Search

Pseudomonas exotoxin (PE) is a cytotoxin which, after endocytosis, is delivered to the cytosol where it inactivates protein synthesis. Using diaminobenzidine cytochemistry, we found over 94% of internalized PE in transferrin (Tf) -positive endosomes of lymphocytes. When PE translocation was examined in a cell-free assay using purified endocytic vesicles, more than 40% of endosomal 125I-labeled PE was transported after 2 h at 37 degrees C, whereas a toxin inactivated by point mutation in its translocation domain was not translocated. Sorting of endosomes did not allow cell-free PE translocation, whereas active PE transmembrane transport was observed after > 10 min of endocytosis when PE and fluorescent-Tf were localized by confocal immunofluorescence microscopy within a rab5-positive and rab4- and rab7-negative recycling compartment in the pericentriolar region of the cell. Accordingly, when PE delivery to this structure was inhibited using a 20 degrees C endocytosis temperature, subsequent translocation from purified endosomes was impaired. Translocation was also inhibited when endosomes were obtained from cells labeled with PE in the presence of brefeldin A, which caused fusion of translocation-competent recycling endosomes with translocation-incompetent sorting elements. No PE processing was observed in lymphocyte endosomes, the full-sized toxin was translocated and recovered in an enzymatically active form. ATP hydrolysis was found to directly provide the energy required for PE translocation. Inhibitors of endosome acidification (weak bases, protonophores, or bafilomycin A1) when added to the assay did not significantly affect 125I-labeled PE translocation, demonstrating that this transport is independent of the endosome-cytosol pH gradient. Nevertheless, when 125I-labeled PE endocytosis was performed in the presence of one of these molecules, translocation from endosomes was strongly inhibited, indicating that exposure to acidic pH is a prerequisite for PE membrane traversal. When applied during endocytosis, treatments that protect cells against PE intoxication (low temperatures, inhibitors of endosome acidification, and brefeldin A) impaired 125I-labeled PE translocation from purified endosomes. We conclude that PE translocation from a late receptor recycling compartment is implicated in the lymphocyte intoxication procedure.

The new phases Ln_1/3Zr₂(PO₄)₃ (Ln = Rare Earth) crystallize with the Nasicon-type structure. The rare earth is located in the usually labeled M₁ site with rather ionic Ln-O bonds. The ceramics resulting from the decomposition of these phosphates have been characterized in the case of lanthanum and europium. They exhibit a very low thermal expansion between room temperature and 1340°C. Copyright 1994, 1999 Academic Press

BackgroundIron is used like a medicine to treat or prevent haemolytic anaemia. When iron is administered concomitantly with certain drugs, it can change absorption of these drugs by complex reaction. Consequently, treatments become ineffective.PurposeTo study in vitrophysicochemical behaviour of iron with different cytotoxic drugs used in oncology therapeutic protocols.Material and methodsWe prepared several mixtures of bivalent and trivalent iron solutions with 13 anticancer drugs after their reconstitution. We mixed 0.1 ml of 5% iron solution (Fe 2+or Fe3+) with 1 mL of diluted drugs in glass tubes, and we observed in the presence or absence of a precipitate.The formed precipitates were washed, dried and identified by infrared spectroscopy and UV-visible spectroscopy. Spectra obtained are compared with those of the anticancer drugs studied.ResultsResults are represented in the following table:Abstract 3PC-033 Table 1Cytotoxic drug (1 ml)Interaction with ironCytotoxic drug (1 ml)Interaction with ironFe 2+ (0.1 ml) Fe3+ (0.1 ml) Fe2+ (0.1 ml) Fe3+ (0.1 ml) Etoposide +RedDoxorubicin/Epirubicin black+Carboplatin – Yellow Vincristine – – Cyclophosphamide – Yellow Ifosfamid – Yellow Cytarabine +RedCisplatin – Yellow Vinblastine – Yellow Methotrexate ++Dacarbazine – Yellow Bleomycin – – +: presence of precipitate –: no precipitateSpectra obtained by UV-visible and IR spectroscopy of the precipitates correspond to the spectra of cytotoxic drugs. We can deduce that the iron complex is incompatible with etoposide, cytarabin, doxorubicin, epirubicin and methotrexate.ConclusionThe findings suggest that iron (Fe3 +and Fe2+) is not compatible with etoposide, cytarabine doxorubicin, epirubicin, and methotrexate. We can deduce that intravenous iron should preferably be taken at least 2 hours before or 2 hours after taking these anticancer drugs to limit the risk of developing complications. For oral formulae like etoposide and methotrexate, concomitant administration of oral iron should be avoided in order to ensure good absorption.References and/or Acknowledgements1. Arlet J-B, et al. Iron therapy: indications, limitations and modality. Rev Méd Int2012;34:26–31.2. Dan L Longo MD. Iron-deficiency anaemia. N Engl J Med2015;372:1832–43.No conflict of interest

BackgroundFurosemide is a diuretic widely indicated in paediatric diseases especially for the treatment of oedema associated with congestive heart failure, cirrhosis of the liver or renal disease. Its stability is very important and must be proved to ensure paediatric patient safety.PurposeThe aim of this study was to determine the physicochemical stability for furosemide 1 mg/ml in polypropylene syringes stored in different conditions.Material and methodsNine polypropylene syringes were prepared using the generic product of furosemide (1 mg/ml) in NaCl 0.9%. The nine syringes were stored in different conditions for 72 hours. The following table describes these conditions:Abstract 3PC-009 Table 1Number of syringes of furosemide 1 mg/ml 3 3 3 Temperature25°C±3°C 8°C±3°C 25°C±3°C LightDaylight Absent Artificial We studied several physical and chemical parameters immediately after preparation (0 hour) and after 6, 24, 48 and 72 hours. These parameters are colour, opacity, presence of precipitation or microagregate, pH and absorbance.Each preparation was visually inspected in front of a black and white background. Preparations were centrifuged and aliquots were examined by microscope. pH measurements were carried out by pH-metre and spectrophotometric measurements were obtained after dilution of solutions, at three wavelengths: 229, 278 and 331 nm with a UV-visible spectrophotometer.ResultsAfter 72 hours, no colour change, no opacity, no precipitation and no microaggregate were observed. For chemical parameters, there was no variation in pH absorbance in all conditions of storage.For spectrophotometric measurements, there is no significant change in absorbance in all conditions of storage. Studies showed that degradation products do not absorb at the same wavelengths of furosemide. We can deduce that the method used is specific for the determination of furosemide.ConclusionFurosemide 1 mg/ml in NaCl 0.9% propylene syringes preserved its physical and chemical properties for at least 72 hours in all conditions of storage. So we can prepare many paediatric injections in our hospital that we can store for 72 hours.References and/or Acknowledgements1. HansBundgaard, et al. Photodegradation and hydrolysis of furosemide and furosemide esters in aqueous solutions. Int J Pharma, 1988; 42: 217–224.No conflict of interest

BackgroundEncephalopathy is a rare but serious central nervous system toxicity of ifosfamide. Its clinical symptoms are confusion, stupor, seizures, hallucinations and blurred vision.1The methylene blue (MB) is administered as an antidote to the encephalopathy.PurposeDescription of MB formulation and control quality analysis of the preparation and safety case of encephalopathy associated with ifosfamide in the absence of MB injectable in the pharmaceutical market in the country.Material and methodsInitially the MB solution 10 mg/ml for intravenous administration was prepared. A disposable closed system transfer device with filter 0. 15 µm was used, so as to perform a sterile filtration. Next, an analytical control of drug substance and drug product was carried out in accordance with United States Pharmacopoeia. Finally, the preparation was administrated to the patient.ResultsA 60-year-old woman had a uterine leiomyosarcoma in February 2016. The patient received the first cure of doxorubicin (20 mg/m2), ifosfamide (2.5 g/m2) and mesna (2.5 g/m2). On the third day of treatment, the patient had obnubilation and awareness troubles. Ifosfamide-induced encephalopathy was suspected. A treatment with MB was proposed, but unfortunately the product is not marketed in the country. The MB was prepared at the pharmacy with serum glucose 5%: every 1 ml contains 10 mg of drug substance. It has the same visible absorption spectrum as the MB standard solution, contains less than 2.5 USP endotoxin unit per ml, has an osmolality of 308 mmol/Kg, a pH of 4.76 and the preparation was sterile. The drug substance was identified with infrared absorption, The patient received the MB solution in a dose of 6×50 mg day-1. The encephalopathy was resolved with recovery at the neurological level.ConclusionThe MB continues to be an effective antidote for encephalopathy associated with ifosfamide. As was seen in our patient, a dose of 6×50 mg day-1was sufficient for the management of encephalopathy. Our result is consistent with a previous report.Reference and/or Acknowledgements1. Pelgrims J, De Vos F, Van den Brande J, Schrijvers D, Prové A, Vermorken JB. Methylene blue in the treatment and prevention of ifosfamide-induced encephalopathy: report of 12 cases and a review of the literature. Brit J Cancer2000;82(2):291–294.No conflict of interest

BackgroundPhysicochemical incompatibilities of parenteral drugs cause several problems in hospital practice. These incompatibilities can be represented by precipitation, complexation or colour change before or during administration to patients. Understanding these incompatibilities allow pharmacists to avoid many problems during preparation and administration.PurposeTo determine physicochemical incompatibilities of a cytotoxic drug widely used in paediatric oncology (methotrexate) with certain trace elements existing in food and medicines, as well as in food supplements.Material and methodsWe performed several mixtures to study physicochemical reactions between methotrexate reconstituted in infusion bags (25 mg/ml) and five cations: calcium (Ca2+), copper (Cu2+), iron (bivalent and trivalent), magnesium (Mg2+) and zinc (Zn2+). An interaction was elucidated by formation of a precipitate visible to the naked eye. Infrared spectroscopy was the method of authentication of precipitates.ResultsPrecipitates were formed with the copper, zinc, bivalent and trivalent iron. On the other hand, there was no precipitate with calcium and magnesium. Functional analysis of infrared spectra of precipitates showed the presence of methotrexate.ConclusionThe study of the physicochemical incompatibilities of methotrexate can avoid possible interactions with medicines, food or nutritional supplements containing trace elements.Recording to the results, methotrexate precipitates in the presence of copper, zinc and iron ions. The absence of the precipitate or change of colour in the other mixtures does not exclude a possible complexation.Reference and/or Acknowledgements1. Benaji B, et al. Compatibility study of methotrexate with PVC bags after repackaging into two types of infusion admixtures. Int J Pharma1994;105(1):83–87.No conflict of interest

BackgroundDrug reaction with eosinophilia and systemic symptoms (DRESS syndrome) was first described for anticonvulsant drugs and the same symptoms were subsequently observed with a variety of other drugs such us anti-inflammatory drugs. An effective approach for objective causality assessment is necessary to make consistent and accurate identification of this adverse drug reaction (ADRs).PurposeTo evaluate the incidence and the clinical characteristics of DRESS syndrome associated with anti-inflammatory drugs and the causality assessment for estimating the strength of relationship between drug(s) exposure and occurrence of ADR.Material and methodsThe database of the national pharmacovigilance centre (NPC) was used from January 2008 to January 2016 and the WHO causality assessment method was used as a tool for the clinical assessment of ADRs.ResultsOf the 72 reports of DRESS syndrome recorded in the NPC during 8 years, we reviewed 16 reports coded DRESS associated with anti-inflammatory drugs (22.2% of all patients) and which meet the inclusion criteria. The average age was 27 years and 56.2% were in males. The average time to DRESS onset after the start of administration of the suspected drug was 18 days. The outcome was serious in 14 cases (87.5%). The most common causative agents were prednisolone (31.2%) and ibuprofen (12.5%). Clinical presentation: fever 100%, skin rash 100%, 82% eosinophilia, lymphadenopathy 22%, cheilitis 12.5% and an altered state of consciousness 12.5%. For causality assessment: 57.7% of suspected drugs had a ‘Possible’ score and 42.1% had ‘Probable’ score.ConclusionIn this retrospective study, prednisolone was the major case of DRESS syndrome and an altered state of consciousness were associated, and cheilitis with indometacin, although all patients recovered after corrective treatment.References and/or Acknowledgements1. Bannwarth B. Critères d’imputabilitèé des effets indèéésirables des mèééédicaments. Revue du Rhumatisme Monographies2010;77(2):173—5.2. Akarin Hiransuthikul, Thanapoom Rattananupong, Jettanong Klaewsongkram, et al. Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS): 11 years retrospective study in Thailand. Allergology International2016;65:432–438.No conflict of interest

BackgroundHyperpigmentation is a potential side-effect of antimalarial drugs, such as chloroquine. It has generally been explained that the hyperpigmentation associated with chloroquine is due to the affinity for melanin and it gets concentrated in pigmented structures.PurposeTo describe a case of a middle-aged female, who developed a skin hyperpigmentation associated with chloroquine after 6 years of treatment.Material and methodsA 36-year-old female diagnosed with lupus nephritis and arterial hypertension since 2006, received medical treatment with chloroquine (100 mg/day), acetylsalicylic acid (100 mg/day), enalapril (20 mg/day) and mycophenolate mofetil (2 g/day).ResultsThe patient was referred to the dermatology service for evaluation of a dark stain on the back and both lower limbs that had appeared around 6 years after starting treatment, without any painful symptoms.On the basis of the causality assessment according to the French method, a score of I6B4 was attributed to chloroquine, I1B1 to acetylsalicylic acid, enalapril and mycophenolate mofetil.A score of I6B4 was the high score observed which means that the delay in onset was compatible, the adverse effect persisted after the reintroduction of chloroquine and the drug effect mechanism is evocative of the drug’s role in the occurrence of this adverse effect and the drug reaction was reported in the literature.ConclusionThe chronological, semiotic criteria and bibliographic data are in favour of a relationship with chloroquine and the skin hyperpigmentation, especially as this adverse effect is not described with the other associated drugs. However, an eye examination is necessary to detect any infringement of the retina that can lead to blindness.References and/or Acknowledgements1. Marie G, Claire G, Francoise H, Dominique H-B, et al. Réactualisation de la mééthode francaise d’imputabilitééé des effets indéééésirables des mééééédicaments. Théééééérapie2011Novembre–Dééééééécembre;66(6):517–525.2. Panamboor S, Matti PA, Maria K. Hyperpigmentation of the skin following chloroquine treatment: case series report. IJPTJanuary 2005;4(1).No conflict of interest

BackgroundCisplatin, carboplatin and oxaliplatin are three major platinum salts used for intravenous chemotherapy. However, their efficacy is accompanied by different toxicities.PurposeThe aim of our study is to identify adverse drug reactions of platimum salts.Material and methodsAn observational prospective analysis was conducted between March 2014 and September 2015 in the oncology sector of a central hospital. Data were collected and analysed using Excel 2013. We collaborated with the National Centre of Pharmacovigilance for fresh imputability analysis.ResultsThe study included 70 patients, the average age was 52 years and the sex ratio (F/M) was 0.41. The most frequent cancers were colorectal cancer (46% of patients) and cervical cancer (18%). Oxaliplatin was the most commonly reported molecule (45%).During 18 months of study, we collected 222 adverse drug reactions with sensory and neurosensory toxicities (26% and 21%, respectively).Peripheral neuropathy, digestive intolerance and haematological toxicities were attributed to platinum salts with an I2B4 score.ConclusionPlatinum salts cause several complications, especially neurosensory toxicities. The pharmacist has an important role in monitoring post-chemotherapy, which avoids and prevents many adverse events.Reference and/or Acknowledgements1. Jean-Pasto MJ. Hypersensitivity to platinum salts: pharmacovigilance, pulmonology. Revue des Maladies RespiratoiresNovember 2006;23(5):487–488.No conflict of interest