A case of severe toxicity during coadministration of vincristine and piperacillin: are drug transporters involved in vincristine hypersensitivity and drug-drug interactions?

Neurotoxicity is frequent with vincristine treatment, but severe autonomic neuropathy is rare. A decreased activity of drug transporters in the presence of an interacting drug may favor such events by increasing systemic or tissue exposure to the drug. We encountered severe autonomic neuropathy and cholestasis in a child receiving vincristine, after the introduction of piperacillin-tazobactam. A causality assessment of the adverse reaction identified the antibiotic as the most probable cause of the observation. The patient was heterozygous for several common polymorphisms of ABCC2 (multidrug-related protein-2), CYP3A5, and ABCB1 (multidrug-related protein-1, P-glycoprotein), but their role in the toxicity cannot be ascertained.

[Recurrent acute fatty liver of pregnancy]. / Stéatose hépatique aiguë gravidique récidivante.

Acute fatty liver of pregnancy (AFLP) is a rare liver disease unique to pregnancy potentially fatal for both mother and child. Only a few cases of recurrence have been published. We report a new case. A 27-year-old primiparous patient presented a first episode of AFLP in 1991 at 37 week's gestation. Diagnosis was suspected because of vomiting, thrombocytopenia, and liver function tests abnormalities. It was confirmed by liver ultrasonography and abdominal computed tomography. Clinical and biological improvement was observed after caesarean delivery. Six years later, the woman began a second pregnancy. Liver function tests and complete blood count were regularly checked. At 30 weeks' gestation, recurrent AFLP occurred and caesarean section was performed. Again, diagnosis was confirmed by both ultrasonography and abdominal computed tomography. In 2006, the mother and the two girls, 15 and 8-year-old respectively, were in good health. The study of the HADHA gene, coding alpha subunit long chain 3-hydroxyacyl coenzyme A dehydrogenase (LCHAD) in the patient failed to find mutations, particularly the common mutation c.1528G>C (Glu474-Gln, p.E474Q). In conclusion, after an episode of AFLP, women should be clearly warned of the risk of recurrence and regularly monitored during the next pregnancy, even if the search of HADHA gene mutation is negative.

Ursodeoxycholic acid therapy in intrahepatic cholestasis of pregnancy: Results in real-world conditions and factors predictive of response to treatment.

BACKGROUND: Ursodeoxycholic acid (UDCA) therapy is commonly used in intrahepatic cholestasis of pregnancy (ICP). AIM: To evaluate the efficacy and tolerance of UDCA in real-world conditions and to search for factors predictive of response to treatment. METHODS: This observational study included 98 consecutive patients suffering from pruritus during pregnancy associated with increased ALT levels or total bile acid (TBA) concentrations, without other causes of cholestasis. The entire ABCB4 gene coding sequence was analyzed by DNA sequencing. RESULTS: UDCA was prescribed until delivery in all patients (mean dose 14.0mg/kg/day; mean duration 30.4 days). Pruritus improved in 75/98 (76.5%) patients, and totally disappeared before delivery in 25/98 (25.5%). After 2-3 weeks of treatment, ALT levels decreased by more than 50% of base line in 67/86 (77.9%) patients and normalized in 34/86 (39.5%), and TBA concentrations decreased in 28/81 (34.6%). Only one patient stopped the treatment before delivery. On multivariate analysis, ALT >175IU/l before treatment was associated with improvement of pruritus (OR 2.97, 95% CI 1.12-7.89, P=0.029) and with decreased ALT (OR 18.61, 95% CI 3.94-87.99, P=0.0002). ABCB4 gene mutation was not associated with response to treatment. CONCLUSION: This study supports the use of UDCA as first line therapy in ICP.

Preanalytical conditions of point-of-care testing in the intensive care unit are decisive for analysis reliability.

BACKGROUND: Point-of-care testing (POCT) systems enable a wide range of tests to be rapidly performed at the bedside and have attracted increasing interest in the intensive care unit (ICU). However, previous studies comparing the concordance of POCT with central laboratory testing have reported divergent findings. Most reported studies on POCT reliability have focused on analyzer performance rather than the preanalytical phase. The aim of this study was to assess the reliability of results provided by point-of-care analyzers according to the organization of the care units and the preanalytical process. METHODS: In three adult critical care units, 491 paired blood samples were analyzed for hemoglobin, potassium, and sodium concentrations by blood gas analyzers (identical reference) and the central laboratory. The clinical significance of agreement was assessed using Bland-Altman plots. A quality improvement program was then implemented to improve the preanalytical POCT process for one ICU where there was poor agreement. A second comparison was performed on 278 paired blood samples in this unit. RESULTS: Biases were clinically nonsignificant for potassium and sodium concentrations for all tested critical care units, relative to the reference method. However, biases [limits of agreements] for hemoglobin analyses were clearly affected by the preanalytical process: -3 [-6; 1] g/L in the operating room, -5 [-28; 17] g/L in a 10-bed ICU, and -19 [-64; 27] g/L in a 37-bed ICU. The quality approach was implemented in the 37-bed ICU and led to corrective actions that: (1) reduced the time for the POCT preanalytical phase; (2) implemented a checklist to validate the preanalytical conditions; (3) used technical innovations. The improvement of the preanalytical process resulted in a substantial decrease of the bias for hemoglobin concentration measurements: -3 [-10; 5] g/L in the 37-bed ICU. CONCLUSION: We clearly demonstrate that an identical analyzer can provide results of varying quality depending on the local constraints of the ICUs. We demonstrate that quality management focused on the preanalytical process and performed by the partners involved in the POCT can overcome these issues.

Iron metabolism disturbance in a French cohort of ALS patients.

OBJECTIVE: The aim of this study was to assess iron status in a cohort of amyotrophic lateral sclerosis (ALS) patients compared to controls in order to evaluate these parameters as a risk factor or a modifying factor of ALS. METHODS: We collected serum iron, ferritin, transferrin, total iron-binding capacity, and transferrin saturation coefficient (TSC) from 104 ALS patients at the time of diagnosis and from 145 controls. We reported phenotypic characteristics and evolution parameters such as ALSFRS-R and forced vital capacity at diagnosis and after one year of follow-up. In a first step we compared iron status between ALS patients and controls, and then we evaluated the relation between iron status and disease evolution of ALS patients using univariate and multivariate analysis. RESULTS: We observed increased concentrations of serum iron (P = 0.002) and ferritin (P < 0.0001) and increased TSC (P = 0.017) in ALS patients. We also showed an association between markers of iron status and high body weight loss in ALS patients. The multivariate analysis of survival highlighted a significant relation between ferritin level and disease duration (P = 0.038). CONCLUSION: This is the first study showing a higher concentration of serum iron in ALS patients, strengthening the involvement of a deregulation of iron metabolism in ALS.

Study of the HFE gene common polymorphisms in French patients with sporadic amyotrophic lateral sclerosis.

Our objective was to investigate whether the C282Y (p.Cys 282 Tyr) and H63D (p. His 63 Asp) HFE polymorphisms were associated with sporadic amyotrophic lateral sclerosis (SALS) in the French population. We searched for a relation of HFE polymorphisms with the clinical characteristics of the disease. The HFE polymorphisms were studied in 824 patients with SALS and 583 controls. We compared the frequency of the polymorphisms between SALS and controls groups by univariate and multivariate statistics, taking into account gender, site, age-at-onset and survival. We did not observe significant difference in the frequency of H63D polymorphism between SALS and control group. We observed a significant difference for C282Y between patients and controls with a low frequency of the Y allele in patients (3.2%) compared to our control group (5.9%). Disease duration, distribution of gender, site-of-onset, age-at-onset did not differ between groups taking into account genotypes of each polymorphism. Our results in this large cohort of ALS patients indicate that H63D polymorphism is not associated with SALS in the French population. This conclusion does not exclude a weak effect of the HFE gene polymorphisms in certain ALS populations, or an effect of other rare HFE gene variants.

MECP2 gene mutations in non-syndromic X-linked mental retardation: phenotype-genotype correlation.

Non-syndromic X-linked mental retardation (MRX) is a frequent cause of inherited mental retardation. It is a heterogeneous condition in which the first 12 genes discovered to date explain no more than 15% of the MRX situations ascertained by recurrence in multiplex families. In Rett syndrome (RTT), an X-linked dominant condition mostly sporadic and usually lethal in males, most affected females have been shown to be mutated in the Methyl-CpG binding protein 2 gene (MECP2) that maps at Xq28. Some mentally retarded males related to RTT females carry the same mutation. Several MRX families mapping to Xq28 were subsequently tested for MECP2 and a causative mutation was discovered in three families, suggesting that it could be one of the main genes involved in MRX. We report here the corresponding phenotypes in these three families of increasing severity. In family 1, an in-frame deletion DeltaP387-M466 was found in the 3' region. The patients had severe to mild non-progressive MR, with better motor skills than verbal abilities. In family 2, an Arg to Trp substitution (R167W) was found between the transcription repression domain (TRD) and the methyl binding domain (MBD). The patients had brisk reflexes and essential tremor with mild and non-progressive MR, poor motor co-ordination and written language difficulties. In the third family (MRX16), a Glu to Gly substitution (E137G) was found in the MBD. The patients had manifestations similar to those of family 2, but MR was mild to moderate, speech articulation was poor and some had verbal stereotypies. Regression of language skills was suspected in three patients. Phenotype-genotype correlation could thus be suspected and is discussed in these three families.