Pascale Jolliet
University of Nantes, Pharmacology, Faculty Member
Interferon beta-1a is available as an immunomodulating agent for relapsing forms of multiple sclerosis. Common side effects include flu-like symptoms, asthenia, anorexia, and administration site reaction. Kidney disorders are rarely... more
Interferon beta-1a is available as an immunomodulating agent for relapsing forms of multiple sclerosis. Common side effects include flu-like symptoms, asthenia, anorexia, and administration site reaction. Kidney disorders are rarely reported. In this study we describe the case of a woman who has been undergoing treatment with interferon beta-1a for multiple sclerosis for 5 years. She developed a hemolytic-uremic syndrome with intravascular hemolysis in a context of severe hypertension. A kidney biopsy showed a thrombotic microangiopathy. This observation highlights an uncommon side effect of long-term interferon beta-1a therapy. Pathophysiological mechanisms leading to this complication might be explained by the antiangiogenic activity of interferon.
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The influence of saquinavir hard-gel capsules on lopinavir pharmacokinetic parameters was investigated using a population approach. Forty-nine patients infected with human immunodeficiency virus type 1 and treated with... more
The influence of saquinavir hard-gel capsules on lopinavir pharmacokinetic parameters was investigated using a population approach. Forty-nine patients infected with human immunodeficiency virus type 1 and treated with lopinavir/ritonavir, nucleoside/nucleotide reverse transcriptase inhibitors plus saquinavir (group A), and 118 patients treated with lopinavir/ritonavir plus nucleoside/nucleotide reverse transcriptase inhibitors (group B) were included in the study. No significant relationship was established between the presence or the daily dosage of saquinavir in the treatment and lopinavir population pharmacokinetic parameters. The values (mean+/-standard deviation) of the individual apparent clearance (5.0+/-1.8 vs. 5.0+/-3.2 L/h), volume of distribution (66.6+/-1.6 vs. 66.8+/-1.9 L), absorption rate constant (0.37+/-0.01 vs. 0.37+/-0.03 hours), and trough plasma concentration (5.5+/-2.3 vs. 5.3+/-1.9 mg/L) of lopinavir are not significantly different between groups A and B. This lack of influence of saquinavir on lopinavir pharmacokinetics makes the use of this combination in salvage therapy easier.
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A global method is proposed for therapeutic drug monitoring of atazanavir, a novel protease inhibitor and of all other protease inhibitors (PI) and non nucleoside reverse transcriptase inhibitors (NNRTI) which are currently used to treat... more
A global method is proposed for therapeutic drug monitoring of atazanavir, a novel protease inhibitor and of all other protease inhibitors (PI) and non nucleoside reverse transcriptase inhibitors (NNRTI) which are currently used to treat HIV patients. All drugs are extracted after a liquid–liquid extraction and separated on a C18 column with a binary gradient elution except lopinavir which is
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A simple HPLC assay to determine plasma concentration of tipranavir is presented. A liquid/liquid extraction of the drugs in ethyl acetate/hexane from 250μL of plasma is followed by a reversed phase isocratic HPLC assay with UV detection... more
A simple HPLC assay to determine plasma concentration of tipranavir is presented. A liquid/liquid extraction of the drugs in ethyl acetate/hexane from 250μL of plasma is followed by a reversed phase isocratic HPLC assay with UV detection at 205nm. The imprecision and inaccuracy are lower than 10%, the low limit of quantitation is 0.4mg/L. Thus, this method can be used
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Self-injection of high-dose buprenorphine is responsible for well-described complications. In 2011, we have been alerted by unusual but serious cutaneous complication among injection buprenorphine users. A prospective data collection... more
Self-injection of high-dose buprenorphine is responsible for well-described complications. In 2011, we have been alerted by unusual but serious cutaneous complication among injection buprenorphine users. A prospective data collection identified 30 cases of necrotic cutaneous lesions after injection of filtered buprenorphine solution, among which 25 cases occurred following injection of buprenorphine generics. The main goal of our study was to put forward particularities that could explain the cutaneous complications, by qualitatively and quantitatively confronting particles present in Subutex and generics solutions. We used the same protocol that injected-buprenorphine users: generic or subutex tablets were crushed in sterile water and filtered through 2 filters commonly used (cotton-pad and sterifilt). Solutions were analyzed by laser granulometry, flow cytometry and scanning electron microscopy. We have highlighted the wide variation of the quantity and the size of the particles p...
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evaluate the impact of Health Authorities' communication on medical practices through 2 examples: celecoxib, taking into account the recent countra indication related to cardio vascular risks; pergolide, taking into account the risk... more
evaluate the impact of Health Authorities' communication on medical practices through 2 examples: celecoxib, taking into account the recent countra indication related to cardio vascular risks; pergolide, taking into account the risk of cardiac valvulopathy. Use of the Pays de Loire Health Insurance Administration data base to monitor the number of cardio vascular patients at risk who receive celecoxib, and cardiac surveillance of pergolide exposed patients. Communication from Health Authorities resulted in a major decrease (71.9%) of the number of risking patients who take celecoxib, and a significant 14% decrease of pergolide treated patients needing cardiac monitoring Unlike the information related to pergolide, the information related to celecoxib was fully taken into account. The difference seems to come from the fact that one was widely relayed by medias, not the other.
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The objective of this work was to assess the influence of binding to plasma proteins and to serum on the brain extraction of four antiinflammatory oxicams. The brain extraction of isoxicam, tenoxicam, meloxicam and piroxicam was... more
The objective of this work was to assess the influence of binding to plasma proteins and to serum on the brain extraction of four antiinflammatory oxicams. The brain extraction of isoxicam, tenoxicam, meloxicam and piroxicam was investigated in rats using the carotid injection technique. Blood protein binding parameters were determined by equilibrium dialysis using human serum, human serum albumin (HSA) and alpha-l-acid glycoprotein (AAG) solutions at various concentrations. All oxicams had low values of brain extraction, between 19% and 39% when dissolved in serum, i.e. under physiological conditions. Brain efflux rate constants calculated from the wash-out curves were the same in the absence or presence of serum. Brain efflux was inversely related to the polarity of the oxicams, such that the higher their H-bonding capacity, the lower their brain efflux. The free dialyzable drug fraction was inversely related to protein concentration. However, rat brain extraction was always highe...
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Today, prescribers need to distinguish between the clinical practices based on randomized clinical trialing information and those based on animal physiological data or theory. Now the information on therapeutics is becoming more dense,... more
Today, prescribers need to distinguish between the clinical practices based on randomized clinical trialing information and those based on animal physiological data or theory. Now the information on therapeutics is becoming more dense, more complex and less available to the clinicians. Information sources are numerous and varied, including data whose quality differs. These data are unhierarchised in terms of methodological quality and clinical relevance. It will be optimal if each prescriber could himself collect and analyse scientific information. In fact this situation cannot be effective in private physician's practices. An international collaboration, the Cochrane Collaboration, including volunteers, university researchers, and clinical investigators has the following objective: to prepare, maintain and disseminate systematic reviews of the effects of health care. The Cochrane Collaboration is thus the most adapted intermediairy between scientifically actualized data and cli...
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Make it possible to spot falsified prescriptions which were delivered and reimbursed. 1- Use health insurance administration data bases to single patients liable to suspicion of fraud (repeated presentations of the same prescription to... more
Make it possible to spot falsified prescriptions which were delivered and reimbursed. 1- Use health insurance administration data bases to single patients liable to suspicion of fraud (repeated presentations of the same prescription to several pharmacies the same day) 2- Attribution of a diagnosis of fraud, by the CEIP (Center of Evaluation and Information about Pharmacodependence) based on transferred data, and by the medical department analysis of the complete file, and convocation when applicable 3- Calculation of quantitative performance of the tool. We have singled 2030 patients. Among them 25 were able to get 553 deliveries out of 288 pharmacies from 114 prescriptions in one year. Our tool specificity is 99.5% and its sensitivity 69.4%. Creating this tool which can become automatic and used on a large scale, brings a new light in the evaluation, by making hindsight fraud detection possible.
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ABSTRACT Today, prescribers need to distinguish between the clinical practices based on randomized clinical trialing information and those based on animal physiological data or theory. Now the information on therapeutics is becoming more... more
ABSTRACT Today, prescribers need to distinguish between the clinical practices based on randomized clinical trialing information and those based on animal physiological data or theory. Now the information on therapeutics is becoming more dense, more complex and less available to the clinicians. Information sources are numerous and varied, including data whose quality differs. These data are unhierarchised in terms of methodological quality and clinical relevance. It will be optimal if each prescriber could himself collect and analyse scientific information. In fact this situation cannot be effective in private physician's practices. An international collaboration, the Cochrane Collaboration, including volunteers, university researchers, and clinical investigators has the following objective: to prepare, maintain and disseminate systematic reviews of the effects of health care. The Cochrane Collaboration is thus the most adapted intermediairy between scientifically actualized data and clinical practitioners.
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The data on consumption of cannabis in the young people are well documented on the other hand this consumption is less described in subjects presenting a drug dependency. The consumption of cannabis in 2006 and the principal tendencies... more
The data on consumption of cannabis in the young people are well documented on the other hand this consumption is less described in subjects presenting a drug dependency. The consumption of cannabis in 2006 and the principal tendencies since 2004 were studied from the OPPIDUM (Observation of Illegal Drugs and Misuse of Psychotropic Medications) program's. OPPIDUM is an annual transverse national study pharmaco-epidemiologic which recruits subjects presenting a drug dependency or benefiting of a maintenance treatment. In October 2006, 3743 subjects were included. Thirty eight per cent (n=1437) of them are consumers of cannabis, among them 27% announced consumed only cannabis and 73% consumed it with other psychoactive substances. The consumers of cannabis alone are younger, have better social-economical indicators and presented consumption of cannabis in term of abuse and dependence more important. This study underlines the problems of the polyconsommation. No change related to the characteristics of consumers of cannabis was observed between 2004 and 2006. This study underline the presence of two groups of consumers of cannabis presented in structures of care who are different on level of the social-economical indicators and its consumptions.
Research Interests: France, Humans, Female, Male, Middle Aged, and 5 moreAdult, Narcotics, Marijuana abuse, Socioeconomic Factors, and Therapie
The French system for the evaluation of abuse and dependence created in 1990 was definitely implemented in 1999 with the decree no99-249 making in particular mandatory the reporting of all serious cases of abuse or dependence to... more
The French system for the evaluation of abuse and dependence created in 1990 was definitely implemented in 1999 with the decree no99-249 making in particular mandatory the reporting of all serious cases of abuse or dependence to psychoactive drugs. This decree was also important to define the role of each party (regulatory agencies, pharmaceutical companies, health professionals and the network of the regional Centres for Evaluation and Information of Pharmacodependence) for all marketed psychoactive drugs in France. The first meeting on pharmacodependence was organized during the last annual congress of the French Society of Therapeutic Pharmacology and Physiology (P2T) held in Toulouse in April 2007. The aim of this meeting was that the role of the French system for the evaluation of abuse and dependence during the different steps of drug approval and after marketing in the context of real life would be better known. The French approach includes classical data obtained from experimental and clinical trials, but also and mainly data obtained from the specific tools installed since the creation of the CEIP.
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The ionization and lipophilicity behavior of the antihistamine (H1-receptor antagonist) cetirizine was investigated, showing the drug to exist almost exclusively as a zwitterion in the pH region 3.5-7.5. In this pH range, its... more
The ionization and lipophilicity behavior of the antihistamine (H1-receptor antagonist) cetirizine was investigated, showing the drug to exist almost exclusively as a zwitterion in the pH region 3.5-7.5. In this pH range, its octanol/water lipophilicity is constant and low compared to cationic antihistamines (log D = log PZ = 1.5), whereas its H-bonding capacity is relatively large (delta log PZ > or = 3.1). Conformational, electronic, and lipophilicity potential calculations revealed that zwitterionic cetirizine experiences partial intramolecular charge neutralization in folded conformers of lower polarity. Pharmacokinetic investigations have shown the drug to be highly bound to blood proteins, mainly serum albumin, and to have a low brain uptake, explaining its lack of sedative effects. As such, cetirizine does not differ from "second-generation" antihistamines. In contrast, its very low apparent volume of distribution in humans (0.4 L kg-1, smaller than that of exchangeable water) implies a low affinity for lean tissues such as the myocardium and is compatible with the absence of cardiotoxicity of the drug. The zwitterionic nature and modest lipophilicity of cetirizine may account for this pharmacokinetic behavior. The suggestion is offered that cetirizine and analogous zwitterions, whose physicochemical, pharmacokinetic, and pharmacodynamic properties differ from those of "first-" and "second-generation" drugs in this class, could be considered as "third-generation" antihistamines.
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There are no studies on medically examined persons in custody which specifically focus on identifying dependence profiles among users of intoxicants. Nonetheless, the characterisation of dependence profiles for intoxicants such as... more
There are no studies on medically examined persons in custody which specifically focus on identifying dependence profiles among users of intoxicants. Nonetheless, the characterisation of dependence profiles for intoxicants such as alcohol, cannabis, cocaine, heroin, amphetamines and their by-products is a medical necessity in this setting. A prospective, monocentric, open-ended study conducted by structured questionnaire was carried out on detainees who admitted to having taken an intoxicant/s (tobacco, alcohol, drugs or illegal substances). Social, legal and medical data were collected. The aim of the study was to explore characteristics of these persons in police custody. 817 questionnaires were examined. More than one-third have a dependence on at least one substance. 37.7% were dependant of tobacco, 86.5% of drinkers, 24.7% of cannabis users. Of these, 90.1% were from men with a mean age of 29.4 years, 40% from individuals living alone, 25.7% from persons with no financial means and 19.6% from homeless persons. 10% were believed to be suffering from mental illness, 7.2% were thought to be asthmatic, 3% to have a chronic infection, and 2.9% to have epilepsy. 36.2% reportedly received treatment, 37.5% of which included benzodiazepine and 20.3% opiate substitution therapy. Incidence of psychological and psychiatric disorders is close to 10% of intoxicant detainees. In this study, some of the stated pathologies occur in ratios similar to those in other published results. But, there is a high, and probably underestimated, prevalence of psychological and psychiatric disorders in this population of detainees reporting exposure to intoxicant or illegal substances.
Research Interests: Poverty, Epilepsy, Police, Asthma, Adolescent, and 19 moreFrance, Prospective studies, Humans, Crime, Smoking, Female, Infection, Male, Young Adult, Mental Disorders, Clinical Sciences, Aged, Middle Aged, Prisoners, Questionnaires, Adult, Cardiovascular Diseases, Homeless Persons, and Substance-Related Disorders
The relationship between the cerebral pharmacokinetics of diazepam and its active metabolites (desmethyldiazepam, oxazepam) and the anxiolytic effect evaluated by the four-plates test and the light/dark test were investigated after a... more
The relationship between the cerebral pharmacokinetics of diazepam and its active metabolites (desmethyldiazepam, oxazepam) and the anxiolytic effect evaluated by the four-plates test and the light/dark test were investigated after a single intra-peritoneal injection of diazepam (1 mg/kg or 1.5 mg/kg). For up to 30 min after administration, the sedative effect interfered with the anxiolytic effect, thus the results of the anxiolytic effect were not interpretable. From 30 min to 60 min after administration, this interference disappeared, the cerebral level of benzodiazepines was stable (the brain elimination of diazepam was compensated for by the appearance of desmethyldiazepam followed by oxazepam) but the anxiolytic effect decreased dramatically in all the tests with diazepam 1 mg/kg or 1.5 mg/kg. The acute tolerance to benzodiazepines and the difference of affinity for subtypes of GABA(A) receptors between diazepam, desmethyldiazepam, oxazepam could explain this result.
Research Interests: Psychology, Cognitive Science, Anxiety, Cerebral Cortex, Mice, and 6 moreDarkness, Animals, Lighting, Male, ANXIETY, and Diazepam
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The interindividual variability of imipenem pharmacokinetic parameters in burn patients suggest that these parameters have to be estimated with a large number of patients. The aim of this study is (i) to estimate these parameters with a... more
The interindividual variability of imipenem pharmacokinetic parameters in burn patients suggest that these parameters have to be estimated with a large number of patients. The aim of this study is (i) to estimate these parameters with a population pharmacokinetic approach, and (ii) to test the influence of factors on pharmacokinetics parameters. Data are provided by therapeutic drug monitoring (n = 47,118 samples) and analysed by a nonlinear mixed effect modelling method. Among the tested covariates (age, gender, body weight, height, size of burn and creatinine plasma level) creatinine plasma level affects imipenem pharmacokinetic parameters substantially. The best fit is obtained with a two-compartment model integrating a linear-inverse relationship between imipenem clearance and creatinine plasma level. The estimates of imipenem clearance (16.37 +/- 0.204 L/h) and of the distribution volume of the central compartment (0.376 +/- 0.039 L/kg) are higher in the population of burn patients than the estimates in healthy subjects. This result is connected with high values of glomerule filtration rate and confirms the interest of therapeutic drug monitoring of imipenem in burn patients and particularly for patients with extreme values of creatinine clearance.
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Research Interests: Long Term Care, Drug interactions, France, Therapeutic drug monitoring, Humans, and 15 moreDiuretics, Female, Male, Cohort Study, Risk factors, Aged, General practitioner, Drug Therapy, Combination drug therapy, Risk Factors, Side Effect, Summary of Product Characteristics, Logistic Models, Cohort Studies, and National Health Insurance
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Research Interests: Drug interactions, Humans, Mixed Effects Models, Female, Male, and 3 moreAdult, Bayes Theorem, and Nevirapine
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Pharmacokinetic studies of contrast media are usually performed as preclinical trials in anaesthetised animals; however, results in humans have also been reported for this type of compounds. This paper reviews the existing data about... more
Pharmacokinetic studies of contrast media are usually performed as preclinical trials in anaesthetised animals; however, results in humans have also been reported for this type of compounds. This paper reviews the existing data about x-ray contrast media in humans. In some cases, animal data are used in areas where no human data are available. The administration of contrast media is generally made via the intravenous, intra-arterial or intrathecal route. Diagnostic procedures are based on differential distribution to organs and between normal and abnormal tissue. Data are available for iodixanol, iohexol, iopamidol, iopromide, iothalamate and ioxaglate, but the kinetic distribution of all contrast media is similar. With the exception of biliary contrast agents, all compounds display limited plasma protein binding and do not undergo biotransformation. From the pharmacokinetic viewpoint, the main area of interest for these compounds is elimination. The majority of the data were obtained with iopamidol (of which 66 to 72% of the dose is excreted in the urine), iohexol, ioxaglate and iopromide. Some studies were performed in patients with renal impairment: in this case, metabolic clearance was abnormally elevated, suggesting the existence of significant compensatory factors such as hepatic metabolism, enterohepatic circulation and biliary elimination. New compounds, such as iodinated polymers for x-ray perfusion imaging and iopromide- or metrizamide-containing liposomes allowing liver enhancement are discussed.
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More perioperative cefazolin use has resulted in an increased risk of cefazolin-associated reactions. The aim of this article is to study immediate reactions to cefazolin and attempt to determine possible allergic cross-reactivity with... more
More perioperative cefazolin use has resulted in an increased risk of cefazolin-associated reactions. The aim of this article is to study immediate reactions to cefazolin and attempt to determine possible allergic cross-reactivity with other ß-lactams using data from the Drug Allergy and Hypersensitivity Database (DAHD). All 25 cefazolin-associated reactions in the DAHD were reviewed. The cases identified were then investigated according to the European Network for Drug Allergy (ENDA) recommendations by skin testing and challenges. A total of 10 individuals with proven IgE-mediated cefazolin hypersensitivity were identified between January 1999 and July 2009. All the index reactions were compatible with an acute IgE-mediated process, six with anaphylaxis, two with systemic allergic reactions without hypotension, and two with urticaria/angioedema. Cefazolin skin tests were positive in seven individuals and cefazolin challenges were positive in three more individuals. In the eight cefazolin allergic patients who had challenges with other ß-lactams, there was no positive reaction noted. In this cohort of patients with IgE-mediated reactions to cefazolin, a majority tolerated amoxicillin and several patients tolerated other cephalosporins. This implies that the R1 side-chain may play an essential role in IgE-mediated reactions to cefazolin. No clear rule to predict cross-reactivity with other ß-lactams could be determined. More research on IgE-mediated hypersensitivity to cefazolin and other cephalosporins is needed.