) are able to mediate the up-regulation by FAs of the gene encoding L-FABP in vitro. Through analysis of LCFA- and fibrate-mediated effects on L-FABP mRNA levels in wild-type and PPARalpha-null mice, we have found that PPARalpha in the intestine does not constitute a dominant regulator of L-FABP gene expression, in contrast with what is known in the liver. Only the PPARdelta/alpha agonist GW2433 is able to up-regulate the gene encoding L-FABP in the intestine of PPARalpha-null mice. These findings demonstrate that PPARdelta can act as a fibrate/FA-activated receptor in tissues in which it is highly expressed and that L-FABP is a PPARdelta target gene in the small intestine. We propose that PPARdelta contributes to metabolic adaptation of the small intestine to changes in the lipid content of the diet.

A new neuropsychological instrument measuring effects of age and drugs on fitness to drive: development, reliability, and validity of MedDrive

Background: Current guidelines underline the limitations of existing instruments to assess fitness to drive and the poor adaptability of batteries of neuropsychological tests in primary care settings. Aims: To provide a free, reliable, transparent computer based instrument capable of detecting effects of age or drugs on visual processing and cognitive functions. Methods: Relying on systematic reviews of neuropsychological tests and driving performances, we conceived four new computed tasks measuring: visual processing (Task1), movement attention shift (Task2), executive response, alerting and orientation gain (Task3), and spatial memory (Task4). We then planned five studies to test MedDrive's reliability and validity. Study-1 defined instructions and learning functions collecting data from 105 senior drivers attending an automobile club course. Study-2 assessed concurrent validity for detecting minor cognitive impairment (MCI) against useful field of view (UFOV) on 120 new senior drivers. Study-3 collected data from 200 healthy drivers aged 20-90 to model age related normal cognitive decline. Study-4 measured MedDrive's reliability having 21 healthy volunteers repeat tests five times. Study-5 tested MedDrive's responsiveness to alcohol in a randomised, double-blinded, placebo, crossover, dose-response validation trial including 20 young healthy volunteers. Results: Instructions were well understood and accepted by all senior drivers. Measures of visual processing (Task1) showed better performances than the UFOV in detecting MCI (ROC 0.770 vs. 0.620; p=0.048). MedDrive was capable of explaining 43.4% of changes occurring with natural cognitive decline. In young healthy drivers, learning effects became negligible from the third session onwards for all tasks except for dual tasking (ICC=0.769). All measures except alerting and orientation gain were affected by blood alcohol concentrations. Finally, MedDrive was able to explain 29.3% of potential causes of swerving on the driving simulator. Discussion and conclusions: MedDrive reveals improved performances compared to existing computed neuropsychological tasks. It shows promising results both for clinical and research purposes.

Composition and cost of drugs stored at home by elderly patients.

BACKGROUND: Elderly people often have multiple chronic diseases, are frequently treated by several physicians, and also use over-the-counter medications. Excessive prescribing, imperfect therapeutic adherence, treatment modifications after hospitalization, and oversized drug packages result in home storage of leftover drugs, resulting in a waste of healthcare resources. PATIENTS AND METHODS: All patients aged >/=75 years hospitalized for >24 hours during a 6-month period in an urban teaching hospital in Switzerland were eligible for inclusion in a study collecting sociodemographics, medical, functional, and psychosocial characteristics. Six months later, a research nurse visited the patients at home and recorded the names, number of tablets, and expiration dates of all open or intact drug packages, and the doses actually taken. Acquisition costs of these drugs were computed. RESULTS: One hundred ninety-five patients were included (127 women; mean age 82.2 +/- 4.8 y, range 75-96). They had a total of 2059 drugs (mean per patient 10.3 +/- 6.7, range per patient 1-42), corresponding to a total cost of (US) $62 826 (mean per patient 322 +/- 275, range per patient 10-1571). Self-reported drug intake was regular for 36% of the drugs (46.5% of total costs) and occasional for 11% (6.1%), whereas 35.7% (30.1%) had been stopped during the last month. Cardiovascular drugs amounted to 36.6% of the drugs and 55.5% of the costs. None of the patients' characteristics was significantly associated with a greater number of drugs and higher costs. CONCLUSIONS: Drugs stored at home by elderly patients were worth about $320 per patient. Only about one-third of these drugs were regularly taken. In the context of resources shortage, innovative solutions should be found to reduce the waste linked with drugs stopped in previous months.

Drugs, schizotypy and cognition: Cognitive attenuations seem more consistently associated with substance use than schizotypal symptoms

Psychosis is a debilitating disease, causing harm to the individual and society. Since early detection of the disease is associated with a more benign course, factors are warranted that enable the early detection of psychosis. In the present thesis we will be focusing on two potential risk factors, namely schizotypy and drug use. The schizotypy concept, originally developed by Meehl (1962), states that schizophrenia symptoms exist on a spectrum, with symptoms ranging from the most severe in patients with schizophrenia to the least affected individual in the general population. Along the schizophrenia spectrum cognitive impairments are commonly found, for instance reduced hemispheric asymmetry or frontal lobe functions. The second risk factor (drug use), affects similar cognitive functions as those attenuated along the schizophrenia spectrum, and drug use is elevated in schizophrenia and people scoring high on schizotypy. Therefore, we set out to investigate whether cognitive attenuations formerly allocated to schizotypal symptoms could have been influenced by elevated substance use in this population. To test this idea, we assessed various drugs (nicotine, cannabis, mephedrone, general substance dependence) and schizotypy symptoms (O-LIFE), and measured either hemispheric asymmetry of function (left hemisphere dominance for language, and right hemisphere dominance for facial processing) or functions largely relying on the frontal lobes (such as cognitive flexibility, working memory, verbal short-term memory, verbal learning and verbal fluency). Results of all studies suggest that it is mostly drugs, and not schizotypy in general that predict cognitive functioning. Therefore, cognitive attenuations subscribed to schizotypy dimensions are likely to have been affected by enhanced drug use. Future studies should extend the list of potential risk factors (e.g. depression and IQ) to acquire a comprehensive overview of the most reliable predictors of disadvantageous cognitive profiles.

Binding of amitriptyline to alpha 1-acid glycoprotein and its variants.

Binding studies have been performed between amitriptyline and i) native alpha 1-acid glycoprotein (AAG); ii) its desialylated form; iii) its two variants, S-AAG and F-AAG; and iv) a mixture of S-AAG and F-AAG. Scatchard analysis revealed the presence of two classes of binding sites on AAG. For native AAG, the first class (of high affinity) has an association constant (Ka1) of 1.5 x 10(6) L mol-1 and a number of binding sites per mole of protein (n1) of 0.25, while the second class (of low affinity) has a Ka2 of 3.2 x 10(4) L mol-1 and a n2 of 0.94. Similar data were found for desialylated AAG. S-AAG and F-AAG do not differ in their association constants measured with amitriptyline, but in their number of binding sites per mole of protein (n): S-AAG: n1 = 0.56, n2 = 0.52; F-AAG: n1 = 0.17, n2 = 0.71. These results confirm those of a previous study, in which a higher affinity of S-AAG towards various basic drugs in comparison with F-AAG has been found.

Prediction of infant drug exposure through breastfeeding: population PK modeling and simulation of fluoxetine

BACKGROUND: Risks of significant infant drug exposurethrough breastmilk are poorly defined for many drugs, and largescalepopulation data are lacking. We used population pharmacokinetics(PK) modeling to predict fluoxetine exposure levels ofinfants via mother's milk in a simulated population of 1000 motherinfantpairs.METHODS: Using our original data on fluoxetine PK of 25breastfeeding women, a population PK model was developed withNONMEM and parameters, including milk concentrations, wereestimated. An exponential distribution model was used to account forindividual variation. Simulation random and distribution-constrainedassignment of doses, dosing time, feeding intervals and milk volumewas conducted to generate 1000 mother-infant pairs with characteristicssuch as the steady-state serum concentrations (Css) and infantdose relative to the maternal weight-adjusted dose (relative infantdose: RID). Full bioavailability and a conservative point estimate of1-month-old infant CYP2D6 activity to be 20% of the adult value(adjusted by weigth) according to a recent study, were assumed forinfant Css calculations.RESULTS: A linear 2-compartment model was selected as thebest model. Derived parameters, including milk-to-plasma ratios(mean: 0.66; SD: 0.34; range, 0 - 1.1) were consistent with the valuesreported in the literature. The estimated RID was below 10% in >95%of infants. The model predicted median infant-mother Css ratio was0.096 (range 0.035 - 0.25); literature reported mean was 0.07 (range0-0.59). Moreover, the predicted incidence of infant-mother Css ratioof >0.2 was less than 1%.CONCLUSION: Our in silico model prediction is consistent withclinical observations, suggesting that substantial systemic fluoxetineexposure in infants through human milk is rare, but further analysisshould include active metabolites. Our approach may be valid forother drugs. [supported by CIHR and Swiss National Science Foundation(SNSF)]

In vitro compatibility of remifentanil hydrochloride and sufentanil citrate with selected drugs

: Objectives Physicochemical incompatibilities between intravenous drugs are a recurrent problem in intensive care units. The present study was aimed at investigating the physical compatibility of remifentanil and sufentanil with other drugs (insulin, midazolam, propofol, potassium chloride, magnesium sulfate, furosemide, heparin, monobasic potassium phosphate) that are frequently administered together intravenously. In addition, the physicochemical compatibility of three common associations of drugs was evaluated in glass tube tests and during dynamic simulated Y site administrations (remifentanil-insulin-midazolam; remifentanil-insulin-propofol; sufentanil-insulin-midazolam). Methods Physical compatibility was verified by visual inspection of the various mixtures (two, three or four drugs) in glass tubes and by pH determination of the mixtures collected during simulated Y site administrations. Solutions were considered as compatible in the absence of any visual change in the solution and of any significant variation in pH value. In addition, chemical stability was checked during in vitro dynamic simulations. The solutions were prepared in 50 ml syringes, placed on syringe pumps and connected to a Swan-Ganz catheter; the liquid collected at the tip was assayed by high performance liquid chromatography. Results In the visual examinations, only the associations of remifentanil and furosemide were incompatible. The three assayed associations were compatible in the tested proportion range over 24 h. Conclusions Remifentanil was physically compatible with the tested drugs, except for furosemide (Lasix; Sanofi-Aventis, 250 mg/25 ml) and physicochemically compatible with insulin and midazolam and insulin and propofol. Sufentanil was physically compatible with all tested drugs and physicochemically compatible with insulin and midazolam

Peroxisome proliferator-activated receptors and lipid metabolism.

PPARs are nuclear hormone receptors which, like the retinoid, thyroid hormone, vitamin D, and steroid hormone receptors, are ligand-activated transcription factors mediating the hormonal control of gene expression. Two lines of evidence indicate that PPARs have an important function in fatty acid metabolism. First, PPARs are activated by hypolipidemic drugs and physiological concentrations of fatty acids, and second, PPARs control the peroxisomal beta-oxidation pathway of fatty acids through transcriptional induction of the gene encoding the acyl-CoA oxidase (ACO), which is the rate-limiting enzyme of the pathway. Furthermore, the PPAR signaling pathway appears to converge with the 9-cis retinoic acid receptor (RXR) signaling pathway in the regulation of the ACO gene because heterodimerization between PPAR and RXR is essential for in vitro binding to the PPRE and because the strongest stimulation of this gene is observed when both receptors are exposed simultaneously to their activators. Thus, it appears that PPARs are involved in the 9-cis retinoic acid signaling pathway and that they play a pivotal role in the hormonal control of lipid metabolism.