Nicolas Simon

Bio: Nicolas Simon is an academic researcher from Aix-Marseille University. The author has contributed to research in topics: Population & Pharmacokinetics. The author has an hindex of 31, co-authored 158 publications receiving 2612 citations. Previous affiliations of Nicolas Simon include University of the Mediterranean.

Vancomycin: a review of population pharmacokinetic analyses.

Abstract: Despite nearly five decades of clinical use, vancomycin has retained a significant and uncontested niche in the antibacterial arsenal because of its consistent activity against almost all Gram-positive bacteria. Nevertheless, major vancomycin toxicities have been reported in the literature - in particular, nephrotoxicity and ototoxicity. Vancomycin pharmacokinetics have been described in numerous studies for 25 years. This review presents a synthesis of the reported population pharmacokinetic models of vancomycin. The objective was to determine if there was a consensus on a structural model and which covariates were identified. A literature search was conducted from the PubMed database, from its inception through December 2010, using the following terms: 'vancomycin', 'pharmacokinetic(s)', 'population', 'model(ling)' and 'nonlinear mixed effect'. Articles were excluded if they were not pertinent. The reference lists of all selected articles were also evaluated. Twenty-five articles were included in this review: 15 models concerned paediatric patients and ten models were conducted in adults. In neonates and infants, the pharmacokinetics of vancomycin were mainly described by a one-compartment model, whereas in adults, a two-compartment model was preferentially used. Various covariates were tested but only three (age, creatinine clearance [CL(CR)] and body weight) were included in almost all of the described models. After inclusion of these covariates, the mean (range) values of the interindividual variability in the clearance and volume of distribution were 30% (15.6-45%) and 23% (12.6-48%), respectively. The mean (range) value of the residual variability was 20% (7-39.6%). This review highlights the numerous population pharmacokinetic models of vancomycin developed in recent decades and concludes with relevant information for clinicians and researchers. To optimize vancomycin dosage, this review points out the relevant covariates according to the target population. In adults, dosage optimization depends on CL(CR) and body weight, while in children, it depends on age, body weight and CL(CR). For future population pharmacokinetic studies, a sensitive liquid chromatography-tandem mass spectrometry method could be used and new covariates such as cardiac output or possible renal transporters could be tested. Finally, we suggest that external evaluation should be the first step in a pharmacokinetic analysis of vancomycin rather than describing a new model.

Off-Label Prescribing of Antipsychotics in Adults, Children and Elderly Individuals: A Systematic Review of Recent Prescription Trends.

Abstract: Introduction: New antipsychotics continuously arrive on the market, which thereby influences the approved and off-label prescribing (OLP) schemes. We aimed to identify the recent trends in the OLP of antipsychotics. We conducted a literature review based on three different populations: adult, pediatric, and elderly patients. Methods: A literature search was performed in the PubMed and ScienceDirect databases using the following keyword algorithm: “offlabel” AND (“antipsychotic*” OR “neuroleptic*”). The period investigated ranged from January 2000 to January 2015. Only Englishwritten pharmacoepidemiological studies were included. Results: Seventy-seven relevant results were identified. Among adults, OLP consisted of 40 to 75% of all antipsychotic prescriptions. The main indications were mood disorders, anxiety disorders, insomnia and agitation. Quetiapine was the most frequently prescribed offlabel antipsychotic, especially for anxiety and insomnia. Among children, OLP was estimated between 36 and 93.2% of all antipsychotic prescriptions. Risperidone and aripiprazole were primarily used and were most often prescribed for attention deficit hyperactivity disorder, anxiety, or mood disorders. Among elderly individuals, OLP consisted of 22 to 86% of all antipsychotic prescriptions. Antipsychotic OLP was particularly frequent for agitation; however, a recent decrease in this OLP was identified. Discussion: Antipsychotics have largely been prescribed off-label in recent years. The types of antipsychotic OLP practices differ according to the age category of patients. OLP is often used in cases of therapeutic dead-ends or for specific disorders with few or no currently approved medications. However, other OLP practices only reflect temporary prescription trends for mild symptoms, which may induce safety concerns.

Vemurafenib for Refractory Multisystem Langerhans Cell Histiocytosis in Children: An International Observational Study

Abstract: PURPOSEOff-label use of vemurafenib (VMF) to treat BRAFV600E mutation–positive, refractory, childhood Langerhans cell histiocytosis (LCH) was evaluated.PATIENTS AND METHODSFifty-four patients from ...

Biologic rhythms and Parkinson's disease: a chronopharmacologic approach to considering fluctuations in function.

Abstract: The existence of circadian rhythms and their implication in many pathologic processes have been underlined in several diseases but have not been evaluated in Parkinson's disease. The aim of this paper is to review diurnal variations of clinical, biologic, or experimental factors described with Parkinson's disease. Clinical data often report daily fluctuations of motor activity pattern, but the effect of the stage of the disease and the respective roles of drugs are difficult to evaluate. Sleep disturbances in Parkinson's disease patients also reveal alterations of circadian rhythms. Autonomic dysfunction, described in Parkinson's disease, reveals numerous alterations in circadian regulations including loss of circadian rhythm of blood pressure, increased diurnal blood pressure variability, and postprandial hypotension. Many biologic indices such as cortisol, catecholamines, and melatonin are also altered. Circadian rhythms in dopaminergic systems as well as possible daily fluctuations in kinetics of drug treatments are likely involved in such variations. Few clinical studies have been devoted to circadian patterns of drug response. As for other diseases where biologic rhythms are concerned Parkinson's disease therapy may be influenced by further understanding of circadian influence.

Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury

Abstract: Acute kidney injury (AKI) is a complex disorder for which currently there is no accepted definition. Having a uniform standard for diagnosing and classifying AKI would enhance our ability to manage these patients. Future clinical and translational research in AKI will require collaborative networks of investigators drawn from various disciplines, dissemination of information via multidisciplinary joint conferences and publications, and improved translation of knowledge from pre-clinical research. We describe an initiative to develop uniform standards for defining and classifying AKI and to establish a forum for multidisciplinary interaction to improve care for patients with or at risk for AKI. Members representing key societies in critical care and nephrology along with additional experts in adult and pediatric AKI participated in a two day conference in Amsterdam, The Netherlands, in September 2005 and were assigned to one of three workgroups. Each group's discussions formed the basis for draft recommendations that were later refined and improved during discussion with the larger group. Dissenting opinions were also noted. The final draft recommendations were circulated to all participants and subsequently agreed upon as the consensus recommendations for this report. Participating societies endorsed the recommendations and agreed to help disseminate the results. The term AKI is proposed to represent the entire spectrum of acute renal failure. Diagnostic criteria for AKI are proposed based on acute alterations in serum creatinine or urine output. A staging system for AKI which reflects quantitative changes in serum creatinine and urine output has been developed. We describe the formation of a multidisciplinary collaborative network focused on AKI. We have proposed uniform standards for diagnosing and classifying AKI which will need to be validated in future studies. The Acute Kidney Injury Network offers a mechanism for proceeding with efforts to improve patient outcomes.

The Pharmacological Basis of Therapeutics

Abstract: The Pharmacological Basis of Therapeutics A Textbook of Pharmacology, Toxicology and Therapeutics for Physicians and Medical Students. By Prof. Louis Goodman and Prof. Alfred Gilman. Pp. xiii + 1383. (New York: The Macmillan Company, 1941.) 50s. net.

The Self-medication Hypothesis of Substance Use Disorders: A Reconsideration and Recent Applications

Abstract: The self-medication hypothesis of addictive disorders derives primarily from clinical observations of patients with substance use disorders. Individuals discover that the specific actions or effects of each class of drugs relieve or change a range of painful affect states. Self-medication factors occur in a context of self-regulation vulnerabilities--primarily difficulties in regulating affects, self-esteem, relationships, and self-care. Persons with substance use disorders suffer in the extreme with their feelings, either being overwhelmed with painful affects or seeming not to feel their emotions at all. Substances of abuse help such individuals to relieve painful affects or to experience or control emotions when they are absent or confusing. Diagnostic studies provide evidence that variously supports and fails to support a self-medication hypothesis of addictive disorders. The cause-consequence controversy involving psychopathology and substance use/abuse is reviewed and critiqued. In contrast, clinical observations and empirical studies that focus on painful affects and subjective states of distress more consistently suggest that such states of suffering are important psychological determinants in using, becoming dependent upon, and relapsing to addictive substances. Subjective states of distress and suffering involved in motives to self-medicate with substances of abuse are considered with respect to nicotine dependence and to schizophrenia and posttraumatic stress disorder comorbid with a substance use disorder.

Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation

Abstract: Background: A substantial proportion of patients receiving fibrinolytic therapy for myocardial infarction with ST-segment elevation have inadequate reperfusion or reocclusion of the infarct-related artery, leading to an increased risk of complications and death. Methods: We enrolled 3491 patients, 18 to 75 years of age, who presented within 12 hours after the onset of an ST-elevation myocardial infarction and randomly assigned them to receive clopidogrel 8300-mg loading dose, followed by 75 mg once daily) or placebo. Patients received a fibrinolytic agent, aspirin, and when appropriate, heparin (dispensed according to body weight) and were echeduled to undergo angiography 48 to 192 hours after the start of study medication. The primary efficacy end point was a composite of an ocluded infarct-related artery (defined by a Thrombolysus in Myocardial Infarction flow grade of 0 or 1) on angiography or death or recurrent myocardial infarction before angiography. Results: The rates of the primary efficacy end point were 21.7 percent in the placebo group and 15.0 percent in the clopidogrel group, representing an absolute reduction of 6.7 percentage points in the rate and a 36 percent reduction in the odds of the end point with clopidogrel therapy (95 percent confidence interval, 24 to 47 percent; P<0.001). By 30 days, clopidogrel therapy reduced the odds ol the composite end point of death from cardiovascular causes, recurrent myocardial infarction, or recurrent ischemia leading to the need for urgent revascularization by 20 percent (from 14.1 to 11.6 percent, P=0.03). The rates of major bleeding and intracranial hemorrhage were similar in the two groups. Conclusions: In patients 75 years of age or younger who have myocardial infarction with ST-segment elevation and who receive aspirin and a standard fibrinolytic regimen, the addition of clopidogrel improves the patency rate of the infarct-related artery and reduces ischemic complications.

Calcineurin Inhibitor Nephrotoxicity

Abstract: The use of the calcineurin inhibitors cyclosporine and tacrolimus led to major advances in the field of transplantation, with excellent short-term outcome. However, the chronic nephrotoxicity of these drugs is the Achilles' heel of current immunosuppressive regimens. In this review, the authors summarize the clinical features and histologic appearance of both acute and chronic calcineurin inhibitor nephrotoxicity in renal and nonrenal transplantation, together with the pitfalls in its diagnosis. The authors also review the available literature on the physiologic and molecular mechanisms underlying acute and chronic calcineurin inhibitor nephrotoxicity, and demonstrate that its development is related to both reversible alterations and irreversible damage to all compartments of the kidneys, including glomeruli, arterioles, and tubulo-interstitium. The main question--whether nephrotoxicity is secondary to the actions of cyclosporine and tacrolimus on the calcineurin-NFAT pathway--remains largely unanswered. The authors critically review the current evidence relating systemic blood levels of cyclosporine and tacrolimus to calcineurin inhibitor nephrotoxicity, and summarize the data suggesting that local exposure to cyclosporine or tacrolimus could be more important than systemic exposure. Finally, other local susceptibility factors for calcineurin inhibitor nephrotoxicity are reviewed, including variability in P-glycoprotein and CYP3A4/5 expression or activity, older kidney age, salt depletion, the use of nonsteroidal anti-inflammatory drugs, and genetic polymorphisms in genes like TGF-beta and ACE. Better insight into the mechanisms underlying calcineurin inhibitor nephrotoxicity might pave the way toward more targeted therapy or prevention of calcineurin inhibitor nephrotoxicity.