of 1

Quantitation design of ephedrines by GC/MS – Multivariate optimization, validation of methods and applications in urines

5 views
All materials on our website are shared by users. If you have any questions about copyright issues, please report us to resolve them. We are always happy to assist you.
Share
Description
Quantitation design of ephedrines by GC/MS – Multivariate optimization, validation of methods and applications in urines
Transcript
  duration of VRC was 77 days. Ninety-nine trough concentrations (Cmin) of VRCand MVRC were measured. Median Cmin VRC values were 1.40 mg/L [0–8.30] andmedian Cmin MVRC were 2.20 mg/L [0.40–24]. Median VRC N-oxidation index(ratio [MVRC]/[VRC] ) was 2.4. Cmin VRC was <1 mg/L in 32% of cases and<0.5 mg/L in 20% of them. Patients with Cmin VRC <1 mg/L had a higher ratiothan patients with Cmin>1 mg/L (median ratio 5.7 vs. 1.0, respectively). Amongthe 28 patient, seven died. The clinical course of 13 patients was considered as acomplete resolution of invasive fungal infection (IFI), six patients had a lack of response and two patients switched to other antifungals . Eight adverse-effects wereobserved (visual hallucinations two patients, hepatic disturbances four, cutaneousreaction one, neurological trouble one); for four of them Cmin VRC>2 mg/L, andfor five patients Cmin MVRC>2 mg/L. No correlation was found between VRC Cminand IFI outcome. Conclusion:  VRC TDM is now recommended to optimize the benefit/risk ratio. Inthe absence of CYP2C19 polymorphism determination, the measurement of MVRCin patients with subtherapeutic VRC Cmin (<1 mg/L) could be helpful to improvethe knowledge about the influencing factors. Moreover, the role of MVRCconcentrations in the occurrence of adverse-effects needs to be further investigated. 130 Neurological disorders due to cefepime: two cases in 2 months C Durand-Maugard, A Bernardy, C Andre´jak, H Masson, L Hary, M Andre´jak,AS Lemaire-Hurtel Introduction:  Neurological disorders are well-known adverse side effects of cephalosporin antibiotic treatment. But few cases are described with cefepime.These side effects are described more often in patients with kidney failure treated byhigh dosages. We report two cases of neurological disorders. Cefepime overdosagewas confirmed by blood assays. Methods:  Two cases of cefepime overdosage were notified to the Regional Centerof Pharmacovigilance of Amiens in September and October 2008. Results:  Case1: A man, 82-year-old, with oligo-anuric acute kidney disease(creatinin clearance (Cr Cl) = 27 mL/min), was treated by cefepime 2 g/day for apneumonia. Three days after the beginning of the antibiotherapy, he went into acoma. The renal failure increased (CrCl = 10 mL/min). An overdosage of cefepime,due to an increase of kidney failure, was suspected 2 days later. It was confirmed byan assay 8 h after last administration (blood cefepime = 48.1  l g/mL). The CrCl atthis time was much lower (7.05 mL/min). After four dialyses, cefepime had aresidual concentration of 1.1  l g/mL. The disorders vanished. Case 2: A woman, 71-year-old, was treated by cefepime 4 g  ·  2/day for an infection on hip prosthesis.After 3 weeks of antibiotherapy, convulsions and alteration of consciousness wereobserved. In the same time, CrCl decreased from 36 to 15 mL/min (MDRD).Overdosage of cefepime was confirmed by blood and cerebrospinal fluid (CSF) assays: Cefepime concentrations (hours after convulsions) Blood ( l g/mL) CSF ( l g/mL)20 h 16032 h 29 1392 h 7 Conclusion:  Cefepime is mostly eliminated by kidneys (85%) (1) . In these two cases,dosages were too high and/or not appropriate to the renal function. Neurologicaldisorders due to cefepime mostly occur in patients with impaired renal function ortreated with high dosages (1) . In those patients, half life of cefepime is longer due to adrug accumulation. The blood-brain barrier permeability is increased. In our 2ndcase, the ratio of blood/CSF concentrations was increased and close to 2, as it isusually of 10 (2) . This woman had presented several acute kidney failure bouts withprevious aminosid treatments and should have been viewed as a high-risk patient.So, it is essential to adjust dosage to the renal function and/or to check bloodconcentrations of cefepime especially in patients with risk factors. References: 1. Sonck J et al. The neurotoxicity and safety of treatment with cefepime in patientwith renal failure. Nephrol Dial Transplant 2008;23:966–970.2. Chatellier et al. Cefepime-induced neurotoxicity: an underestimated complicationof antibiotherapy in patients with acute renal failure. Intensive Care Med2002;28:214–217. 131 Methotrexate exposure and outcome in patients receiving a MBVPchemotherapy for a primary central nervous system lymphoma H Blasco, D Senecal, A Le Gouge, E Pinard, I Benz, JS Hulot, E Chatelut, C Le Guellec Introduction:  Methotrexate-basedchemotherapyiswidelyusedinthetreatmentof primary central nervous system lymphoma (PCNSL) but the optimal methotrexate(MTX) administration schedule is still unknown. It was previously advocated thatschedules leading to a higher area under the concentration-time curve (AUC) wereassociated with a better response with no higher incidence of toxicity. However, theheterogeneityofthetreatmentsanalyzeddidnotallowtheauthorstostudyexposure-effects relationships within each type of treatments. We aimed at analysing theserelationships in patients treated by a MBVP (methotrexate, BCNU, VP16, methyl-prednisolone) chemotherapy, administered according to two different modalities. Methods:  We retrospectively analysed patients with PCNSL treated with two(schedule 1) or three cycles (schedule 2) of MBVP between 1995 and 2005. Clinical,demographicdataandknownprognostic factorswere collected.MTXconcentrationswere measured at specific times from the start of the infusion (H24, H48, H72 andevery 24 h if necessary, i.e. Until serum concentration was <0.2  l M ). Methotrexatepharmacokinetic parameters were estimated using a population pharmacokineticapproach with NONMEM. Objective response (OR), overall survival (OS) and failure-free survival (FFS) were evaluated in all patients after the last administration of thetwo or three cycles. Post-methotrexate toxicity was evaluated and graded. Results:  Forty-one patients were included. Sixteen (38%) patients received twocycles and 25 patients (62%) received three cycles of MBVP. A total of 425 serumsamples were analysed and a two-compartment pharmacokinetic model was fittedto the data. A higher exposure (cumulative area under the curve) was found withschedule 2 compared to schedule 1.Thirty-two (78%) patients had an OR, fromthese 50% being complete response. A significantly higher rate of OR was obtainedwith schedule 2. In our study, the known prognostic factors were not associ-ated with OR. The 2-year FFS and OS were estimated at 61.8% and 64.2%,respectively with higher rates in schedule 2 compared with schedule 1. We noticed41.9% of toxicity with high level of haematotoxicity as commonly described withthis chemotherapy. Conclusion:  This is the first study evaluating the impact of MTX exposure onoutcome in patients treated with a MBVP chemotherapy for a PCNSL. We foundthat the schedule involving three cycles of MBVP was associated with a higherresponse rate. It also led to a higher MTX exposure due to the higher cumulativedose. MTX exposure within a given schedule was not associated with response andindividual dose adjustment is not required. 132 Determination of imatinib by HPLC with photodiode-array UV detection inhuman plasma from patients with chronic myeloid leukaemia: comparisonwith a LC-MS-MS method O Roth, S Bouchet, P Rousselot, S Castaigne, F Samdjee, P Devillier,O Spreux-Varoquaux, P Therond, M Molimard, B Maneglier Introduction:  Imatinib is a competitive inhibitor of the Bcr-Abl tyrosine kinaseand represents the first-line option for patients who have chronic myelogenousleukemia (CML). Recently, it has been shown that trough imatinib plasma levels areassociated with both complete cytogenetic and major molecular responses in CMLwith a plasma threshold of 1000 ng/mL. Methods:  A HPLC coupled with UV-Diode Array Detection (DAD) method isdescribed for the determination of imatinib concentrations in human plasma.Imatinib trough levels in human plasma ( n  = 38) were assessed by the authors andwere compared with determinations using a LC-MS-MS method, considered as thereference method, with Deming regression, Chi square test and sign test Results:  The calibration curves were linear over the range 80–4000 ng/mL; thelimit of quantitation was set at 80 ng/mL with a within-day coefficient of variationof 8.1%. The between-day variations were 6.1% at XX ng/mL and the recoveryafter direct deproteinization of plasma was higher than 96% and the recovery fromthe column was higher than 98%. No significant difference was observed forimatinib concentrations between the HPLC-UV-DAD and the LC-MS-MS methods. Conclusion:  HPLC with UV-DAD detection system used by the authors providedthe required level of specificity and sensitivity devoid of potential interferences forimatinib therapeutic drug monitoring. 133 Quantitation design of ephedrines by GC/MS – Multivariate optimization,validation of methods and applications in urines Y Hadef, L Abou, C Mikail, M Vergnes, A Nicolay, H Portugal, J Kaloustian Introduction:  Ephedrine and its derivatives belong to the family of amphetamines.They own various therapeutic properties. They are stimulant on the centralnervous system. For this reason, some of them are used in alimentary supplementsand in sport. They are wanted, mainly in anti doping control of sportsmen. Methods:  The goal of this work was, first to search the optimal conditions(resolution >1.5; short time test analysis) by GC/MS in the separation of sevencompounds: ephedrine, pseudoephedrine, norephedrine, norpseudoephedrine, fen-fluramine, fentermine and mephentermine (as internal standard). These moleculeswere studied after trimethylsilyl and trifluoroacetic derivatization. The softwareNemrod-W was used in the building and the analysis of the experimental design,which allowed determining the optimal conditions for their separation. Results:  Optimal conditions were deduced: column HP5-MS, 30 m  ·  0.25 mmi.d.  ·  0.25  l m film thickness; Ti = 73  C (1 min), 1st heating rate at 10  C/minuntil 150  C (0.5 min), then 2nd heating rate at 25  C/min until 230  C (5 min).The validation of the quantitation was applied to urines. Study was done afterextraction and purification by a C18 adsorbent phase. Quantitation was done withthe use of GC/MS with mode SIM ( single ion monitoring ) and with internal standard.The results of linearity, repeatability, precision, accuracy, sensibility, LOD, LOQ,yields of extraction, for these studied compounds (actives and urinary extracts)show the good validation of this analytical method GC/MS. Conclusion:  The study of seven ephedrine-like compounds was done successfullyafter realisation of the Nemrod-W experimental design, with the goal to separatethem with good resolutions and short time analysis, followed by an application inurines. 134 Therapeutic drug monitoring in lung transplant recipients receivingconcomitant posaconazole and tacrolimus S Quaranta, M Reynaud-Gaubert, C Solas, S Boniface, B Lacarelle, E Sampol-Manos Introduction:  Fungal infections are an important cause of morbidity andmortality in lung transplant recipients (LTR). Posaconazole (POS) is a noveltriazole antifungal used as curative therapy in LTR affected with fungal bronchialcolonization, acute necrotizing bronchitis and more rarely, invasive fungalinfection. Triazole agents are known to inhibit the metabolism of immunosuppres-sive drugs such as tacrolimus (TAC) and therapeutic drug monitoring of both drugsis required to limit toxicity and optimize efficacy. The aim of this study was topresent a follow up of simultaneous posaconazole plasma concentrations andtacrolimus whole blood levels in LTR. Methods:  We determined POS plasma levels between January and November2008 in 14 lung transplant recipients of whom eight were affected with cysticfibrosis. There were nine females and five males with a mean age of 33.2 ± 9.1 years. All the patient received POS therapy for a symptomatic and   2009 The Authors 26  Journal compilation    2009 Socie´te´ Franc¸aise de Pharmacologie et de The´rapeutique  23  (Suppl. 1) 1–112 P2T Abstracts 2009 View publication statsView publication stats
Related Search
Advertisements
Related Docs
View more...
We Need Your Support
Thank you for visiting our website and your interest in our free products and services. We are nonprofit website to share and download documents. To the running of this website, we need your help to support us.

Thanks to everyone for your continued support.

No, Thanks