Impact of Infection Status and Cyclosporine on Voriconazole Pharmacokinetics in an Experimental Model of Cerebral Scedosporiosis.

Cerebral Scedosporium infections usually occur in lung transplant recipients as well as in immunocompetent patients in the context of near drowning. Voriconazole is the first-line treatment. The diffusion of voriconazole through the blood-brain barrier in the context of cerebral infection and cyclosporine administration is crucial and remains a matter of debate. To address this issue, the pharmacokinetics of voriconazole was assessed in the plasma, cerebrospinal fluid (CSF), and brain in an experimental model of cerebral scedosporiosis in rats receiving or not receiving cyclosporine. A single dose of voriconazole (30 mg/kg, i.v.) was administered to six groups of rats randomized according to the infection status and the cyclosporine dosing regimen (no cyclosporine, a single dose, or three doses; 15 mg/kg each). Voriconazole concentrations in plasma, CSF, and brain samples were quantified using ultra-performance liquid chromatography-tandem mass spectrometry and high-performance liquid chromatography UV methods and were documented up to 48 hours after administration. Pharmacokinetic parameters were estimated using a noncompartmental approach. Voriconazole pharmacokinetic profiles were similar for plasma, CSF, and brain in all groups studied. The voriconazole Cmax and area under the curve (AUC) (AUC0 ≥ 48 hours) values were significantly higher in plasma than in CSF [CSF/plasma ratio, median (range) = 0.5 (0.39-0.55) for AUC0 ≥ 48 hours and 0.47 (0.35 and 0.75) for Cmax]. Cyclosporine administration was significantly associated with an increase in voriconazole exposure in the plasma, CSF, and brain. In the plasma, but not in the brain, an interaction between the infection and cyclosporine administration reduced the positive impact of cyclosporine on voriconazole exposure. Together, these results emphasize the impact of cyclosporine on brain voriconazole exposure.

Experimental models of disseminated scedosporiosis with cerebral involvement.

Scedosporium apiospermum is a soil fungus which can cause severe and often fatal cerebral infections in both immunocompetent patients in the event of near drowning and immunosuppressed patients such as lung transplant recipients. Because of the low susceptibility of this fungus to antifungal drugs, and the low permeability of the blood-brain barrier (BBB), therapeutic drug monitoring is necessary to reach an effective tissue concentration with limited side effects. Indeed, diffusion of the drug in the brain is dependent on several parameters, such as the integrity of the BBB and the activity of efflux pumps. To evaluate drug diffusion, two experimental models were developed in immunocompetent and immunosuppressed rats. Inocula were administered via the penile vein and a clinical scale (0-9) was established, based on weight and clinical and neurologic signs evaluated by the tail suspension test. Cerebral involvement was confirmed by magnetic resonance imaging and histologic examination of brain sections after hematoxylin-eosin-safran or silver staining. Voriconazole or posaconazole was given to the rats at doses ranging from 10 to 75 mg/kg/day via i.v. or oral routes, respectively. Whatever the immune status, the effective doses (defined by a doubling of the survival time and the absence of neurologic sequelae) were 30 mg/kg/day for voriconazole and 50 mg/kg/day for posaconazole. Overall, the results demonstrated that these models may constitute valuable tools for the performance of pharmacokinetic and pharmacodynamic studies for pharmacokinetic-pharmacodynamic modeling.

COVID-19 pandemic's impact on French Health Students: A cross-sectional study during the third wave.

BACKGROUND: COVID19 pandemic had a huge impact on global mental health. Health students, because of their age and status, are a more at-risk population. National survey during the first wave already found high levels of psychological distress. OBJECTIVE: This nationwide study aimed to assess health's student mental health during the third wave in France. METHODS: We did an online national cross-sectional study, which addressed all health students from April 4th to May 11th 2021. The questionnaire included sociodemographic and work conditions questions, Kessler 6 scale, and numeric scales. RESULTS: 16,937 students answered, including 54% nurse and 16% medical students. Regarding K6 scale, 14% have moderate (8-12) and 83% high (≥13) level of psychological distress. In multivariate analysis, being a man (OR = 0.54, 95% CI [0.48; 0.60], p < 0.001) and not living alone (OR = 0.71, 95% CI [0.62; 0.82], p < 0.001), are associated with a reduced risk of psychological distress. Not having the ability to isolate themselves (OR = 1.58, 95% CI [1.39; 1.81], p < 0.001), and having low (OR = 2.31, 95% CI [2.08; 2.56], p < 0.001) or important (OR = 4.58, 95% CI [3.98; 5.29], p < 0.001) financial difficulties are associated with an increased risk of psychological distress. LIMITATIONS: The response rate was low regarding the target population (300,000 health students). CONCLUSION: Compared to the first national survey, we noticed mental health deterioration. Psychological distress (83% high level versus 21%), substance use (21% versus 13%), and psychotropic treatment use (18% versus 7.3%) hugely increased. These results highlighted the need to increase support actions for health students.

Riluzole pharmacokinetics in young patients with spinal muscular atrophy.

AIMS: The objective of the present study was to assess the pharmacokinetics of riluzole in patients with spinal muscular atrophy (SMA). METHODS: Fourteen patients were enrolled in an open-label, nonrandomized and repeat-dose pharmacokinetic study. All participants were assigned to receive 50mg riluzole orally for 5 days. Riluzole plasma concentrations were determined from samples obtained at day 5. RESULTS: The pharmacokinetic analysis demonstrated that a dose of 50mg once a day was sufficient to obtain a daily total exposure [AUC(0,24h)=2257ng ml(-1) h] which was comparable with results obtained in adult healthy volunteers or ALS patients in whom a dose of 50mg twice a day is recommended. The pharmacokinetic simulation demonstrated that the administration of 50mg twice a day could result in higher concentrations, hence reduced safety margin. CONCLUSION: The dose of 50mg once a day was chosen for the clinical trial evaluating the efficacy of riluzole in SMA patients.

Patterns of quadruple therapy use including bismuth for Helicobacter pylori eradication: A cohort study in the French national claims database.

BACKGROUND: Quadruple therapy using a single capsule formulation of bismuth, metronidazole and tetracycline (BMT; Pylera®), associated with omeprazole for the eradication of Helicobacter pylori, represents the reintroduction of bismuth in France after 40 years. OBJECTIVE: To describe the real-life patterns of use of BMT following a request from the French health authorities. METHODS: Patients with a first BMT dispensing (index date, ID), with one year of data before and after ID, were identified in the French nationwide claims database 1/97 sample. Misuse of BMT was defined as dispensing>1 pack of BMT at ID or absence of a diagnostic test in the preceding year. RESULTS: In total, 540 patients were included. Prescribers were gastroenterologists (n=243; 45%) and general practitioners (n=160; 30%). A proton pump inhibitor was co-dispensed to 504 patients (96%). Ten patients (2%) had contraindications to BMT. Fifty-nine patients (11%) met the misuse criteria: ten (2%) were dispensed>1 pack of BMT and 49 (9%) had not had a diagnostic test for H. pylori in the previous year. During follow-up, 27 patients (5%) required retreatment (treatment failure). CONCLUSION: In this real-life study, most patients were dispensed only one pack of BMT, consistent with recommendations. Misuse related principally to the absence of prior diagnostic test for H. pylori.

Therapeutic management of allergic diseases.

Allergic diseases are characterized by the activation of inflammatory cells and by a massive release of mediators. The aim of this chapter was to describe succinctly the modes of action, indications, and side effects of the major antiallergic and antiasthmatic drugs. When considering the ideal pharmacokinetic characteristics of a drug, a poorly metabolized drug may confer a lower variability in plasma concentrations and metabolism-based drug interactions, although poorly metabolized drugs may be prone to transporter-based disposition and interactions. The ideal pharmacological properties of a drug include high binding affinity, high selectivity, and appropriate association and dissociation rates. Finally, from a patient perspective, the frequency and route of administration are important considerations for ease of use.

Bismuth Concentrations in Patients Treated in Real-Life Practice with a Bismuth Subcitrate-Metronidazole-Tetracycline Preparation: The SAPHARY Study.

INTRODUCTION: A fixed-dose association of bismuth subcitrate, metronidazole and tetracycline (BMT) (Pylera®, Allergan, NJ, USA) was made available in France in 2013 for the eradication of Helicobacter pylori. Due to a historical issue of bismuth encephalopathy, the French Health Authorities requested a study of blood and plasma bismuth concentrations with BMT in daily practice. AIMS: The aim of the study was to measure eventual bismuth accumulation and neurological toxicity in patients prescribed BMT. METHODS: Patients initiating BMT for H. pylori between March 2014 and December 2015 were included. A blood sample was taken before first BMT intake and 24 h after the last intake, for assay of bismuth. A concentration > 50 µg/L was considered abnormal. Neurological complaints were assessed at inclusion, at the end of the 10-day treatment course, and 28 days later. RESULTS: 202 patients were included, of whom 190 took at least one dose of BMT, and 167 provided both required blood samples. Mean blood bismuth concentrations after the BMT course were 16.9 µg/L (95% confidence interval 15.6-18.3). Concentrations were > 50 µg/L (56.0 µg/L and 50.9 µg/L) in two elderly patients, one of whom presented mild, transient memory impairment during treatment. Non-serious neurological symptoms occurred in 20% of all patients and treatment failure was documented in 5% of patients. CONCLUSIONS: In this study measuring blood bismuth concentrations in real-life practice, in < 1% of patients the BMT course resulted in blood bismuth concentrations > 50 µg/L. No serious neurological adverse events were observed. STUDY REGISTRATION: EU-PAS register EUPAS3142 at www.encepp.eu ; ENCePP study seal.

High-performance liquid chromatography coupled with electrospray tandem mass spectrometry (LC/MS/MS) method for the simultaneous determination of diazepam, atropine and pralidoxime in human plasma.

A high-performance liquid chromatography coupled with electrospray tandem mass spectrometry (LC/MS/MS) procedure for the simultaneous determination of diazepam from avizafone, atropine and pralidoxime in human plasma is described. Sample pretreatment consisted of protein precipitation from 100microl of plasma using acetonitrile containing the internal standard (diazepam D5). Chromatographic separation was performed on a X-Terra MS C8 column (100mmx2.1mm, i.d. 3.5microm), with a quick stepwise gradient using a formate buffer (pH 3, 2mM) and acetonitrile at a flow rate of 0.2ml/min. The triple quadrupole mass spectrometer was operated in positive ion mode and multiple reaction monitoring was used for drug quantification. The method was validated over the concentration ranges of 1-500ng/ml for diazepam, 0.25-50ng/ml for atropine and 5-1000ng/ml for pralidoxime. The coefficients of variation were always <15% for both intra-day and inter-day precision for each analyte. Mean accuracies were also within +/-15%. This method has been successfully applied to a pharmacokinetic study of the three compounds after intramuscular injection of an avizafone-atropine-pralidoxime combination, in healthy subjects.

Study of the use of a spironolactone and angiotensin-converting enzyme inhibitor combination: a population-based analysis.

PURPOSE: To analyse the conditions of use of the drug combination in outpatients. METHODOLOGY: The first section consisted of a population-based analysis using computerized records from the French national health insurance system. The study population consisted of adult patients, receiving long-term treatment with spironolactone (SPIR) and angiotensin-converting enzyme inhibitor (ACEI). For each patient, the reimbursement of serum potassium and creatinine determinations was searched for in the database during the 6-month period preceding the date of the last dispensation. The second section comprised a written questionnaire on use practises, sent to practitioners who prescribed the drug combination to randomly selected patients. Analysis of the answers to the questionnaire made it necessary to develop a reference system. In the third section, procedure one was repeated at a later stage, following an information campaign, in order to measure its impact. RESULTS: The exhaustive population under procedure 1 consisted of 3620 patients (71 +/- 11 years). During the 6 months prior to the index date, 51% of patients underwent at least one determination of both serum potassium and serum creatinine. The randomised population under procedure two consisted of 441 patients (70 +/- 13 years) and their 375 practitioners. When compared with the reference system, SPIR-ACEI was used for the recommended indications, at the appropriate SPIR-ACEI dosages, and under minimal monitoring of biological parameters in only 65 patients (15%). After the information campaign, results were disappointing because only 55% of patients underwent the minimal laboratory monitoring. CONCLUSION: The use of the drug combination in general practice was mainly inappropriate.

Antimalarial activity of crambescidin 800 and synthetic analogues against liver and blood stage of Plasmodium sp.

Structural features associated with the antimalarial activity of the marine natural product crambescidin 800 were studied using synthetic analogues of the related compound ptilomycalin A. The study suggests that the guanidine moiety is cytotoxic, whereas the spermidine-containing aliphatic chain increases activity. The most active analogue, compound 11, had in vitro activity against Plasmodium falciparum strain 3D7 (IC50=490 nM) that was stronger than the in vitro activity against murine L5178Y cells (IC50 = 8.5-59 microM). In vitro growth inhibition of liver stages of P. yoelii yoelii in mouse hepatocytes was observed (IC50 = 9.2 microM). The compound did not significantly prolong median survival time after a single subcutaneous administration of 80 mg/kg in P. berghei-infected mice. Compound 11 did not cause DNA fragmentation in an in vitro micronucleus assay.

High variability of indinavir and nelfinavir pharmacokinetics in HIV-infected patients with a sustained virological response on highly active antiretroviral therapy.

OBJECTIVES: To describe plasma concentrations of indinavir alone or combined with ritonavir, and of nelfinavir and its active metabolite M8, and to measure their variabilities in HIV-infected patients treated with a stable antiretroviral regimen and experiencing a sustained virological response for at least 12 months. PATIENTS AND METHODS: In this prospective trial, blood samples were drawn during a 6-hour time interval between two doses at enrolment to assess protease inhibitor (PI) pharmacokinetic parameters, and 4 months later to assess plasma trough and peak concentrations. Safety and adherence assessments and laboratory data were collected during an 8-month period. PI pharmacokinetic characteristics were analysed using a non-compartmental approach. Inter- and intrapatient variabilities were estimated using a linear mixed-effect model. The impact of different covariates on plasma trough concentrations was investigated. Eighty-eight patients were analysed: 42 treated with indinavir and 46 with nelfinavir. RESULTS: The interquartile range (IQR) of the plasma trough concentration corrected for the sampling time (Ccalc) was 116-374 microg/L for indinavir alone and 163-508 microg/L for indinavir/ritonavir. Ritonavir significantly increased indinavir elimination half-life and plasma exposure. For nelfinavir, the IQR of Ccalc was 896-2059 microg/L for three-times-daily administration and 998-2124 microg/L for twice-daily administration. Variabilities were high for both PIs. Intrapatient variability for indinavir alone (and indinavir + ritonavir) was 76% (107%) and interpatient variability was 58% (10%) in adherent patients. Intrapatient variability for nelfinavir three times daily (and twice daily) was 41% (74%) and interpatient variability was 62% (50%). Intrapatient variability was lowered in patients with a high adherence level. CONCLUSION: Although performed in a homogeneous population, this study documented a high interpatient but also intrapatient variability of indinavir and nelfinavir pharmacokinetics, which should be taken into account when interpreting therapeutic drug monitoring. Once patients have reached a sustained virological response, plasma PI monitoring may have a limited impact.

[How practitioners view generic drugs: an opinion study from general practitioners in Maine-et-Loire (France)]. / Medicaments génériques, le point de vue des médecins : enquête d'opinion réalisée auprès des médecins libéraux du Maine-et-Loire.

INTRODUCTION: Generic drugs are copies of original drugs, hence their low cost. In France, expansion of the use of generic drugs is not significant and the support of practitioners is essential in increasing this. AIM: The purpose of this study was to survey the opinion and practical experience of physicians regarding generic drugs, in order to develop a proposal for the safer use of these drugs. METHODS: A form was sent to the 1235 general and specialist practitioners in the Maine-et-Loire "département" with assistance from the regional health insurance, in March 2002. The main topics studied were prescribing practices, risks associated with generic drugs and pharmacist substitutions. The chi2 test and Fisher's exact test were used in the data analysis. RESULTS: Four hundred and twenty-nine forms were returned (34.7%). Only 55% of practitioners considered generic drugs to be as safe and effective as original drugs. Fifty-nine percent prescribe generics rarely or never. The prescribing depends on many factors, linked to the practitioner, the patient or the drug. Many practitioners reported adverse events with generic medicines. With regard to the switch by the pharmacist, it was reported that 45% of prescribers would refuse it in some instances. Among the proposals, cooperation between practitioners and pharmacists in the choice of the generic drugs was approved by 57% of physicians. DISCUSSION: The main perception is that the vastness of the generic world and the fear of adverse events are somewhat bewildering for both patients and health professionals. Among the proposals made by practitioners, a decrease in the number of generics for a same molecule and the institution of a standard price are widely approved. CONCLUSION: Practitioners do not refuse to use generic drugs but are very concerned about the risks of adverse effects for their patients. They regard it as important that a patient receiving chronic treatment be given the same generic drug each time.

Dopaminergic drug response and the genotype (Taq IA polymorphism) of the dopamine D2 receptor.

The genotype of the receptor with which a particular drug interacts may be a between- subject factor that modifies the pharmacodynamic and consequently the therapeutic response to drugs. Subjects with A1 allele (Taq IA restriction fragment length polymorphism) of the gene encoding for the dopamine D2 receptor (DRD2) seem to express lower number of DRD2 compared to subjects who do not have this allele. We investigated whether subjects homozygous for the A1 allele of the DRD2 gene have decreased response to DRD2 stimulation by apomorphine when compared with those homozygous for the A2 allele. Two hundred and two Caucasian subjects were genotyped for DRD2 Taq IA polymorphism, 6.9 % had the genotype A1A1 and 65% A2A2. Nine homozygous subjects/group were selected for the apomorphine study. Five, 10 and 20 &mgr;g/kg of apomorphine were administered subcutaneously according to a randomized crossover design. The main pharmacodynamic criterion was the plasma growth hormone increase induced by apomorphine. Secondarily, we measured oral temperature responses and yawns in response to apomorphine. Plasma apomorphine concentrations were similar for the two matched and only genotypically different groups. Apomorphine dose-dependently increased serum growth hormone concentration, and significant effect of time, dose by time interaction but no effect of genotype or genotype by dose interaction was shown. Apomorphine decreased body temperature, significant effect of dose, time, dose by time interaction but no effect of genotype or genotype by dose interaction were observed. The number of apomorphine-induced yawns increased dose-dependently but no significant difference between groups occurred. Thus, in this study apomorphine-induced responses were not modified by DRD2 Taq IA polymorphism although the power of the study could be insufficient to detect subtle differences.

Relationship between exposure to zidovudine and decrease of P24 antigenemia in HIV-infected patients in monotherapy.

The link between virological response and exposure to zidovudine was studied in 40 HIV-infected patients of the protocol ANRS 01. During this 45-day trial, the patients received only oral zidovudine in six treatment groups. Our objectives were: to analyze and model the pharmacokinetics of zidovudine and the decrease of P24 antigenemia; to study the links between exposure and efficacy. For the pharmacokinetic study, 12 blood samples were collected from 0.16 to 24 h after the first dose and a compartmental model was used. For the pharmacodynamic study of P24 antigenemia, blood samples were collected before treatment and every 3 days until day 45; an exponantial decay model was used. The pharmacokinetic and pharmacodynamic parameters were estimated for each patient by nonlinear regression. The correlations between efficacy parameters and exposure parameters, were then studied in the 40 patients. The mean (+/- SD) apparent volume of distribution and clearance were 151 L (+/- 94) and 184 L/h (+/- 72), respectively. The mean initial antigen level was 472 pg/mL (+/- 409), the coefficient of reduction of antigenemia was 0.27 (+/- 0.21) and the rate of decrease was 0.27/day (+/- 0.16). The coefficient of P24 reduction was found to be significantly correlated to the daily area under the curve (P < 0.0014). This relationship was adequately described by an Imax model and the daily area under the curve, leading to 50% of antigenemia decrease, was estimated to be 2.32 mg x h/L (+/- 0.33). In conclusion, a significant relationship between exposure to zidovudine at day 1, and decrease of P24 antigenemia was found. It was estimated that the average steady-state concentration, which corresponds to 70% of maximal efficacy, was 0.22 mg/L. Together with the large interpatient variability of zidovudine pharmacokinetics, these findings confirmed that zidovudine should be monitored and a clinical target concentration was defined.

Pharmacokinetic-pharmacodynamic study of apomorphine's effect on growth hormone secretion in healthy subjects.

Apomorphine (APO) stimulates growth hormone (GH) release via dopamine D2 receptors (DRD2). There is no specific study assessing the relationship between APO pharmacokinetic (PK) and the pharmacodynamic (PD) response e.g. GH release. The objective of the study is the PK-PD modelling of APO in healthy subjects. This is a randomized crossover study with s.c. administration of 5, 10, and 20 micro g/kg of APO in 18 healthy subjects. APO concentrations were modelled according to both a bi-compartmental model with zero-order absorption and a bi-compartmental model with first-order absorption. PK-PD relationship was modelled in accordance with the Emax Hill equation using plasma concentrations of APO calculated according to the bi-compartmental model with zero-order absorption. Modelled parameters were very similar to the experimental parameters. PK of APO was linear and there was no significant difference between the tested doses for AUC0--> infinity and Cmax (normalised to the dose 1 micro g/kg), t1/2alpha and t1/2beta. These parameters expressed as mean (CV%: SD/mean) were: 17.2 (26.9) ng/mL.min, 0.26 (33.3) ng/mL, 17.1 (54.2) and 45.2 (20.6) min, respectively (n = 53). An anticlockwise hysteresis loop (effect function of APO plasma concentration) appeared for each dose and each subject. The predicted and measured GH concentrations for all subjects and times were similar whatever the dose (P > 0.27). Emax values were 246 (121), 180 (107), 205 (139) ng/mL, respectively, and EC50 were 0.98 (48.1), 1.70 (62.3), 3.67 (65.2) ng/mL, respectively at dose 5, 10, and 20 micro g/kg (P < 10-4). APO and GH concentrations were predicted with good accuracy using bi-compartmental with zero-order absorption PK model and sigmoid Emax PD model, respectively.

A pharmacokinetic-pharmacodynamic model for predicting the impact of CYP2C9 and VKORC1 polymorphisms on fluindione and acenocoumarol during induction therapy.

BACKGROUND AND OBJECTIVE: Vitamin K epoxide reductase complex, subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) polymorphisms are taken into account when predicting a safe oral dose of coumarin anticoagulant therapy, but little is known about the effects of genetic predictors on the response to fluindione and acenocoumarol. The aims of this study were to characterize the relationship between fluindione and acenocoumarol concentrations and the international normalized ratio (INR) response, and to identify genetic predictors that are important for dose individualization. METHODS: Fluindione concentrations, S- and R-acenocoumarol concentrations, the INR and genotype data from healthy subjects were used to develop a population pharmacokinetic-pharmacodynamic model in Monolix software. Twenty-four White healthy subjects were enrolled in the pharmacogenetic study. The study was an open-label, randomized, two-period cross-over study. The subjects received two doses of an oral anticoagulant: 20 mg of fluindione (period A) or 4 mg of acenocoumarol (period B). The pharmacokinetics and pharmacodynamics were studied from day 2 to day 3. RESULTS: A two-compartment model with a first-order input model was selected as the base model for the two drugs. The pharmacodynamic response was best described by an indirect action model with S-acenocoumarol concentrations and fluindione concentrations as the only exposure predictors of the INR response. Three covariates (CYP2C9 genotype, VKORC1 genotype and body weight) were identified as important predictors for the pharmacokinetic-pharmacodynamic model of S-acenocoumarol, and four covariates (CYP2C9 genotype, VKORC1 genotype, CYP1A2 phenotype and body weight) were identified as predictors for the pharmacokinetic-pharmacodynamic model of fluindione. Because some previous studies have shown a dose-response relationship between smoking exposure and the CYP1A2 phenotype, it was also noted that smokers have greater CYP1A2 activity. CONCLUSION: During initiation of therapy, CYP2C9 and VKORC1 genetic polymorphisms are important predictors of fluindione and acenocoumarol pharmacokinetic-pharmacodynamic responses. Our result suggests that it is important to take the CYP1A2 phenotype into account to improve individualization of fluindione therapy, in addition to genetic factors.