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Biomedical subjects

F Lokiec

Publications and source records attributed to F Lokiec.

At least 19 recordsLinked to original sources
PubMed2006

Variations in schedules of ifosfamide administration: a better understanding of its implications on pharmacokinetics through a randomized cross-over study.

PURPOSE: The metabolism of ifosfamide is a delicate balance between a minor activation pathway (4-hydroxylation) and a mainly toxification pathway (N-dechloroethylation), and there remains uncertainty as to the optimal intravenous schedule. METHODS: This study assesses ifosfamide pharmacokinetics (PK) according to two standard schedules. Using a 1:1 randomized trial design, we prospectively evaluated ifosfamide PK on two consecutive cycles of 3 g/m2/day for 3 days (9 g/m2/cycle) given in one of two schedules either by continuous infusion (CI) or short (3 h) infusion. Highly sensitive analytical methods allowed determination of concentrations of ifosfamide and the key metabolites 4-hydroxy-ifosfamide, 2- and 3-dechloroethyl-ifosfamide. RESULTS: Extensive PK analysis was available in 12 patients and showed equivalence between both schedules (3 h versus CI) based on area under the curves (micromol/l x h) for ifosfamide, 4-hydroxy-ifosfamide, 2- and 3-dechloroethyl-ifosfamide (9,379 +/- 2,638 versus 8,307 +/- 1,995, 152 +/- 59 versus 161 +/- 77, 1,441 +/- 405 versus 1,388 +/- 393, and 2,808 +/- 508 versus 2,634 +/- 508, respectively, all P > 0.2). The classical auto-induction of metabolism over the 3 days of infusion was confirmed for both schedules. CONCLUSION: This study confirms similar PK for both active and toxic metabolites of ifosfamide in adult cancer patients when 9 g/m2 of ifosfamide is administered over 3 days by CI or daily 3-h infusions.

Adult↗
PubMed2006

Phase I study of high-dose topotecan with haematopoietic stem cell support in the treatment of ovarian carcinomas: the ITOV 01 protocol.

Topotecan has demonstrated activity in ovarian carcinomas. In order to increase the tumour response rate and to define the maximum tolerated dose (MTD) of topotecan, we decided to develop a high-dose phase I regimen supported by stem cell support. High-doses schedules using a 1-day single administration have MTDs of 10.5 (24 h continuous infusion (CI)) or 22.5 mg/m2 (30 min infusion). Five-day CI induces grade IV mucositis at high doses (MTD<12 mg/m2). We chose to administer topotecan in a 5-day schedule with a 30 min daily infusion. Patients were scheduled to receive one cycle of therapy. The first dose level was 4.0 mg/m2/day x 5 days. Limiting toxicities were defined as toxic death, grade IV non-haematopoietic or haematopoietic toxicity >6 weeks. From August 1998 to April 2002, 49 patients were included. Forty-three patients have completed one course and 15 have received two cycles. One patient treated at level 7 mg/m2/day died of sepsis. Median duration of grade IV neutropenia was 9 days. Two episodes of grade IV diarrhoea were observed at level 9.5 mg/m2/day. Pharmacokinetic data were linear within the dose range of 4-9.0 mg/m2/day. The MTD was reached at 9 mg/m2/day x 5 days.

Adolescent↗
PubMed2006

Ifosfamide: pharmacokinetic properties for central nervous system metastasis prevention.

The incidence of central nervous system (CNS) recurrence in patients with lymphoma is about 5%. Nevertheless, this complication is very serious because it is almost always fatal. Its incidence is not sufficiently high to warrant the use of CNS prophylaxis in all patients. The identification of subgroups for whom CNS prophylaxis may be of benefit is therefore important and the age-adjusted international prognostic index (aa-IPI) may be useful in this respect. Ifosfamide (IFO) is a widely used antitumor agent, requiring activation to isophosphoramide mustard (IPM) for DNA alkylation. IFO anabolism occurs through the hepatic microsomal cytochrome P450 system. As with the majority of antineoplastic agents, IFO has toxic side-effects. These include neurotoxicity due to the chloroacetaldehyde (CAA) catabolite. However, the incidence of neurotoxicity is low when IFO is administered as a continuous intravenous infusion. Both inactive IFO and active IPM cross the blood-brain barrier, making IFO treatment effective in the prevention of CNS metastasis in lymphoma patients at high risk of recurrence. The benefit/risk ratio for such patients should evaluated.

Antineoplastic Agents, Alkylating↗
PubMed2005

A phase I clinical and pharmacokinetic study of capecitabine (Xeloda) and irinotecan combination therapy (XELIRI) in patients with metastatic gastrointestinal tumours.

Capecitabine is a highly active oral fluoropyrimidine that is an attractive alternative to 5-fluorouracil in colorectal cancer treatment. The current study, undertaken in 27 patients with gastrointestinal tumours, aimed to assess the toxicity and potential for significant pharmacokinetic interactions of a combination regimen incorporating capecitabine with 3-weekly irinotecan (XELIRI). Irinotecan (200 and 250 mg m(-2)) was administered as a 90-min infusion on day 1 in combination with escalating capecitabine doses (700-1250 mg m(-2) twice daily) administered on days 2-15 of a 3-week treatment cycle. Pharmacokinetics were characterised on days 1 and 2 of the first two cycles. A total of 103 treatment cycles were administered. The principal dose-limiting toxicities were diarrhoea and neutropenia. Capecitabine 1150 mg m(-2) twice daily with irinotecan 250 mg m(-2) was identified as the maximum-tolerated dose and capecitabine 1000 mg m(-2) with irinotecan 250 mg m(-2) was identified as the recommended dose for further study. Analyses confirmed that there were no significant pharmacokinetic interactions between the two agents. The combination was clinically active, with complete and partial responses achieved in heavily pretreated patients. This study indicates that XELIRI is a potentially feasible and clinically active regimen in patients with advanced gastrointestinal cancer.

Adult↗
PubMed2003

Phase I population pharmacokinetics of irofulven.

Our aim was to develop a population pharmacokinetic model for irofulven and to assess covariates that might affect irofulven pharmacokinetics. Irofulven was administered by 5- or 30-min i.v. infusion to cancer patients during a phase I study. Blood samples were collected over 4 h. Plasma samples were analyzed to quantitate irofulven by high-performance liquid chromatography. Population pharmacokinetic analysis was performed using a non-linear mixed effects modeling program, MP2. Fifty-nine patients were available for pharmacokinetic analysis. Irofulven plasma concentration-time profiles were best described by a two-compartment pharmacokinetic model. Clearance and central volume of distribution were not significantly influenced by individual characteristics, i.e. body weight (BW), body surface area (BSA), age and gender. Final parameter estimates of clearance and central volume of distribution were 616 l/h and 37 l, respectively, resulting in a very short terminal half-life of less than 10 min. A relatively high level of variability was observed in irofulven pharmacokinetics, which was mainly due to a significant residual variability, 39%. For a 30-min irofulven infusion, the optimal sampling schedule for clearance estimation using the Bayesian method was the three time points 0.35-0.45, 0.80 and 1-1.2 h from the beginning of a 30-min infusion. We conclude that after i.v. infusion of irofulven, plasma clearance was high and not dependent upon patient age, gender, BSA or BW.

Adult↗
PubMed2002

Identification of cultured progenitor cells from human marrow stroma.

The marrow stromal cells (MSC) are essential for regulation of bone remodeling and hematopoiesis. It is of prime importance to isolate MSC and to expand the proliferating cells ex vivo. In this study, we analyzed cultured MSC for various cellular parameters, including cell morphology, cell cycle, and expression of cell surface antigens by flow cytometry. MSC were divided based on cell size to small (S-cells) and large (L-cells) and were visualized by light and electron microscope. The S-cells were proliferating cells correlated with G0/G1 phase of cell cycle, and expressed cFOS. The expression of surface markers CD-34, -44, -51, -61, -62E, -62P, -62L was quantified using flow cytometry. CD-44 was ubiquitously expressed by S and L cells, CD-51 and -61 were expressed by 30%-38% of S-cells. CD-34 and -62 expressed 20% positive of the analyzed cells that were of the proliferating progenitors (S-cells). This study enables the identification of subpopulations from MSC with special attention paid to the proliferating cells from ex vivo cultures of marrow stroma.

Antigens, CD34↗
PubMed2002

Topotecan preceded by oxaliplatin using a 3 week schedule: a phase I study in advanced cancer patients.

Combinations of topoisomerase I (topo I) poisons and platinum derivatives have synergistic antitumoral effects. However, their clinical development is limited by supra-additive haematological toxicity. The aim of this study was to determine whether sustained doses of topotecan and oxaliplatin could be achieved using a synergistic sequence. 34 advanced cancer patients and 186 cycles were evaluable for toxicity over five dosing levels. Oxaliplatin at 85-110 mg/m(2) was given on day 1, followed by topotecan 0.5-1.25 mg/m(2)/day x 5 from day 1 to 5, every 3 weeks. Plasma pharmacokinetics (PK) of total and ultrafiltrable platinum, total and lactone forms of topotecan were determined in the first cycle. The dose-limiting toxicity (DT) was identified as grade 4 thrombocytopenia. The occurrence of grade 4 thrombocytopenia did not correlate with topotecan PK, but it did with the patient's characteristics. Severe thrombocytopenia was seen in 1/8 of patients without clinical or biological evidence of malnutrition, with a creatinine clearance higher than 1 ml/s, and no more than two previous chemotherapy regimens, while it was seen in 8/10 patients with one of these characteristics (P<0.004). In conclusion, the recommended doses of oxaliplatin 110 mg/m(2) and topotecan 1 mg/m(2)/day, every 3 weeks can be administered to patients with a favourable general status and pretreatment characteristics and a phase II study is worthwhile in ovarian cancer patients.

Adult↗
PubMed2002

Phase I-II and pharmacokinetic study of gemcitabine combined with oxaliplatin in patients with advanced non-small-cell lung cancer and ovarian carcinoma.

BACKGROUND: The aim of this study was to determine the toxicity profile, the recommended dose (RD) and the pharmacokinetic parameters, and to evaluate the antitumor activity of gemcitabine combined with oxaliplatin in patients with advanced non-small-cell lung cancer (NSCLC) and ovarian carcinoma (OC). METHODS: Gemcitabine was administered as a 30-min infusion followed by a 2-h infusion of oxaliplatin, repeated every 2 weeks. Doses of gemcitabine and oxaliplatin ranged from 800 to 1500 and 70 to 100 mg/m(2), respectively. RESULTS: Forty-four patients (26 males, 18 females; median age 55 years) including 35 NSCLC (five platinum pretreated) and nine OC patients (all platinum pretreated) received a total of 355 cycles. All patients were evaluable for toxicity. No dose-limiting toxicity at any dose level occurred during the first two cycles; therefore, the highest dose-level of gemcitabine (1500 mg/m(2)) and oxaliplatin (85 mg/m(2)) was considered as the RD. Hematological toxicity was moderate amongst the 22 patients treated (167 cycles) at that dose level. Thirteen cycles were associated with grade 3-4 non-febrile neutropenia in six patients, and eight cycles with grade 3-4 thrombocytopenia in two patients. Other toxicities were mild to moderate, consisting of asthenia and peripheral neurotoxicity. Four of the 35 patients treated with oxaliplatin 85 mg/m(2) experienced grade 3 neurotoxicity requiring treatment discontinuation at cycle 10. In the range of the doses used, gemcitabine and its main metabolite 2',2'-difluorodeoxyuridine appeared not to be affected by oxaliplatin 70-100 mg/m(2). Of the 44 patients evaluable for activity, 12 NSCLC patients experienced objective responses (one complete and 11 partial responses) and three OC patients showed tumor stabilization lasting for 6 months with a 50% decrease of CA 125 level. Two partial responses (NSCLC) and one tumor stabilization (OC) occurred in platinum-resistant patients. CONCLUSIONS: The combination of gemcitabine and oxaliplatin could be safely administered on an out-patient schedule in patients with advanced NSCLC and OC. The RD was gemcitabine 1500 mg/m(2) and oxaliplatin 85 mg/m(2) every 2 weeks. Promising antitumor activity was reported in patients with NSCLC and platinum-pretreated OC, and thus, deserves further evaluation.

Adenocarcinoma↗
PubMed2002

Exacerbation of oxaliplatin neurosensory toxicity following surgery.

Combination of chemotherapy and surgical resection of metastases is the most promising strategy to improve the fraction of long-term survivors and cured patients in metastatic colorectal cancer. We reproducibly observed evidence of exacerbation of the oxaliplatin-induced neurosensory toxicity following surgery. Total, protein-bound and intra-erythrocytic concentrations of oxaliplatin were measured, whenever possible, immediately prior to surgery and 4, 24 and 48 h following surgical resection. Among 12 patients, seven (58%) patients reported immediate post-operative aggravation of the pre-existing neurotoxicity. At the time of surgery, we detected high intra-erythrocytic platinum concentrations in all patients (median: 1365 micro g/l, range: 820-2968 micro g/l). While ultrafilterable oxaliplatin was not detectable prior to surgery, it could be detected immediately after surgery and during 48 h. These results suggest that patients heavily pretreated with oxaliplatin may experience aggravation of neurotoxicity after surgery, probably through a redistribution of the pool of intra-erythrocytic oxaliplatin biotransformation products into the plasma. This clinical observation might be the consequence of peroperative hemolysis.

Adenocarcinoma↗
PubMed2002

Efficacy of prenatal ultrasonography in confirmed club foot.

Club foot can be diagnosed by ultrasound of the fetus in more than 60% of cases. We have correlated the accuracy of the prenatal findings in 281 ultrasound surveys with the physical findings after birth and the subsequent treatment in 147 children who were born with club foot. The earliest week of gestation in which the condition was diagnosed with a high degree of confidence was the 12th and the latest was the 32nd. Not all patients were diagnosed at an early stage. In 29% of fetuses the first ultrasound examination failed to detect the deformity which subsequently became obvious at a later examination. Club foot was diagnosed between 12 and 23 weeks of gestation in 86% of children and between 24 and 32 weeks of gestation in the remaining 14%. Therefore it can be considered to be an early event in gestation (45% identified by the 17th week), a late event (45% detected between 18th and 24th weeks) or a very late event (10% recognised between 25th and 32nd weeks). We cannot exclude, however, the possibility that the late-onset groups may have been diagnosed late because earlier scans were false-negative results. The prenatal ultrasonographic findings were correlated with the physical findings after birth and showed that bilateral involvement was more common than unilateral. There was no significant relationship between the prenatal diagnosis and the postnatal therapeutic approach (i.e., conservative or surgical), or the degree of rigidity of the affected foot.

Clubfoot↗
PubMed2001

Differential gene expression of cultured human osteoblasts.

Human cells with osteogenic capacity were studied for differential gene expression. In the first part of the study we compared gene expression of marrow stroma cells (MSC) in comparison to matured osteoblasts cultured from trabecular bone (TBC) that were analyzed by RT-PCR for series of messages. High expression was detected for PTH-r, TGFb1 and biglycan in TBC compared to MSC's. The messages for c-MYC, IL-6, IL-11, M-CSF, osteonectin, and osteocalcin were expressed at the same level in the two populations of cells. In the second part of the study, we analyzed gene expression within the MSC derived from 25 donors (2.5-49 years old) with respect to donors' age and gender. Increased message levels for M-CSF and biglycan were measured in correlation with age of the donors. Gender differences did not affect the expression of cytokines studied (IL-6, IL-11, MCSF, TGFb1). We investigated the effect of Dexamethasone treatment on MSC and monitored an increased expression of IL-11, M-CSF, biglycan, and osteocalcin messages. This study employs primary cell systems (MSC and TBC) to illustrate differential gene expression by osteoblastic cells. The expression was correlated with maturation status of the cells with respect to differences between donors.

Adolescent↗
PubMed2001

Pharmacokinetics of oral acyclovir in neonates and in infants: a population analysis.

Acyclovir is approved for the treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections in children by the intravenous and oral routes. However, its use by the oral route in children younger than 2 years of age is limited due to a lack of pharmacokinetic data. The objectives of the present study were to determine the typical pharmacokinetics of an oral suspension of acyclovir given to children younger than 2 years of age and the interindividual variabilities in the values of the pharmacokinetic parameters in order to support the proposed dosing regimen (24 mg/kg of body weight three times a day for patients younger than 1 month of age or four times a day otherwise). Children younger than age 2 years with HSV or VZV infections were enrolled in a multicenter study. Children were treated for at least 5 days with an acyclovir oral suspension. Plasma samples were obtained at steady state, before acyclovir administration, and at 2, 3, 5, and 8 h after acyclovir administration. Acyclovir concentrations were measured by radioimmunoassay. The data were analyzed by a population approach. Data for 79 children were considered in the pharmacokinetic study (212 samples, 1 to 5 samples per patient). Acyclovir clearance was related to the estimated glomerular filtration rate, body surface area, and serum creatinine level. The volume of distribution was related to body weight. The elimination half-life decreased sharply during the first month after birth, from 10 to 15 h to 2.5 h. Bioavailability was 0.12. The interindividual variability was less pronounced when the parameters were normalized with respect to body weight. Hence, dosage adjustment by body weight is recommended for this population. Simulations showed that the length of time that acyclovir remains above the 50% inhibitory concentration during a 24-h period was more than 12 h for HSV but not for VZV. The proposed dosing regimen seems adequate for the treatment of HSV infections, while for the treatment of VZV infections, a twofold increase in the dose seems necessary for children older than age 3 months.

Acyclovir↗
PubMed2001

Bilateral symmetric stress fractures in a toddler.

Stress fractures are a common injury among adolescent athletes and military recruits. The increase in child participation in organized sport activities has contributed to the inclusion of the skeletally immature age group among those who may suffer from this problem. Bilateral simultaneous symmetric tibial stress fractures that are infrequent in older children are even more rare in toddlers. This entity may cause a diagnostic problem as it must be differentiated from infectious disease, acute trauma or even from the result of a battered child.

Child, Preschool↗
PubMed2001

Primary chronic sclerosing (Garré's) osteomyelitis in children.

Three children with unifocal nonpyogenic inflammatory bony lesions with a prolonged, fluctuating course are reported. The lesions were located at the metaphyseal region of long bones. Three was progressive sclerosis and hyperostosis in the tibia or femur, such as the changes described in Garré's osteomyelitis. No pus was released by exploration of the lesions. Tissue and blood cultures were negative. The histology was typical of chronic osteomyelitis: the symptoms returned intermittently over several years, together with the development of sclerosis but without disturbance of bone growth. It is not clear whether Garré's chronic sclerosing osteomyelitis is a different entity from chronic recurrent multifocal osteomyelitis.

Adolescent↗
PubMed2000

Phase I and pharmacokinetic study of docetaxel and irinotecan in patients with advanced solid tumors.

PURPOSE: We conducted a phase I and pharmacokinetic study of docetaxel in combination with irinotecan to determine the dose-limiting toxicity (DLT), the maximum-tolerated dose (MTD), and the dose at which at least 50% of the patients experienced a DLT during the first cycle, and to evaluate the safety and pharmacokinetic profiles in patients with advanced solid tumors. PATIENTS AND METHODS: Patients with only one prior chemotherapy treatment (without taxanes or topoisomerase I inhibitors) for advanced disease were included in the study. Docetaxel was administered as a 1-hour IV infusion after premedication with corticosteroids followed immediately by irinotecan as a 90-minute IV infusion, every 3 weeks. No hematologic growth factors were allowed. RESULTS: Forty patients were entered through the following seven dose levels (docetaxel/irinotecan): 40/140 mg/m(2), 50/175 mg/m(2), 60/210 mg/m(2), 60/250 mg/m(2), 60/275 mg/m(2), 60/300 mg/m(2), and 70/250 mg/m(2). Two hundred cycles were administered. Two MTDs were determined, 70/250 mg/m(2) and 60/300 mg/m(2); the DLTs were febrile neutropenia and diarrhea. Neutropenia was the main hematologic toxicity, with 85% of patients experiencing grade 4 neutropenia. Grade 3/4 nonhematologic toxicities in patients included late diarrhea (7.5%), asthenia (15.0%), febrile neutropenia (22.5%), infection (7.5%), and nausea (5.0%). Pharmacokinetics of both docetaxel and irinotecan were not modified with the administration schedule of this study. CONCLUSION: The recommended dose of docetaxel in combination with irinotecan is 60/275 mg/m(2), respectively. At this dose level, the safety profile is manageable. The activity of this combination should be evaluated in phase II studies in different tumor types.

Adult↗
PubMed2000

Population pharmacokinetics of topotecan: intraindividual variability in total drug.

The inter- and intraindividual variabilities in topotecan clearance (CL) were explored using a population pharmacokinetic approach. Total (lactone + hydroxy acid) topotecan plasma concentrations were obtained in 31 women with metastatic epithelial ovarian cancer treated by the 30-min intravenous infusion on 5 subsequent days. The data corresponding to three occasions (days 1 and 5 of cycle 1, and day 1 of cycle 2), were analyzed using the nonlinear mixed effect model program. A large interindividual variability was observed, with CL varying from 9.1 to 42.51 per hour (mean 21.0). Topotecan CL was related to serum creatinine level, and age. A close relationship was also observed between topotecan CL and creatinine clearance. Intraindividual variability both within cycle 1 and between the two first cycles was limited, with a mean variation of -2+/-17%, and + 5+/-20%, respectively. A limited sampling strategy using Bayesian estimation based on two samples (5 min before the end of the 30-min infusion, and 4 h after the end of infusion) was developed. The results of this study combine relationships between topotecan pharmacokinetic parameters and patient covariates that may be useful for a priori dose adjustment, and convenient sampling procedure that can be used for further studies and drug monitoring.

Aged↗