[Bilateral adrenal hemorrhage under apixaban in primary antiphospholipid syndrome]. / Nécrose hémorragique bilatérale des surrénales sous apixaban : penser au syndrome des antiphospholipides ?

INTRODUCTION: Adrenal hemorrhage is a classical but rare complication of antiphospholipid syndrome, revealing diagnosis in one third of the cases. Anti-vitamin K therapy is the standard treatment but direct oral anticoagulants are discussed as an alternative. In the latest recommendations, it is advised not to use direct oral anticoagulants in the setting of antiphospholipid syndrome. CASE REPORT: We present a case of bilateral adrenal hemorrhage revealing primary antiphospholipid syndrome with triple positive antibody profile, in a 47-year-old man treated by apixaban for previous venous thromboembolism. CONCLUSION: To our knowledge, it is the first case of adrenal hemorrhage occurring during apixaban treatment in a patient with antiphospholipid syndrome. This case illustrates the inefficacy of direct oral anticoagulants to prevent thrombotic events in antiphospholipid syndrome, in accordance with the latest recommendations.

Severe neurological disorders and refractory aspergillosis in an adolescent treated by vincristine and voriconazole.

WHAT IS KNOWN AND OBJECTIVE: Voriconazole and vincristine are major therapeutics in paediatric haematology. However, the risk-benefit ratio of the treatment of invasive aspergillosis with voriconazole in patients receiving vincristine-based chemotherapy remains unclear. CASE DESCRIPTION: We report severe peripheral and central neurological disorders in a 14-year-old girl with T-cell acute lymphoblastic leukaemia and pulmonary aspergillosis. The case describes a strong exacerbation by voriconazole of the vincristine-induced neuropathic pains. It shows the high variability of the trough serum concentration of voriconazole leading to antifungal treatment failure and suggests that its own central neurotoxicity could also be potentiated by vincristine. WHAT IS NEW AND CONCLUSION: Given the risk of either insufficient antifungal efficacy or excessive neurological disorders, this case warns on a probable unfavourable risk-benefit profile of voriconazole during vincristine-based chemotherapy in adolescents.

A Case of Undiagnosed HIV Infection in a 57-Year-Old Woman with Multiple Myeloma: Consequences on Chemotherapy Efficiency and Safety.

Background. Non-AIDS-defining cancers represent a rising health issue among HIV-infected patients. Nevertheless, HIV testing is not systematic during the initial cancer staging. Here, we report a case of HIV infection diagnosed three years after chemotherapy initiation for multiple myeloma. Results. A 57-year-old woman diagnosed with multiple myeloma underwent a first round of chemotherapy by bortezomib/lenalidomide and then with bortezomib/liposomal-doxorubicine/dexamethasone, with partial remission, poor hematological tolerance, and multiple episodes of pneumococcal infection. Allogenic stem cell transplantation was proposed leading to HIV testing, which revealed seropositivity, with an HIV viral load of 5.5 Log10/mL and severe CD4 T cell depletion (24 cells/mm(3)). Chemotherapy by bendamustin was initiated. Multidisciplinary staff decided the initiation of antiretroviral therapy with tenofovir/emtricitabin/efavirenz and prophylaxis against opportunistic infections. After 34 months, patient achieved complete remission, sustained HIV suppression, and significant CD4 recovery (450 cells/mm(3)), allowing effective pneumococcal immunization without relapse. Conclusion. Our case illustrates the drawback that ignored HIV infection is still causing to cancer patients receiving chemotherapy and highlights the importance of early HIV testing in oncology. A multidisciplinary approach including oncologists/hematologists, virologists, and pharmacists is recommended in order to avoid drug interactions between chemotherapy and antiretroviral drugs. Moreover, prophylactic medication is recommended in these patients regardless of CD4+ cell count at the initiation of chemotherapy.

Non-AIDS-related malignancies: expert consensus review and practical applications from the multidisciplinary CANCERVIH Working Group.

Malignancies represent a major cause of morbidity and mortality in human immunodeficiency virus (HIV)-infected patients. The introduction of combined antiretroviral therapy has modified the spectrum of malignancies in HIV infection with a decreased incidence of acquired immunodeficiency syndrome (AIDS) malignancies such as Kaposi's sarcoma and non-Hodgkin's lymphoma due to partial immune recovery and an increase in non-AIDS-defining malignancies due to prolonged survival. Management of HIV-infected patients with cancer requires a multidisciplinary approach, involving both oncologists and HIV physicians to optimally manage both diseases and drug interactions between anticancer and anti-HIV drugs. The French CANCERVIH group presents here a review and an experience of managing non-AIDS malignancies in HIV-infected individuals.

Seventy-two-hour stability of Taxol in 5% dextrose or 0.9% sodium chloride in Viaflo, Freeflex, Ecoflac and Macoflex N non-PVC bags.

BACKGROUND AND OBJECTIVES: Taxol (paclitaxel), is an antimicrotubule agent widely prescribed for the treatment of many tumoral diseases. Taxol must be used in non-polyvinyl chloride bags, diluted to concentrations of 0.3-1.2 mg/mL in 5% dextrose or in 0.9% sodium chloride. Under these conditions, Taxol is chemically and physically stable for 27 h at 25 degrees C. The aim of the study was to evaluate the 72-h stability of Taxol under common clinical use conditions. METHODS: Taxol was diluted with 5% dextrose and 0.9% sodium chloride to final concentrations of 0.3 and 1.2 mg/mL in four polyolefin bags (Viaflo, Freeflex, Ecoflac and Macoflex N). Taxol-stability, was assessed by turbidimetry and by high-performance liquid chromatography using solutions stored in the dark, over 72 h at +4 degrees C. RESULTS: No haze, turbidity, or precipitate was observed. Paclitaxel concentration remained above 95% of the initial value whatever the solvent or container used. CONCLUSION: Paclitaxel at 0.3 and 1.2 mg/mL in 5% dextrose and in 0.9% sodium chloride is stable in Viaflo, Freeflex, Ecoflac and Macoflex N non-PVC bags for 72 h in the dark at +4 degrees C. The longer stability should make the use of Taxol in clinical practice easier.

Experience of a combination including indinavir 400 mg plus ritonavir 200 mg twice daily in HIV-infected patients: pharmacokinetic data.

Low doses of ritonavir, a strong inhibitor of cytochrome P450 3A4, enhances the pharmacokinetic profile of indinavir with increased serum levels. We assessed the indinavir-ritonavir 400/200 twice daily combination in 17 HIV-infected patients focusing on the pharmacokinetic data and the tolerance of this regimen. IDV trough and peak concentrations were measured by high-performance liquid chromatography. Median indinavir trough and peak concentrations were 553 ng/ml and 3626 ng/ml, respectively. A good tolerance was observed except for three patients who experienced a major toxicity. Only one dose adjustment was related to indinavir toxicity. Considering the fact that Cmax is mainly responsible of the adverse effects, particularly renal stones, the indinavir-ritonavir 400/200 mg twice daily regimen offers a well-tolerated combination with an increased Cmin but a lower Cmax compared with both the standard tid regimen and higher dose of IDV-RTV regimens.

Polymorphisms of human aryl hydrocarbon receptor (AhR) gene in a French population: relationship with CYP1A1 inducibility and lung cancer.

The Ah receptor (AhR) is a ligand-dependent transcription factor that positively regulates the expression of the CYP1A1 gene. We investigated the genetic polymorphisms of the AhR gene including the promoter, and examined the link between these polymorphisms, CYP1A1 inducibility and the lung cancer incidence. The AhR promoter region and the 11 exons of 30 subjects were screened. Among the three polymorphisms found, two [(2417)(A/G) ((157)G/A)] have never been described previously. The (1721)(G/A) and (2417)(A/G) are localized in exon 10 and lead to Arg(554)Lys and Met(786)Val substitutions, respectively. The other polymorphism was found in the 5'-untranslated region, resulting in the substitution of a G by an A at position 157 (157)(G/A). To evaluate the frequency of this allelic variant found, a DNA library of a case-control study of lung cancer (162 controls and 177 patients) was studied. There is no significant association between (1721)(G/A), (157)(G/A) and lung cancer: (1721)(G/A) and (157)(G/A) were detected at the same allele frequency of 0.086 and 0.25, respectively in both controls and patients. (2417)(A/G) was found in only one control of 100 (allele frequency 0.005). Statistical analysis did not show any relationship between both (1721)(G/A) and (157)(G/A) polymorphisms found and CYP1A1 inducibility. Considering the rareness of the (2417)(A/G) allelic variant we were not able to evaluate its association with inducibility. In conclusion, none of the polymorphisms were found to play a key role in the CYP1A1 inducibility or in the susceptibility to develop lung cancer.

Relationship between efficacy, tolerance, and plasma drug concentration of ritonavir in children with advanced HIV infection.

The relationship between ritonavir plasma concentration, efficacy, and tolerance was evaluated in 31 children with advanced HIV infection who were receiving a triple therapy with ritonavir as protease inhibitor. Median CD4+ lymphocyte count and median viral load before the initiation of ritonavir-containing combination therapy were 1320 cells/mL and 5 log10 copies/mL, respectively. Ritonavir was given at a dose ranging from 300 to 450 mg/m2 twice daily. The median follow-up of triple therapy was 19 months. Response was defined as a drop of viremia of more than 1 log. Plasma drug levels were determined twice during the observation period: after at least 4 weeks and after 3 months of combined treatment. Samples were collected before (residual) and 2 hours (T2) after drug intake. Cholesterol, triglycerides, alanine transaminase, aspartate transaminase, and gamma-glutamyl transpeptidase were assessed at the same time. The median values of ritonavir residual and T2 levels were 1.64 mg/L and 5.9 mg/L at observation 1 and 3.35 mg/L and 6.29 mg/L at observation 2, respectively. According to virologic response, median residual concentrations of ritonavir were 3.17, 2.52, and 1.04 mg/L for the complete, the partial, and the no-response groups. The authors observed a wide intersubject variability of ritonavir concentrations with an increase in residual levels between the two observation periods. Residual levels were correlated with virologic response whereas there was no direct association between T2 levels and long-term response. Patients with complete or partial response displayed statistically significantly higher residual concentrations than the no-response group. No correlation could be demonstrated between elevated plasma drug concentrations and abnormal cholesterol or triglycerides values. These results emphasize the importance of a sustained high ritonavir concentration to achieve optimal treatment efficacy. Furthermore, these results prove the clinical benefit of therapeutic drug monitoring and could potentially improve patient evaluation in terms of treatment efficacy, compliance, and viral resistance.

Intracellular nucleotides of (-)-2',3'-deoxy-3'-thiacytidine in peripheral blood mononuclear cells of a patient infected with human immunodeficiency virus.

An analytical methodology was developed to quantitate the intracellular nucleotides including mono-, di-, and triphosphates and the diphosphocholine derivative of (-)-2', 3'-deoxy-3'-thiacytidine (3TC) in human peripheral blood mononuclear cells (PBMCs). The procedure includes the resolution of 3TC nucleotides by solid-phase extraction (SPE) on an anion-exchange cartridge, with subsequent enzyme digestion of the resulting phosphates to the parent drug that is ultimately quantitated by high-performance liquid chromatography with UV detection (HPLC-UV). Validation was performed with PBMCs from healthy donors exposed to [3H]3TC, leading to the formation of intracellular nucleotides that were quantitated by anion-exchange HPLC with radioactive detection (HPLC-RA). These nucleotide levels served as reference values and were used for cross-validation with data obtained by HPLC-UV. An excellent correlation was established between the results obtained by HPLC-RA and those obtained by HPLC-UV, with a slope of the regression lines close to unity and intercepts near nullity as well as a correlation coefficient close to unity for all 3TC phosphates. The assay was characterized by a limit of quantitation below 1 ng (amount on column) with a precision (percentage of coefficient of variation of repeated measurement) ranging from 0.8 to 18.1% and an accuracy (deviation of the amount determined by HPLC-UV from the nominal reference value) varying from -14.8 to 19.4%. This methodology was successfully applied to determine the quantity of 3TC nucleotides in PBMCs of a patient infected with human immunodeficiency virus after oral administration of 3TC and stavudine.