Publication bias in pharmacogenetics of adverse reaction to antiseizure drugs: An umbrella review and a meta-epidemiological study.

Publication bias may lead to a misestimation in the association between pharmacogenetic biomarkers (PGx) and antiseizure drug's adverse effects (AEs). We aimed to assess its prevalence in this field. We searched for systematic reviews assessing PGx of antiseizure drug's AEs. For each unique association between a PGx, a drug and its AE, we used the available odds ratio (ORs) to generate corresponding funnel plots. We estimated the prevalence of publication bias using visual inspections and asymmetry tests. We explored the impact of publication bias using ORs adjusted for potential publication bias. Twenty-two associations were available. Our visual analysis suggested a publication bias in five out twenty-two funnel plots (23% [95%CI: 8; 45]). The Egger's test showed a significant publication bias in one (HLA-B*15:02 and phenytoin-induced Stevens-Johnson syndrome or toxic epidermal necrolysis, p = 0.03) out of nine (11% [95%CI: 0; 48]) and the Begg's test in one (HLA-B*15:02 and carbamazepine-induced serious cutaneous reactions, p = 0.02) out of ten (10% [95%CI: 0; 45]) assessable funnel plots. Adjusting for publication bias may reduce by half the ORs of the pharmacogenetics associations. Publication bias in the pharmacogenetic of antiseizure drug's AEs is not uncommon and may affect the estimation of the effect of such biomarkers. When conducting pharmacogenetic studies, it is critical to publish also the negative one.

Issues and limitations of available biomarkers for fluoropyrimidine-based chemotherapy toxicity, a narrative review of the literature.

Fluoropyrimidine-based chemotherapies are widely used to treat gastrointestinal tract, head and neck, and breast carcinomas. Severe toxicities mostly impact rapidly dividing cell lines and can occur due to the partial or complete deficiency in dihydropyrimidine dehydrogenase (DPD) catabolism. Since April 2020, the European Medicines Agency (EMA) recommends DPD testing before any fluoropyrimidine-based treatment. Currently, different assays are used to predict DPD deficiency; the two main approaches consist of either phenotyping the enzyme activity (directly or indirectly) or genotyping the four main deficiency-related polymorphisms associated with 5-fluorouracil (5-FU) toxicity. In this review, we focused on the advantages and limitations of these diagnostic methods: direct phenotyping by evaluation of peripheral mononuclear cell DPD activity (PBMC-DPD activity), indirect phenotyping assessed by uracil levels or UH2/U ratio, and genotyping DPD of four variants directly associated with 5-FU toxicity. The risk of 5-FU toxicity increases with uracil concentration. Having a pyrimidine-related structure, 5-FU is catabolised by the same physiological pathway. By assessing uracil concentration in plasma, indirect phenotyping of DPD is then measured. With this approach, in France, a decreased 5-FU dose is systematically recommended at a uracil concentration of 16 ng/ml, which may lead to chemotherapy under-exposure as uracil concentration is a continuous variable and the association between uracil levels and DPD activity is not clear. We aim herein to describe the different available strategies developed to improve fluoropyrimidine-based chemotherapy safety, how they are implemented in routine clinical practice, and the possible relationship with inefficacy mechanisms.

Short-term pharmacokinetic study of mycophenolate mofetil in neonatal swine.

BACKGROUND: Mycophenolate mofetil (MMF) is an effective immunosuppressive agent that has been frequently used in laboratory animals including swine; however, the pharmacokinetic properties of MMF in swine have not been studied. This short-term study was designed to evaluate the feasibility and the pharmacokinetic profiles of MMF therapy in neonatal swine. MATERIALS AND METHODS: Twelve neonatal pigs were randomized into four groups including one control and three treated groups with oral MMF administered at 0.5, 1, and 2 g/m(2)/d for 4 days, divided by 2 half-doses at 9:00 and 17:00 (except day 4 during which MMF was not administered at 17:00). Blood samples were collected at 9:00 on days 0, 2, 3 and 4 for complete blood count and hepatic/renal function examination; the trough concentration of plasma mycophenolic acid (MPA) was also determined. On days 2 and 4, blood was collected to determine the area under the curve (AUC) of plasma MPA concentration. Animal body-weight growth and manifestations of MMF side-effects such as anorexia, vomiting, and diarrhea were also observed. RESULTS: MMF has no acute hepatic/renal toxicity in newborn pigs; however, less body-weight growth was observed in treated groups. In the control group, a spontaneous increase of lymphocyte count was observed; in contrast, MMF therapy with doses of 1 and 2 g/m(2)/d reduced both lymphocyte and monocyte counts of piglets. Oral MMF had high bioavailability in neonatal swine. MPA-AUC0-12h of doses 0.5, 1, and 2 g/m(2)/d was 22.00 ± 3.32, 57.57 ± 34.30, and 140.00 ± 19.70 µg × h/mL, respectively. Neither MPA trough concentration (MPA-C0), nor MPA maximum concentration (MPA-Cmax) or MPA-AUC0-6h had high correlation with MMF-dose. For surveillance of MPA exposure, MPA-C0 had significant correlation with MPA-AUC0-12h (Spearman's ρ = 0.933, AUC0-12h = 17.882 × C0 + 14.479, r(2) = 0.966). CONCLUSION: To reach adequate drug exposure and to reduce dose-dependent side effects, an MMF dose of 1 g/m(2)/d is recommended to be used as an initial dose for immunosuppressive therapy in piglets, and MPA-C0 monitoring is the most practical strategy for experimental transplantation study.

[Chronic necrotizing pulmonary aspergillosis following an infection by Mycobacterium malmoense]. / Aspergillose pulmonaire chronique nécrosante compliquant une pneumopathie à Mycobacterium malmoense.

Pneumonia due to Mycobacterium malmoense is rare and usually occurs in damaged lung as is the case with Aspergillus infections. We report the case of a patient who developed chronic necrotizing pulmonary aspergillosis following an infection by atypical mycobacteria. A 53-year-old woman was hospitalized because of weight loss and fever. Direct examination of sputum smear was positive for acid fast bacilli and PCR and culture led to the diagnosis of infection with M. malmoense. Treatment was begun with clarithromycin, rifampicin and ethambutol. Despite initial improvement and excellent adherence to treatment, fever and weight loss recurred 6 months later. Relapse of the mycobacterial infection was excluded and the final diagnosis was necrotizing pulmonary aspergillosis. Infection with A. fumigatus complicating the treatment of M. malmoense is unusual. The management is challenging because of strong interactions between voriconazole and rifampicin, and thus requires a multidisciplinary and specialized approach.

Genotype-based quantitative prediction of drug exposure for drugs metabolized by CYP2D6.

We propose a framework to enable quantitative prediction of the impact of CYP2D6 polymorphisms on drug exposure. It relies mostly on in vivo data and uses two characteristic parameters: one for the drug and the other for the genotype. The metric of interest is the ratio of drug area under the curve (AUC) in patients with mutant genotype to the AUC in patients with wild-type genotype. Any combination of alleles, as well as duplications, may be accommodated in the framework. Estimates of the characteristic parameters were obtained by orthogonal regression for 40 drugs and five classes of genotypes, respectively, including poor, intermediate, and ultrarapid metabolizers (PMs, IMs, and UMs). The mean prediction error of AUC ratios was -0.05, and the mean prediction absolute error was 0.20. An external validation was also carried out. The model may be used to predict the variations in exposure induced by all drug-genotype combinations. An application of this model to a rare combination of alleles (*4*10) is described.

[Molecular pharmacogenetics in hospital laboratories in France: current data and future prospects]. / La pharmacogénétique moléculaire hospitalière en France: données actuelles et perspectives.

Molecular pharmacogenetic units have recently been established in several hospital laboratories in France. The clinical impact of these units is still limited and numerous problems of organizational, ethical, legal, technical, social and economical nature remain to be resolved. However, an increasing number of these units, a rise in their activities and an enlargement of their scope of application are foreseeable in the future. Ultimately, these units would significantly contribute to limit the public health problem caused by interindividual variabilities in drug effects. In view of these prospects, it seems essential that such hospital activity should be quickly recognised by the authorities and the various health sectors in France. It is also essential that the problems that arise from such pharmacogenetic activities should be considered by the authorities and would profit from the organization of a national network and from financial guarantees.

Plasma ribavirin concentrations during treatment of recurrent hepatitis C with peginterferon alpha-2b and ribavirin combination after liver transplantation.

After liver transplantation (LT) for hepatitis C virus (HCV)-related cirrhosis, recurrence of HCV infection is universal. The efficacy of antiviral therapy in this indication is usually reduced because of its poor tolerability. We present herein the results of plasma measurement of ribavirin levels in transplanted patients when using increasing dosage of ribavirin, in comparison with a control cohort of nontransplanted patients. Seventeen control patients (nine women and eight men, median age 51.5 years) were compared with 12 liver transplant patients (2 women and 10 men, median age 55 years). In 76% of patients, HCV infection was genotype 1. All patients were treated by a combination of ribavirin and pegylated-interferon alpha-2b. A total of 54 blood samples were taken (1.8 per patient) for ribavirin level measurement. A virological response was obtained in 8/17 patients in the control group and in 6/12 LT patients. Ribavirin dose was lower in the LT group (8.79 vs 12.98 mg/kg/day), but plasma levels were the same in both groups (2.23 vs 2.43 mg/L for LT and non-LT groups, respectively). This was probably related to impaired renal function in the LT group (serum creatinine: 112.6 vs 73.6 micromol/L). No discontinuation of ribavirin therapy was observed and haemoglobin level was the same in both groups (109.5 g/L in LT patients vs 119.5 g/L in the control group). These results strongly support the interest in plasma measurement of ribavirin concentration during antiviral therapy in LT patients. Ribavirin dosage might be adapted without compromising its efficacy.

Lateralization of the effects of the benzodiazepine drug oxazepam on medial olivocochlear system activity in humans.

Benzodiazepines (Bzd) are known to interact with GABAergic inhibitory neurotransmission. Previous research on their effect on human auditory efferent pathways--through evoked otoacoustic emissions suppression by contralateral acoustic stimulation (CAS)--indicated a decrease in medial olivocochlear (MOC) efferent system inhibitory activity, after oral intake of oxazepam--representative of the Bzd drug class. To date, this pharmacological effect was only assessed in the right ear. Since a leftward asymmetry of Bzd receptors localization in human auditory cortex has been described recently, we explored in this study the hypothesis of an asymmetrical action of Bzd on MOC efferent functioning. The results revealed a significant difference of Bzd effect probing the right ear versus the left ear, with CAS-induced suppression being less effective in the right than left ear after oxazepam intake. This finding raises the question of possible neurochemical left-right asymmetry in the descending auditory pathways. The potential localization of this asymmetry is discussed.

[Redox status in HIV+ patients under HAART]. / Statut oxydatif de patients VIH positifs sous trithérapie.

Oxidative stress decreases immune defences and is also suggested to participate in the activation of HIV virus replication. That is why we decided to explore some biomarkers of oxidative stress (reduced glutathione, lipoperoxides, true malondialdehyde and vitamin C) in 20 HIV positive patients whose HIV replication was determined by measurement of RNA viral load. Reduced glutathione is decreased in HIV positive patients, without correlation with the viral load. The patients mean content of lipoperoxides is twice that of controls but with such a large range that there is no statistical difference.

Influence of benzodiazepines on auditory perception.

The aim of this study was to test for an influence of benzodiazepine (BZD) on various perceptual and/or cognitive auditory processes. Loudness, auditory selective attention, and the ability of subjects to form perceptual streams out of alternating tone sequences were tested. Nine subjects were tested before, 1, 3, 7, and 24 h after a single-dose oxazepam vs placebo administration in a crossover design. A sample of blood allows us to measure plasma oxazepam concentration. The results revealed a significant reduction in stream segregation expressed as d' scores 1 h after oxazepam intake in the test subjects. No significant change occurred across time in the same subjects when they were administrated a placebo in another session. Furthermore, oxazepam had no substantial and systematic influence either on auditory selective attention or on loudness perception. Altogether, these results suggest that the perceptual organization of sound sequences involves inhibitory neural mechanisms, which can be affected by BZDs. This outcome is consistent with existing models of auditory stream segregation and may be paralleled with earlier findings on the effect of BZDs on perceptual binding in the visual modality.

[Antidigoxin Fab fragments and digoxin monitoring: a challenge for the biologist]. / Suivi des digoxinémies chez les patients traités par fragments Fab antidigitaliques: un défi pour le biologiste.

Following administration of anti-digoxin Fab fragments, monitoring unbound digoxin concentrations may help ensure appropriate dosing, and prevent recrudescent toxicity. Ultrafiltration by using Centrifree system and measurement of digoxin in the ultrafiltrate is considered as reference technique. However, ultrafiltration method is cumbersome, costly, and some immunoassays are affected by matrix differences. Another approach is to analyse the serum directly by digoxin immunoassays without ultrafiltering it. The validity of results obtained depends on the architecture of the immunoassay and the amount of Fab in the sample. The old radioimmunoassays and usually the other competitive immunoassays give inaccurate results. The fluorescence polarization immunoassay (FPIA) slightly underestimates the total digoxin concentrations. Total digoxin levels obtained at 24 hours and 48 hours after treatment permit measurement of the half-life of digoxin Fab complexes and can be used to estimate when the patient can be redigitalized, if necessary. The sequential immunoassays usually overestimate the free digoxin concentrations. The differences observed are >25% and cannot be explained solely by albumin binding (normal range, 20% +/- 5%). To date, ultrafiltration remains the best strategy for accurate determination of digoxin concentrations in the presence of antidigoxin Fab fragments.

Benzodiazepines alter cochleo-cochlear loop in humans.

By using otoacoustic emission, we looked for change in outer hair cell (OHC) motile activity and medial olivocochlear (MOC) system inhibition due to benzodiazepine administration, a drug that is known to produce a pharmacological effect by interacting with GABAergic inhibitory neurotransmission. No effect was observed on OHC motile activity, in contrast benzodiazepines decreased MOC system effectiveness suggesting the existence of GABAergic fibers projecting onto the MOC system.

Simple high-performance liquid chromatographic separation of oxazepam and its diastereoisomeric glucuronides in serum. Applications in a pharmacokinetic study in sheep.

This paper describes a highly specific and sensitive method for quantifying oxazepam and its diastereoisomeric glucuronides in serum. The method involves sample clean-up by solid-phase extraction on C18 cartridge followed by quantitation on a reversed-phase HPLC column. Diazepam is used as internal standard. Extraction recovery from serum proved to be more than 86%. Precision, expressed as C.V., was in the range 1.2-9.5%. The limits of quantification were 40, 400, and 200 nmol/l for oxazepam, S-(+)- and R-(-)-glucuronides, respectively. This method was applied to the determination of oxazepam and its diastereoisomeric glucuronides in serum collected during a pharmacokinetic study performed in sheep after oral administration of racemic oxazepam. S-(+)/R-(-) ratios were measured all along the sampling time collection and the pharmacokinetic parameters were determined.

[Value of the cytology of bronchoalveolar lavage in the early diagnosis of nosocomial lung infections in patients with thoracic injuries]. / Intérêt de l'étude cytologique du lavage broncho-alvéolaire pour le diagnostic précoce des pneumopathies nosocomiales chez le traumatisé thoracique.

Mechanically ventilated patients, especially those with thorax trauma, suffer commonly from nosocomial pneumonia. In these patients, conventional diagnostic criteria for bacterial pneumonia may not be completely reliable, as an accurate interpretation of the chest radiograph is too difficult. The invasive means for the diagnosis of pneumonia (protected specimen brush, bronchoalveolar lavage), require 24-48 hours to obtain the results of cultures. Therefore no information is available to guide the initial choice of antimicrobial therapy. For some authors, the quantification of intracellular bacteria, present in cytocentrifuged preparations made from lavage fluid, may provide rapid identification of patients with pneumonia. We evaluated the benefit of this type of analysis in thorax trauma patients. In 36 patients, 48 samples were taken. With a threshold value of 10% of cells containing intracellular organisms, microscopic examination had a sensitivity and a specificity of 83%. We conclude that this technique may be useful for the early diagnosis of nosocomial pneumonia in ventilated thorax trauma patients.

[Intra-macrophage lipid particles collected by bronchoalveolar lavage: incidence and diagnostic value]. / Particules lipidiques intramacrophagiques recueillies par lavage bronchoalvéolaire: fréquence et intérêt diagnostique.

This study aimed to determine the incidence and diagnostic value of fat-laden alveolar macrophages obtained by bronchoalveolar lavage (BAL). In 128 patients, including 66 patients admitted for multiple trauma, 158 BAL were carried out. However, 41 BAL from 32 patients were excluded because of poor quality of samples (not enough macrophages, too many ciliated cells, or haemorrhage). All the patients were intubated and mechanically ventilated, having pulmonary infiltrates on the chest film. BAL samples were examined after staining with oil-red-O. They were considered to be positive when more than 5% of alveolar macrophages contained fat droplets. Among them 14 out of 47 patients (30%) without multiple trauma were positive; 7/14 had never been given any intravenous lipid infusion, and 5/14 had aspiration pneumonia (as opposed to 3/32 patients with negative BAL). Further 27 patients out of the 49 (55%) with multiple trauma were positive. Among them 10/49 had clinical evidence of fat embolism, however, only 7/10 had positive samples. All these last ten patients had been given intravenous lipid infusions. The rate of positive alveolar macrophages was correlated neither with the plasma triglyceride concentration, nor the Fracture Index Score, nor the delay between the end of the lipid infusion and the BAL. There was no significant difference in PaO2/FIO2 ratio between the patients with positive and negative BAL. Positive BAL was significantly associated with lipid infusions. The data therefore suggest that the presence of fat-laden alveolar macrophages are associated with various pathological pulmonary conditions, particularly aspiration pneumonia and lipid infusions.(ABSTRACT TRUNCATED AT 250 WORDS)

Bronchoalveolar lavage in trauma patients for diagnosis of fat embolism syndrome.

Fat embolism syndrome (FES) is a rare but serious complication occurring after long bone fractures. Presence of fat droplets in cells obtained by bronchoalveolar lavage has been proposed as a specific tool for FES diagnosis in trauma patients. We evaluated this technique over a 15-month period in 85 patients. Twenty-eight patients were excluded. The remaining 57 patients were divided into three groups: group 1, 26 patients without trauma as control; group 2, 22 patients with trauma but without evidence of FES; and group 3, nine patients with trauma and evidence of FES. Six of 26 patients in group 1 and nine of 22 patients in group 2 exhibited fat droplets in alveolar macrophages, whereas three of nine patients of group 3 had not. This study suggests that (1) presence of fat droplets in alveolar macrophages is not a reliable method for diagnosis of FES after long bone trauma, and (2) many conditions are associated with fat droplets in alveolar macrophages.