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ABSTRACT: The opportunity to apply a sampling plan was evaluated. Costs were computed by a microcosting study.
In 2003, a sampling plan was defined to reduce the number of chemotherapy quality controls while preserving the same level of quality. Recent qualitative and quantitative changes led us to define a second sampling plan supplemented by an economic evaluation to determine the cost and cost-savings of quality control.
The study considers preparation produced during four semesters classified into three groups. The first one includes drugs produced below 200 batches a semester. Group 2, those for which the lot of preparation lots would have been rejected twice among these four semesters. Group 3, those would have been accepted (≥3 'acceptable lot'). A single sampling plan by attributes was applied to this group with an acceptance quality level of 1.65% and a lot tolerance percent defective below 5%. A micro-costing study was conducted on quality control, from the sampling to the validation of the results.
Among 39 cytotoxic drugs, 11 were sampled which enabled to avoid a mean of 17,512 control assays per year. Each batch of the 28 non-sampled drugs was however analyzed. Costs were estimated at 2.98€ and 5.25€ for control assays depending of the analytical method. The savings from the application of the sampling plans was 153,207€ in 6 years.
The sampling plan allowed maintaining constancy in number of controls and the level of quality with significant costsavings, despite a substantial increase in drugs to assay and in the number of preparations produced.
Journal of Oncology Pharmacy Practice 05/2011; 18(2):163-70.
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ABSTRACT: The prescription of unlicensed oral medicines in paediatrics leads the hospital pharmacists to compound hard capsules, such as busulfan, an alkylating agent prescribed in preparative regimens for bone marrow transplantation. In this study, we have investigated how the general principle of process analytical technology (PAT) can be implemented at the small size of our hospital pharmacy manufacturing unit. Near infrared spectroscopy (NIRS) was calibrated for raw material identification, blend uniformity analysis and final content uniformity of busulfan hard capsules of 11 different strengths. Measurements were performed on capsules from 2 to 40 mg (n=440). After optimisation, accuracy and linearity of the NIRS quantitative method was demonstrated after comparison with a previously validated quantitative high performance thin layer chromatography (HPTLC) method. Such a comparison led to attractive NIRS precision: +/-0.7 to +/-1.0 mg for capsules from 2 to 40 mg, respectively. As NIRS is a rapid and non-destructive technique, the individual control of a whole batch of busulfan paediatric capsules intended to be administrated is possible. Actually, mastering the process of busulfan paediatric capsules with the NIRS integrated into the notion of PAT is a powerful analytical tool to assess the process quality and to perform content uniformity of at least 5mg busulfan-containing capsules.
Journal of Pharmaceutical and Biomedical Analysis 07/2006; 41(4):1171-8. · 2.97 Impact Factor
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ABSTRACT: Morphine and meperidine in Patient-Controlled Analgesic devices are commonly used to treat chronic pain patients. These devices deliver a programmed amount of drug and allow self-administration by the patient depending on the pain. In our department of pharmacy, 300 devices were manufactured in 2003. The aim of this study was to assess their shelf-life. The devices were filled aseptically and without preservatives with 1 and 40 mg/ml morphine solution and 5 and 20 mg/ml meperidine and stored over 30 days at room temperature and protected from light. Culture assay of the solutions showed that they remained sterile for 30 days. No turbidity of any solutions from samples collected twice a week was noticed. pH and osmolarity remained constant. Drug concentrations were determined using stability indicating HPLC method, as we showed that degradation products can be separated from the drugs. Little loss of meperidine occurred within 21 days (<5%) and morphine concentration, which increased, because of solvent evaporation, remained lower than 5% within 21 days but increased up to 10% after 30 days. No traces of degradation products (pseudomorphine or pethidic acid) were detected. The physicochemical and microbiological stability of morphine and meperidine hydrochlorides stored in such devices has been established for 21 days at room temperature and protected from light.
Pathologie Biologie 06/2005; 53(4):210-6. · 1.53 Impact Factor
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D Elias,
T Matsuhisa,
L Sideris,
G Liberale,
L Drouard-Troalen,
B Raynard,
M Pocard,
J M Puizillou,
V Billard, P Bourget,
M Ducreux
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ABSTRACT: The purpose of this study was to report the pharmacokinetics (PK) and tolerance profile of intraoperative intraperitoneal chemo-hyperthermia (IPCH) with oxaliplatin and irinotecan.
Thirty-nine patients with peritoneal carcinomatosis (PC) of either gastrointestinal or peritoneal origin underwent complete cytoreductive surgery followed by IPCH with a stable dose of oxaliplatin (460 mg/m(2)), plus one among seven escalating doses of irinotecan (from 300 to 700 mg/m(2)). IPCH was carried out with the abdomen open, for 30 min at 43 degrees C, with 2 l/m(2) of a 5% dextrose instillation in a closed continuous circuit. Patients received intravenous leucovorin (20 mg/m(2)) and 5-fluorouracil (400 mg/m(2)) just before IPCH to maximize the effect of oxaliplatin and irinotecan.
Irinotecan concentration in tumoral tissue increased until 400 mg/m(2) and then remained stable despite dose escalations. It was 16-23 times higher than in non-bathed tissues. Increasing doses of intraperitoneal irinotecan did not modify the PK of intraperitoneal oxaliplatin, and the drug concentration ratio was 17.8 higher in tumoral tissue (bathed) than in non-bathed tissues. The hospital mortality rate was 2.5% and the non-hematological complication rate was 25%. However, grade 3-4 hematological toxicity rate was 58%.
Intraperitoneal heated oxaliplatin (460 mg/m(2)) plus irinotecan (400 mg/m(2)) presented an advantageous PK profile and was tolerated by patients, despite a high hematological toxicity rate.
Annals of Oncology 11/2004; 15(10):1558-65. · 6.43 Impact Factor
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ABSTRACT: An instrumental quantitative high-performance thin-layer chromatographic (HPTLC) method has been developed for the determination of vinca-alkaloids (antineoplastic compounds) in chemotherapeutic infusion bags prepared in a hospital pharmacy. The method uses automated band application onto silica gel plates containing a fluorescent indicator and scanning densitometry of fluorescence-quenched zones of samples and standards. Samples were analyzed to check the content of the active substance against the label declaration of the preparation. The four compounds were separated using the following solvent system CH(2)Cl(2)-CH(3)OH (93:7, v/v). Vincristine (VCR) and vinorelbine (NVB) were assessed in the same run whilst vinblastine (VLB) and vindesine (VDS) were analyzed in a second run. HPTLC allows the identification and the quantitation of more than 20 samples in the same chromatographic run. The analysis of the samples requires 30 min compared with more than 2 h using a typical HPLC method. Moreover, there is no need for a conditioning step, as with HPLC, and each analysis by HPTLC is less expensive.
Journal of Pharmaceutical and Biomedical Analysis 02/2003; 30(5):1603-10. · 2.97 Impact Factor
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ABSTRACT: We studied the pharmacokinetics of heated intraoperative intraperitoneal (i.p.) oxaliplatin (LOHP) solution and its safety profile in increasingly hypotonic solutions. This is the first clinical study of i.p. chemohyperthermia with hypotonic solutions.
Patients with peritoneal carcinomatosis (PC) underwent complete cytoreductive surgery followed by intraoperative i.p. chemohyperthermia (IPCH) with successive dextrose solutions of 300, 200, 150 and 100 mosm/l. LOHP (460 mg/m(2)) was administered in 2 liters of solution/m(2) at an i.p. temperature of 42-44 degrees C for 30 min. IPCH was performed using an open procedure (skin pulled upwards) with a continuous closed circuit. Patients received intravenous leucovorin (20 mg/m(2)) and 5-fluorouracil (400 mg/m(2)) just before IPCH to maximize the effect of LOHP. i.p. plasma and tissue samples were analyzed by means of atomic absorption spectrophotometry. Sixteen consecutive patients with PC of either gastrointestinal or peritoneal origin were treated. The safety of the procedure was studied.
Pharmacokinetics: The mean duration of the entire procedure was 7.7 +/- 2.6 h. Half the LOHP dose was absorbed within 30 min at all dose levels. Absorption was not higher with hypotonic solutions than with isotonic solutions. The area under the curve of LOHP in plasma did not increase with decreasing osmolarity of the i.p. solutions. Intratumoral LOHP penetration was high; it was similar to that at the peritoneal surface, and about 18 times higher than that in nonbathed tissues. LOHP penetration was not significantly increased by using hypotonic solutions. Safety: There was a very high incidence of unexplained postoperative peritoneal bleeding (50%) and unusually severe thrombocytopenia in the 150 and 100 mosm/l groups.
Contrary to experimental studies, this clinical study showed no increase in tumoral or systemic penetration of LOHP with i.p. hypotonic solutions (200, 150 or 100 mosm/l) during IPCH. A high incidence of i.p. hemorrhage and thrombocytopenia was observed.
Oncology 02/2002; 63(4):346-52. · 2.27 Impact Factor
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ABSTRACT: The Clinical Pharmacy Department (CPD) of the Gustave Roussy Institute, has developed a traceability software package that is integrated with the patient file. The Traceability & Medical Devices Functional Unit manages the Blood Derivative Medicinal Product traceability circuits, the circuits of over 400 Sterile Medical Devices and, generally speaking, those for all pharmaceutical goods for which traceability is imperative. The SIMBAD-TRACE software package has been developed in situ and was first open for access in March 1999. It enables pharmaceutical traceability data to be accessed from 500 networked workstations. The references tracked generated about 10,000 movements per year. In terms of performance, the system achieves three complementary objectives: 1) reporting traceability scores which reflect the ability of CPD and the establishment to pertinently respond to a complex regulatory requirement on a daily basis; 2) the contribution of the tool to cost containment with respect to allocating rare goods; the contribution of the software package to the implementation of medical device vigilance inquiries, particularly descending inquiries. Finally, SIMBAD-TRACE is one of the pillars of our Quality Assurance Program (QAP).
Pathologie Biologie 10/2001; 49(8):624-33. · 1.53 Impact Factor
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ABSTRACT: As part of the development of a quality assurance program (QAP), a high performance thin layer chromatography (HPTLC) analysis unit was installed in the pharmacy department at Gustave-Roussy. The HPTLC-CAMAG consists of: 1) an HPTLC-Vario development chamber for optimization of the mobile phases; 2) TLC Sampler III automated sample applicators; 3) solid teflon migration chambers, i.e., horizontal tanks that enable separation to be carried out either in sandwich or in saturation mode; 4) a TLC Scanner 3 densitometer controlled by CATS 4 software; and 5) a Pentium MMX 233 MHz personal computer with an external backup unit. HPTLC quantitative and qualitative analysis has now reached a remarkably high level of development and performance. The samples (aqueous or non-aqueous solutions) that are to be processed are automatically applied by spraying (50-300 nl) in calibrated bands of a few mm (with up to 64 3-mm bands per 10 x 20 cm plate) on high-performance stationary phases and of wide technological diversity. The chromatogram is obtained in 10 min, and run over a migration pathway of 5-6 cm. The plates are read by absorption-reflection or fluorescence-reflection at an ad hoc wavelength (190-800 nm), then the peak areas which have been scanned are calculated by the trapezoid method. The calibration curves are generated by Michaelis-Menten non-linear regression, and validated by internal quality control. The analytical yield is high, i.e., up to 50 assays and 250 determinations per day. HPTLC analysis covers a wide functional range, and can be used in the following ways: 1) as a teaching tool for separative analysis and GLP; 2) it is an invaluable method for the optimization of mobile phases and for the determination of absorption spectra and absorption maxima, with a view to developing HPLC methods in complex matrices; 3) it provides major support for post-production quality control of prescribed hospital preparations of all types, e.g., those connected with parenteral nutrition, chemotherapy, synthetic narcotic analgesia; and it can also be used for dry dosage analysis; 4) it is useful in pharmaceutical assessment, e.g., in studies on the physico-chemical characteristics of various substances, such as their identity, purity, concentration, stability and compatibility, particularly with regard to generic products; 5) it can contribute to monitoring the safety of medical apparatus and equipment via the analysis of container-content interactions; 6) it provides a qualification system for personnel and procedures for within- and between-center validation of GMP. Setting up such an HPTLC quality control unit requires a basic investment of about 0.9 MF or 70,000 US dollars for a cost of no more than 10 F or 1.5 US dollars (including tax) per routine assay. After 18 months in operation and 16,500 assays, the HPTLC analysis unit has become one of the mainstays of the Gustave-Roussy QAP.
Pathologie Biologie 03/2001; 49(1):86-95. · 1.53 Impact Factor
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European Journal of Cancer - EUR J CANCER. 01/2001; 37.
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ABSTRACT: To better master the use of ciprofloxacin (CPF) in burn patients, a clinical study, including pharmacokinetics in serum and urine, was undertaken in a pathophysiologically homogeneous population of major-burn subjects.
Twelve major-burn patients who were infected with Pseudomonas aeruginosa, enterobacteria and gram-positive cocci, received CPF (600 mg t.i.d.). The mean body surface area affected by third-degree burns was 31.8 +/- 14.5%. Two series of blood samples were drawn after the first and seventh doses; urine was collected during the first infusion. Levels of CPF in serum and urine were measured by means of high-performance liquid chromatography. A non-compartmental method was used for kinetic and graphic analysis of concentration-time pairs.
No adverse effects were noted. Trough concentrations measured on day 3 (mean +/- SD) were above the minimum inhibitory concentration (MIC) for the organism responsible for infection; i.e., 2.0 +/- 1.2 microg. ml(-1), and maximum concentrations were high 9. 9 +/- 3.4 microg. ml(-1). An area under the concentration-time curve (AUC)/MIC ratio above 125 SIT(-1) (where SIT is the serum inhibitory titer), which has been strongly correlated with clinical response and time to bacterial eradication, was achieved in 11 patients with a MIC of 0.5 microg. ml(-1). There was a statistically significant difference between C(min) and AUC determined on day 1 and day 3. In contrast to healthy volunteers, CPF clearance rates were notably decreased.
The pharmacokinetics of CPF was altered in major-burn patients. The recommended dosage regimen for administration of CPF, i.e. 600 mg t.i.d. shows no adverse effects and a good microbiological efficacy.
European Journal of Clinical Pharmacology 10/1999; 55(7):515-9. · 2.85 Impact Factor
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ABSTRACT: The pharmacokinetics of fusidic acid (FA) were studied in 10 infected severe burns patients (35 +/- 5 yrs, 81 +/- 17 kg) i.e. 43 +/- 10% in 3rd degree. Treatment was given at the dose of 500 mg/8 hours (2-hour infusion). The kinetics of FA were evaluated on D1 (1st infusion) and at steady state on D4 (10th infusion), each sequence involving 9 whole blood samples. Samples were assayed by high-performance liquid chromatography. Data were analysed by a non-compartmental method. Mean duration of treatment, considered effective in all cases, was 5.9 +/- 2.1 days. The systemic safety of FA was felt to be good. Kinetic analysis revealed the existence of significant differences between D1 and D4 concerning the parameters Cmax, Cmin, AUC, Cl and Vss. These events are attributable to the non-linear nature of the human kinetics of FA. Accumulation ratios R1 and R2 did not differ i.e. 1.51 +/- 0.25 and R2 = 2.44 +/- 0.68. Kinetic modelling based upon the experimental tracing obtained on D1 revealed good coincidence of the predictive tracing in relation to data determined on D4. The dosage algorithm of 500 mg/8 hours was microbiologically satisfactory with Cmin measured on D1 and at steady state constantly greater than the MIC of the main organisms concerned (< to 2 micrograms/ml). Reduction in the parameters Cmax and AUC in comparison with a group of healthy subjects ultimately led to shortening of the mean T1/2 of FA. In the absence of impaired liver function, this is attributable to the known increase in hepatic clearances in burns patients and, to a certain extent, to the existence of translesional extra-hepatic clearance, which could contribute to the success of treatment.
Pathologie Biologie 05/1999; 47(5):486-90. · 1.53 Impact Factor
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ABSTRACT: The safety/acceptability, blood pharmacokinetics and urinary excretion of the piperacillin-tazobactam (PPR-TZB) combination were studied in six patients between 25 1/7 and 31 5/7 weeks of amenorrhea. The combination was given for a materno-fetal infection due to susceptible organisms i.e. 4/0.5 g/6 h. Whenever possible, the trans-placental transfer (TPT) of the combination was assessed in several sub-compartments of the feto-placental unit i.e. maternal blood sample, cord blood, amniotic fluid, placenta tissue and fetal urine. Two series of nine blood samples were scheduled for each patient, i.e. on D1 (first dose) and D3 (at plateau). Samples were assayed by HPLC and data were analyzed by a non-compartmental method. Safety/acceptability of the treatment proved to be good. The kinetic behavior of both beta-lactams appeared to be identical. Evidence was found during pregnancy of an increase in Vss and Cl of the combination. These increases can be linked to a notable decrease in AUCs. The TPT of the combination was significant. Regarding other accessible compartments (i.e. placenta tissue, amniotic fluid and fetal urine), the ratio of PPR-TZB concentrations was invariably about 8. Maternal circulating levels of PPR-TZB were, by 4 h, less than the MIC of target organisms (i.e. < or = 8 micrograms/ml), both on D1 and at steady state. This raises the question of the pertinence of the dosage regimen. Regarding PPR, it is accepted that antibacterial protection is satisfactory when circulating concentrations are kept at a Css (steady state concentration) of the order of 20 micrograms/ml or more. PPR-TZB combination would be administered by continuous infusion i.e. 8 mg/min to obtain 3 h later a Css of more than 20 micrograms/ml. The daily dosage would then be 12/1.5 g instead of 16/2 g, which is also more satisfactory from a pharmaco-economic standpoint. This proposal must be validated in a sufficient number of patients and, could avoid disqualification of the combination PPR-TZB in the treatment of serious infections during certain pathological pregnancies.
European Journal of Obstetrics & Gynecology and Reproductive Biology 01/1998; 76(1):21-7. · 1.97 Impact Factor
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V Bouton, P Bourget,
A Lesne-Hulin,
P Amstutz,
M Benayed,
D Benhamou,
J L Dufieux,
G Goursot,
S Grobuis,
J P Haberer,
F Jardin,
P Kirstetter,
J Marty,
A Mercatello,
B Page,
J L Pourriat,
T Vassal
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ABSTRACT: We recently developed a simple and fast assay technique, providing the possibility of monitoring of midazolam (M) during sedation. We compared HPLC vs FPIA for the measurement of the sum M plus alpha 1-hydroxymidazolam (OM), its main and pharmacologically active metabolite, in the serum of sedated ICU patients; this activity referred to as M-like. We identified certain patients in whom M-like activity appeared abnormally high in comparison with HPLC assays. Their common denominators were: long-term sedation with M, and seriously impaired renal function. Further, the conjugates of OM (OMG) accumulated in patients with acute renal failure could contribute to the sedation. We compared the metabolic and analytic behavior of M, OM, and OMG in 2 groups of sedated patients either presenting with normal renal functions (group 1) or with a picture of acute renal failure (group 2). Blood samples were assayed by HPLC and by FPIA and analysis was performed before and after hydrolysis of OMG. Before hydrolysis there was a dramatic accumulation of OMG in the patients of group 2, HPLC vs FPIA results were not different within group 1, while in group 2 the FPIA response exceeded that of HPLC. After hydrolysis, measurement by HPLC was greatly increased in group 2, in each group (vs HPLC) and from one group to another, the FPIA signal (the M-like activity) showed a significant increase. It would be important to take OMG into account as a coprotagonist in sedation whenever circumstances predispose to its accumulation.
International journal of clinical pharmacology and therapeutics 12/1997; 35(11):531-8. · 1.18 Impact Factor
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ABSTRACT: Since January 1, 1995, the supply, stockage, dispensing and traceability of Blood Derivative Medicinal Products (BDMP) are subject to pharmaceutical regulations. A review of 24 months' application at Necker-Enfants Malades Hospital is presented and analysed. A distinction is drawn between two categories of BDMP: 1) anti-hemophilia BDMP, factors of plasma or recombinant origin; 2) non-anti-hemophilia BDMP, covering albumin, immunoglobulins (Ig), biological glues and other clotting factors. BDMP are subject to a hospital traceability procedure. In this respect, we have constructed a tryptic nominative model prescription, though dotations are granted for only certain prescription sectors (operating room, ICU) and certain products (biological glues, albumins). A dispensing-administration form is invariably attached to each bottle. Between January 1, 1995 and December 31, 1996, 8225 dispensing procedures for BDMP were recorded, with a total cost of 52,931,586 francs (i.e. 69% anti-hemophilia products v.s. 31% non-antihemophilia products). The Factor VIII market is divided more or less equally between factors of human and recombinant origin. The risk of viral transmission is considered to be virtually nil with recombinant products, despite their being stabilized by human albumin. The traceability rate of anti-hemophilia factors was 100%. Albumin consumption was 182,106 g at a cost of 3,358,250 francs. The following indications were adopted at a Local Medicines Committee: 1) in adults: hypoalbuminemia associated with edema or ascites; 2) in children: digestive disorders leading secondarily to exsudative enteropathy and/or hypoalbuminemia. Consumption of polyvalent Ig was 69,213 g, i.e. 10,856,722 francs. These products were prescribed in accordance with the directives of the Committee for Evaluation and Distribution of Technological Innovations. Consumption of specific Ig and biological glues may seem modest in relation to that of other products. BDMP expenditure appears particularly heavy here (about 26.5 MF/year) but consensual adoption of therapeutic guidelines has enabled rationalization of prescribing conditions with the best possible consideration of benefit/risk vs costs ratios. Traceability and drug safety monitoring procedures are linked to and integrated in the more global concept of Quality Assurance. Since January 1995, several withdrawals of batches have been recorded because of suspicion (or death due to) Creutzfeld-Jakob, or post-donation HIV seroconversion. In this area, the Hospital Pharmacist acts by the establishment in real time of a permanent safety link between the patient, a prescriber, an indication, a product prescribed and the product actually administered.
Pathologie Biologie 11/1997; 45(9):741-50. · 1.53 Impact Factor
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Contraception, fertilité, sexualité (1992) 07/1997; 25(6):429-33.
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ABSTRACT: The concentrations of teicoplanin in the sera and mediastinal and heart tissues of 23 patients undergoing cardiac surgery were measured after two regimens of teicoplanin administration. Intraoperative pharmacokinetic parameters were also obtained. Patients were randomized into two groups. Those in group 1 were given teicoplanin at 6 mg x kg(-1) intravenously at the time of induction of anesthesia. Patients in group 2 were given teicoplanin at 12 mg x kg(-1) during the same period. The maximum concentration in serum (71 +/- 20 and 131 +/- 44 mg x l(-1)), the minimum concentration in serum (3.6 +/- 1.3 and 6.8 +/- 2.1 mg x l(-1)), the area under the concentration-time curve (AUC) from 0 to 12 h (108 +/- 20 and 217 +/- 38 microg x h x ml(-1)), and the AUC from 0 h to infinity (154 +/- 36 and 292 +/- 77 microg x h x ml(-1)) were twice as high after 12-mg x kg(-1) injections as after 6-mg x kg(-1) injections. No differences in mean residence time (9.7 +/- 4.9 and 8.4 +/- 2.7 h) or terminal half-life (8.5 +/- 3.8 and 7.5 +/- 2.3 h) were observed. Teicoplanin penetrated mediastinal and heart tissues but not sternal bone, where the antibiotic was detectable in only 1 of 13 patients in group 1 and 2 of 10 patients in group 2. In group 1, 7 of 13 patients had teicoplanin concentrations in tissue that were lower than the MIC for 90% of the strains of potential pathogens tested (MIC90) that cause infection after cardiac surgery. All of the patients in group 2 but one had teicoplanin concentrations in tissue (other than in sternal bone) far in excess of the MIC90 for the potential pathogens. In conclusion, the 12-mg x kg(-1) regimen of teicoplanin is followed by a significant increase in teicoplanin concentrations in heart and mediastinal tissues and should be preferred to the 6-mg x kg(-1) regimen if teicoplanin is selected for antimicrobial prophylaxis in open heart surgery.
Antimicrobial Agents and Chemotherapy 06/1997; 41(5):1150-5. · 4.84 Impact Factor
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ABSTRACT: The authors report the study of the kinetics in serum and urine and the clinical safety of a high dose of teicoplanin administered in a 19 year-old patient with major burns (60% of body surface area, the half of which consisting of third-degree burns and UBS at 150) and S aureus meticillin-resistant infection. At day 1, he was given two loading infusions of 12 mg.kg-1 teicoplanin followed by 12 mg.kg-1 per day of treatment. At all times, Cmin concentrations were below the limit value of 8 mg.mL-1. Therefore the therapeutic regimen was increased on several occasions. On days 5, 8 and 15, Cmin were measured by FPIA. Pharmacokinetic analysis was performed at day 16, (i.e., 20 mg.kg-1) and urine was also collected over at least 12 hours. At day 16, serum and urine samples were assayed by HPLC. Data were analyzed with a noncompartmental method. The duration of treatment was 20 days and no adverse events were noted. Bacteriological tests performed at the end of treatment demonstrated the elimination of the agent responsible over the infection. While pharmacokinetics were not assessed at plateau, Cmin remained very low. Vss was similar to values obtained in healthy subjects while total clearance was increased. This phenomenon was explained by the increase of total clearance and a nonrenal translesional diffusion suggested by the body surface area affected by third-degree burns. Finally, the cost of increasing doses of teicoplanin must be taken in account.
Annales Françaises d Anesthésie et de Réanimation 02/1997; 16(4):374-7. · 0.84 Impact Factor
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ABSTRACT: There have been few evaluations of the perioperative pharmacokinetics of antibiotics. Piperacillin (PPR) is a widely prescribed ureidopenicillin of established efficacy against enterobacteria and P. aeruginosa. The serum pharmacokinetics and perioperative safety of PPR were evaluated in 8 patients hospitalized for an orthotopic liver transplantation. The subjects were given a 60 mg/kg infusion of PPR once every 8 hours. PPR was assayed by HPLC and data were analyzed by a noncompartmental method. There were no adverse events during surgery. It seems that kinetics of PPR showed no variation during the anhepatic period. However, transplants notably modified the kinetics of PPR in comparison with data previously published in healthy volunteers. Trends were as follows: flattening of Cmax and prolongation of T1/2 (2.2 h vs 0.92 h). This phenomenon seems to be due to a marked increase in V(area) (44.0 1 vs 16.2 1) while C1 were similar. The increase in V(area) is probably the combined results of multiple factors including blood loss, vascular filling, combined prescription of vasoactive drugs, and, obviously, the surgical procedure itself. Concentrations of PPR were after 4 hours below (i.e. 5/8 patients) the MIC of P. aeruginosa (i.e. < or = 16 micrograms/ml). From 6 hours onwards antibacterial cover was insufficient against the majority of enterobacteria (i.e. < or = 8 micrograms/ml). This inadequate protection included the critical anhepatic period. Measured concentrations achieved by the initial dosage regimen were compared to those obtained by simulation using modified dosing pattern in order to ensure circulating levels constantly of 16 micrograms/ml or more. This leads to a suggested modified dosage pattern in which PPR would be given as 1 dose of 60 mg/kg every 4 hours. Under these conditions the expected concentrations should be constantly over 16 micrograms/ml and any risk of systemic accumulation is excluded.
International journal of clinical pharmacology and therapeutics 01/1997; 34(12):550-4. · 1.18 Impact Factor
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P Bourget,
V Bouton,
A Lesne-Hulin,
P Amstutz,
M Benayed,
D Benhamou,
P L Dufieux,
G Goursot,
S Grosbuis,
J P Haberer,
F Jardin,
P Kirstetter,
J Marty,
A Mercatello,
B Page,
J L Pourriat,
T Vassal
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ABSTRACT: Midazolam (M) is used as an induction agent for anesthesia. The main metabolite is alpha-hydroxymidazolam (OM), which is pharmacologically active. Use of M for sedation is a recent application, rapidly gaining favor. Monitoring of the level of sedation is fundamental in that an excessive and prolonged effect is associated with the risk of complications. Thus, it was felt both necessary and useful to measure circulating M levels. We compared a high-performance liquid chromatography (HPLC) assay with fluorescence polarization immunoassay (FPIA) for the measurement of M in the serum of 138 sedated patients in the intensive care unit (i.e., 179 samples). Response of the OM was also assessed. The degree of crossover of the metabolite was between 76.8 and 32.7%. The equation of the regression line for sigma HPLC (i.e., the sum M + OM) versus FPIA was TDx = 1.1585 sigma HPLC + 143.42 (R = 0.966). The 95% confidence interval for the slope was 1.1551, 1.1619. The regression slope differed significantly from 1 (p < 0.001) and shows that FPIA measurements overestimated concentrations obtained by HPLC on the order of 19%. The discrepancy between the two techniques was all the more notable when concentrations were > 1,000 ng/ml. The relative selectivity of Abbott industrial reagent in terms of benzodiazepines leads to the identification of what might be called a midazolam-like (M-like) activity covering both M and OM. The development of a global FPIA method for measurement of this M-like activity in sedated patients provides a satisfactory solution to the question raised.
Therapeutic Drug Monitoring 11/1996; 18(5):610-9. · 2.49 Impact Factor
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ABSTRACT: The pathophysiology associated with major burns is complex and subject to a state of flux. The combination of beta-lactamase inhibitors with powerful penicillins is an interesting and an attractive potential solution to the emergence of bacterial resistance. The kinetics in serum and urine and the clinical safety of a fixed combination of 4 g of piperacillin (PPR) and 0.5 g of tazobactam (TZB) were studied in 10 patients (22 to 50 years old and weighing 45 to 105 kg) with major burns who were infected with Pseudomonas aeruginosa and various entero-bacteria. All of them received additional antimicrobial drugs. Treatment involved one dose every 6 h. The mean body surface area affected by third-degree burns was 30.0% +/- 4.0%. The study took place in accordance with current ethical guidelines. Two series of blood samples were drawn after the first (day 1) and ninth (day 3 at steady state) doses; urine was collected during the same periods. Levels of PPR and TZB in serum and urine were measured by high-pressure liquid chromatography. A noncompartmental method was used for kinetic and graphic analysis of concentration-time pairs. The safety of the treatment was excellent. There was no systemic accumulation of the beta-lactam combination. Residual concentrations measured on days 1 and 3 [mean (standard error of the mean)] were above the MIC for the organism responsible for infection; i.e., C(min)day1 = 26.3 (8.5) and C(min)day3 = 21.0 (9.1) for PPR and C(min)day1 = 1.9 (0.6) and C(min)day3 = 1.4 (0.3) for TZB. There was no statistically significant difference between pharmacokinetic parameters determined for day 1 and day 3. Evidence was found in burn patients, in contrast to healthy subjects, of a marked increase in apparent volumes of distribution, in such a way that the apparent elimination half-lives of the combination were notably prolonged, i.e., 1.8 (0.3) versus 1.5 (0.3) h for PPR in patients and healthy subjects, respectively, and 1.7 (0.3) versus 1.4 (0.3) h for TZB. These findings indicate the possibility of nonrenal translesional diffusion of PPR-TZB in burn patients. The polarity of the association would further support this hypothesis. It has been shown here that the recommended dosage regimen for administration of PPR-TZB must be high in major-burn patients, i.e., 4 g/0.5 g every 6 h. The data obtained provide valuable information, which is suitable for immediate application in everyday clinical practice.
Antimicrobial Agents and Chemotherapy 02/1996; 40(1):139-45. · 4.84 Impact Factor
