Phase II study of fotemustine in recurrent supratentorial malignant gliomas.

38 adults with recurrent supratentorial malignant gliomas, including glioblastoma multiforme (21), anaplastic astrocytomas (9), probably transformed low-grade astrocytomas (6), pinealoblastoma (1) and non-metastatic tumour of unknown histology (1), were treated with fotemustine 100 mg/m2 intravenously every week for 3 consecutive weeks followed by a 5-week rest period. Maintenance treatment consisted of one infusion every 3 weeks. Patients were divided into three groups according to treatment effect. 10 objective responses (26%) with a median time without progression of 32.7 weeks, 18 stabilisations (47%) and 10 failures (26%) were observed. Pathological findings of the initial primary tumour and neurological functional status were unequally distributed in these groups. Haematological and liver toxicities were mild, delayed, transient and reversible. Thrombocytopenia and leukopenia were more frequent (30%) in patients treated with prior chemotherapy. Fotemustine is a well tolerated active drug in recurrent malignant gliomas with an original and short treatment schedule.

Phase I pharmacological study of intra-arterially infused fotemustine for colorectal liver metastases.

Fotemustine was investigated in 17 patients with progressive hepatic metastases from colorectal carcinoma to define the maximally tolerated dose for a daily hepatic intra-arterial infusion (HAI) schedule. Haematotoxicity was delayed, dose-dependent and related to pretreatment, with thrombo- and leucocytopenia being dose-limiting. Local side-effects at the liver were mild. Infection (WHO grade III) occurred in 1 patient due to neutropenia. Other side-effects, particularly renal, pulmonal, neurological or cardiac toxicity, mucositis and diarrhoea, hair loss or allergic reactions did not occur. Pharmacokinetic analysis indicated a short plasma half-life (t1/2 = 25.8 +/- 11.5 min) and a high body clearance (CL = 2193 +/- 870 ml/min) with large inter- and intra-individual variations. Of 15 evaluable patients, one complete and three partial responses were observed (ORR = 27%; CI95% [4.5-49.5%]). All tumour remissions appeared at higher dose levels in previously untreated patients. Considering the absence of mucosal side-effects, such as mucositis/diarrhoea and of hepatic toxicity, this agent was well tolerated. The recommended intra-arterial dose for consecutive phase II trials is 125 mg/m2/day1-3.

A phase II trial of fotemustine and cisplatin in central nervous system metastases from non-small cell lung cancer.

A phase II study was conducted in order to determine the feasibility and toxicity of cisplatin combined with the nitrosourea fotemustine in central nervous system metastases from non-small cell lung cancer. 31 chemotherapy-naïve patients were included between November 1990 and April 1993. Computed tomography scan-documented tumour regression in brain metastases was observed in 7 of the 25 evaluable patients, but only 4 of these (16%) lasted more than 4 weeks. In 2 of these 4 patients, the response on central nervous system metastases was considered as complete. The median duration of response was 20.5 weeks and the median survival was 16 weeks overall and 28.5 weeks for responding patients. The limiting toxicity of this regimen was haematological. 2 patients died from infectious pneumonitis while in neutropenia. Treatment delays due to haematological toxicity occurred in 57% of patients. Despite the rather encouraging response rate, such toxicity appears too high when compared to the overall bad prognosis of this population of patients. Cranial radiotherapy remains the standard treatment in this setting and should only be compared in the future to less aggressive schedules.

Phase II study of a new vinca alkaloid derivative, S12363, in advanced breast cancer.

Vinca alkaloids are widely used in the medical treatment of breast cancer. Our study aimed to evaluate the therapeutic activity of a new vinca alkaloid derivative, S12363 (vinfosiltine), which is 36 and 72 times more cytotoxic in vitro than vincristine and vinblastine, respectively. Because phase I studies did not allow a choice of the best treatment schedule, a randomization was performed between two schedules with the same dose intensity, that is, 0.3 mg/m2 given weekly or 0.6 mg/m2 given every 2 weeks. A total of 16 patients with advanced breast cancer who had failed a first-line treatment without any vinca alkaloid were entered in the study. Additionally, 6 women received the bimonthly regimen as first-line treatment of advanced breast cancer. Altogether, 17 patients received, prior to vinfosiltine, an anthracycline-based regimen given either as adjuvant (n = 4) or as first-line palliative treatment (n = 13). All 22 patients were evaluable for both toxicity and response. Neutropenia was the main toxic event (maximal toxicity per patient) with grade 3 (WHO) toxicity developing in 7/22 patients and grade 4, in 8/22. Other severe toxicities included leukopenia (n = 9), anemia (n = 1), diarrhea (n = 1), constipation (n = 1), and fatigue (n = 1). No patient achieved a complete or partial response. Vinfosiltine does not appear to have significant single-agent activity in advanced breast cancer at the doses and the schedules used in our study.

Phase I pharmacokinetics study of high-dose fotemustine and its metabolite 2-chloroethanol in patients with high-grade gliomas.

The pharmacokinetics of high-dose fotemustine followed by autologous bone-marrow transplantation during a phase I-II clinical trial in 24 patients with glioblastoma or astrocytoma (grade III-IV) was investigated. Plasma levels of fotemustine were determined by high-performance liquid chromatography (HPLC) and UV detection. The metabolite, 2-chloroethanol, was simultaneously followed in six patients by gag liquid chromatography and electron capture detection (GLC-ECD) assay. The drug was given as a 1-h infusion on 2 consecutive days. In all, 40 pharmacokinetic determinations of fotemustine were made at dose levels ranging from 2 x 300 to 2 x 500 mg/m2. Plasma drug elimination was best described by a bi-exponential model, with short distribution and elimination half-lives of 4.15 +/- 2.57 and 28.8 +/- 12.1 min being observed, respectively. No significant difference in half-lives or clearance was seen between the first and the second administration. During dose escalation, the mean area under the concentrationtime curve (AUC) increased from 5.96 +/- 2.89 to 12.22 +/- 3.95 mg l-1 h. Drug clearance was independent of the dose given and equal to 109 +/- 65 l/h, indicating no possible saturation of metabolism and elimination mechanisms at these high-dose levels. The metabolite 2-chloroethanol appeared very early in plasma samples. Its elimination was rapid and rate-limited by the kinetics of the parent compound, giving the same apparent terminal half-life. A close relationship between AUC and C45 values was evidenced (r = 0.890). Associated with the stability of fotemustine kinetic parameters, this could be used in future studies for individual dose adjustment, particularly for high-dose fractionated regimens.

[Effect of renal insufficiency on the pharmacokinetics of captopril and converting enzyme inhibition in the hypertensive patient]. / Influence de l'insuffisance rénale sur la pharmacocinétique du captopril et le blocage de l'enzyme de conversion chez l'hypertendu.

The influence of renal insufficiency (RI) on the pharmacokinetics of captopril (1 mg/kg, orally) and on the kinetics of the induced converting enzyme inhibition (CEI) was investigated in three groups of hypertensive patients: without RI (n = 10, plasma creatinine less than 100 mumol/l), with moderate RI (MRI) (n = 10,200 less than creatinine less than 400 mumol/l) and with severe RI (SRI) (n = 8, creatinine greater than 500 mumol/l). Captopril pharmacokinetic parameters were not modified by RI, with the exception of elimination half-life which was lengthened, but relative bioavailability of the drug was not modified. In contrast, captopril-induced CEI was strongly potentiated in patients with RI, an effect correlated with plasma creatinine values. This apparent discrepancy between the lack of modification in captopril plasma bioavailability and the prolongation of its biological effects can probably be accounted for by a decreased elimination and/or an increased formation of captopril metabolites during RI.

Comparisons between surface electrodes and intramuscular wire electrodes in isometric and dynamic conditions.

The purpose of this study was to compare EMG surface electrodes (SE) and intramuscular wire electrodes (IWE) for isometric and dynamic contractions during an occupational cervico-brachial working task (OCWT). Six normal adult male subjects were tested on two days (two conditions with three trials each). Raw EMG signals from middle deltoid, anterior deltoid and trapezius muscles were recorded by both IWE and SE for two conditions (isometric and dynamic contractions). Full wave rectified and low pass filtered EMG, and integrated EMG were processed from raw EMG signals. The statistical analysis performed on the integrated EMG was a factorial analysis model with repeated measures. Statistical results confirmed that EMG signals, from both SE and IWE, are reliable between trials on the same day. These statistical results also confirmed that SE are more reliable than IWE on day-to-day investigations. Both electrodes recorded statistically similar signals, although the coefficient of variability between electrodes was very high (STDE%; 48% and 84%, for isometric and dynamic conditions respectively).

[Neonatal detection of central hypothyroidism]. / Hypothyroïdie centrale de découverte néonatale.

BACKGROUND: Congenital hypothyroidism is very rare compared to primary hypothyroidism. Its early diagnosis may escape neonatal mass screening using TSH assay. CASE REPORT: Anthony was born at 37 weeks, weighing 3,060 g. He presented with hypotony, jaundice, tongue protrusion evoking congenital hypothyroidism. Thyroid function tests favored hypothyroidism central in origin, while the systematic neonatal screening was normal. CONCLUSION: Clinical signs of congenital hypothyroidism must lead to more specific tests when neonatal screening is normal.

Net shoulder joint moment and muscular activity during light weight-handling at different displacements and frequencies.

The purpose of this study was to calculate net shoulder (gleno-humeral) joint moments from inverse dynamics and to measure muscular activity from six shoulder muscles (supraspinatus, infraspinatus, middle deltoid, anterior deltoid, trapezius, and pectoralis major) during light weight-handling at two different displacements (horizontal and vertical) and frequencies (40 and 60 cycles/min), to simulate an occupational cervicobrachial working task (light weight displacement). Ten normal adult male subjects were asked to move a known weight, representing 15% of the maximal lifted weight, in both horizontal and vertical conditions at frequencies of 40 cycles/min and 60 cycles/min. Raw EMG signals from six shoulder muscles were recorded and synchronized with the cinematographic data during three trials of 6 s each. The raw EMG signals of each muscle were full wave rectified and filtered at 3 Hz. The linear envelope (LE EMG) signals were normalized by time (% cycle) and by amplitude (% MVC), and for the analysis of variance, the normalized LE EMG signals were integrated (IN LE EMG). The average shoulder angular velocities, joint moments, and moment powers were computed from cinematographical data. No significant differences were observed between both tasks for the supraspinatus, infraspinatus, and pectoralis major IN LE EMG data as well as for integrated normalized shoulder joint moment for the whole cycle of movement. IN LE EMG data from middle deltoid, anterior deltoid, and trapezius muscles were significantly higher (p less than 0.05) when performing the vertical displacement task for the whole cycle of movement. This muscular activity difference between vertical and horizontal tasks indicated that the vertical displacement conditions induced higher muscular loads on the shoulder than the horizontal weight displacement conditions, although the vertical displacements were approximately 15% longer than the horizontal displacements. The non-significant difference of IN LE EMG between frequencies obtained for all muscles indicated that neither frequencies induced more muscular activity.

Permeability of two nitrosoureas, carmustine and fotemustine in rat cortex.

Carmustine and fotemustine were perfused using a bolus retrograde infusion into the right external carotid artery of rats. The right jugular vein gave blood samples. Using a previously described method, nitrosoureas were continuously measured in rat brain by voltammetry and in blood samples by high-performance liquid chromatography for 15 min. Cerebrovascular permeability coefficients calculated in the first 2 min were 0.9.10(-4) cm.s-1 for carmustine and 0.5.10(-4) cm.s-1 for fotemustine. These high brain permeability coefficients were compared to literature values for carmustine and other nitrosoureas determined with a radioactive procedure.

Tissue extraction of amiodarone and N-desethylamiodarone in man after a single oral dose.

The hepatic extraction of amiodarone and N-desethylamiodarone has been investigated in seven patients following catheterization of the portal and hepatic veins under general anaesthesia. Amiodarone (600 mg) was administered orally 4 h before regional blood sampling. Concentrations of amiodarone and N-desethylamiodarone, determined by h.p.l.c., were about twice as high in the portal vein compared with those in the hepatic vein, the calculated hepatic extraction ratios of both compounds being 0.39 +/- 0.07 and 0.34 +/- 0.03, respectively. The presence of N-desethylamiodarone in the portal vein in higher concentrations than in the hepatic vein strongly suggests that N-dealkylation of amiodarone occurs in the gut wall or lumen, a finding which might account for the low and highly variable intersubject amiodarone bioavailability.

Comparative diffusion study of two nitrosoureas: carmustine and fotemustine in normal rat brain, human and rat brain biopsies.

In order to assess the apparent diffusion coefficient of two nitrosoureas (carmustine and fotemustine) in the brain, a model of planar diffusion was used in the rat brain and in rat and human brain biopsies. Drugs were deposed on the brain surface at a constant concentration for 30 min. At the end of the diffusion time, the concentration gradient was determined with microelectrodes using voltammetry at 5 different depths in the extracellular space of the gray matter (0-304 microns). Voltammetry with microelectrodes measured quantitatively intact drug in the brain extracellular space (CV 4% for the 2 drugs) in the range studied. The same procedure was used for human and rat brain biopsies which were held in a small cup. The apparent diffusion coefficients in living animals were 0.49 x 10(-6) cm2.s-1 for carmustine and 0.23 x 10(-6) cm2.s-1 for fotemustine; in human biopsies, they were 0.84 x 10(-6) cm2.s-1 for carmustine and 0.37 x 10(-6) cm2.s-1 for fotemustine. Significant differences in the apparent diffusion coefficients of the drugs were accounted for by the fact that the intracellular penetration of fotemustine was better than that of carmustine.

Captopril: pharmacokinetics, antihypertensive and biological effects in hypertensive patients.

The kinetics of captopril plasma levels and of the drug-induced plasma converting enzyme activity (PCEA), plasma renin activity (PRA) and diastolic blood pressure (DBP) modifications were studied over 24 h after oral administration of captopril, 1 mg/kg, to ten hypertensive patients. Free unchanged captopril pharmacokinetic parameters were: t1/2, alpha: 0.45 +/- 0.06 h; tmax: 0.98 +/- 0.13 h; Cmax: 1.31 +/- 0.20 mg l-1; t1/2,z: 0.66 +/- 0.13 h; V: 0.614 +/- 0.104 1 kg-1 and CLtot: 0.690 +/- 0.082 l h-1 kg-1. At 6 h captopril was no longer detectable in plasma. The onset of PCEA inhibition and of DBP decrease closely followed the rise of captopril's plasma levels, while that of PRA increase was delayed. In contrast, while captopril rapidly disappeared from plasma, its biological and antihypertensive effects were long-lasting. The lack of correlation between the relative bioavailability of captopril and the induced reduction in DBP (evaluated by the corresponding AUCs) suggests that free unchanged captopril plasma monitoring is not an adequate indicator of hypertensive patients' potential responsiveness to captopril's blood pressure lowering effects.

Influence of chronic renal failure on captopril pharmacokinetics and clinical and biological effects in hypertensive patients.

The pharmacokinetic parameters of unchanged plasma captopril and the kinetics of the drug effects on plasma converting enzyme activity (PCEA), plasma renin activity (PRA), plasma aldosterone (PA) and mean blood pressure (MBP) were studied over 24 h after oral administration in three groups of hypertensive patients: with normal renal function (group 1, plasma creatinine less than 110 mumol/l, n = 10), with moderate chronic renal failure (group 2, 135 less than plasma creatinine less than 450 mumol/l, n = 10) and with severe chronic renal failure (group 3, plasma creatinine greater than 500 mumol/l, n = 10). Renal impairment had no effect on plasma captopril Cmax, CLtot and relative bioavailability (AUC). In contrast, captopril kel decreased while T1/2 increased progressively from group 1 to group 3. PCEA blockade (T1/2 and AUC) was increased significantly and proportionally to the degree of renal impairment. However, there were no differences between the three groups regarding captopril-induced modifications of PRA and PA. Although the maximal reduction in MBP was identical in the three groups, the overall antihypertensive effect (AUC) of captopril increased significantly and progressively from group 1 to group 3, especially in duration. There was no correlation between basal plasma creatinine values and unchanged captopril relative bioavailability (AUC) and between unchanged captopril relative bioavailability (AUC) and the drug effects (AUC) on PCEA, PRA, PA and MBP. However there was a correlation between basal plasma creatinine values and plasma captopril T1/2, PCEA blockade (AUC) and overall antihypertensive effect (AUC). The apparent discrepancy between the lack of effects of chronic renal failure on plasma unchanged captopril bioavailability and its potentiating effects on PCEA blockade and MBP reduction may be accounted for by the renal impairment-induced accumulation of captopril metabolites.

Fotemustine in the treatment of brain primary tumors and metastases.

Fotemustine is a new chloroethylnitrosourea characterized by the grafting of a phosphonoalanine group onto a nitrosourea radical. Clinical studies using fotemustine have been conducted in malignant glioma, brain metastasis of non-small cell lung cancer, and disseminated malignant melanoma. In recurrent malignant glioma, fotemustine has been used as a single agent: assessed by computed tomography scan, after 8 weeks, the objective response rate was 26.3% among 38 evaluable patients. Median duration of response was 33 weeks. The main toxicity was hematological (thrombocytopenia and leucopenia). A trial with high-dose fotemustine and autologous bone marrow rescue in newly diagnosed glioma was conducted in 26 patients, and 6 showed a partial response. The median overall survival was approximately 11 months. Myelosuppression was noted in all patients except 1, and other toxicity reported was central nervous system toxicity and epigastric pain. Combined with radiotherapy in 55 patients, a 29% response rate was observed, and this combination was well tolerated and easily manageable on an outpatient basis. Finally, fotemustine has been used intraarterially, with 10 objective responses observed among 26 evaluable patients. In brain metastases of non-small cell lung cancer, fotemustine proved to be active with a response rate of 16.7%. Combined with cisplatinum, fotemustine is still under study, but preliminary results are promising. In cerebral metastases of disseminated malignant melanoma, fotemustine has been evaluated in a total of 140 patients in the various studies: median response rate is 24.3%, ranging from 8.3% to 60.0%. Fotemustine appears to be a good candidate in the treatment of primary brain tumors and metastases.

Modulation of daunorubicin cellular resistance by combination of P-glycoprotein blockers acting on drug efflux and intracellular drug sequestration in Golgi vesicles.

BACKGROUND: S9788 and PSC833 were developped as P-glycoprotein (Pgp) blockers and found to act additionally on daunorubicin subcellular distribution, involving different putative targets. On this basis, combinations of S9788 and PSC833 were evaluated in Pgp-expressing MCF7(DXR) cells in which we recently demonstrated that daunorubicin was sequestered in Golgi vesicles (Bour-Dill et al.: Cytometry, 39: 16-25, 2000). METHODS: Combinations of S9788 and PSC833 consisted in complementary fractions of iso-effective concentrations (IEC) leading to 90% (IEC90) and median (IEC50) reversion of daunorubicin resistance. Resistance modulation was assessed using cytotoxicity assays, flow cytometry determination of intracellular daunorubicin, and fluorescence microscopy analysis of daunorubicin subcellular distribution. RESULTS: Individually, both S9788 and PSC833 were found to be very potent with IEC90 of 5 and 15 micromol/l, and IEC50 of 0.1 and 0.2 micromol/l, respectively, for S9788 and PSC833. When combined, synergistic cytotoxicity was observed for both IEC90 and IEC50 combinations while intracellular daunorubicin fluorescence was only synergistically increased for IEC90 combinations. For IEC50 combinations, no increase in intracellular fluorescence was observed, and fluorescence microscopy examination of the cells suggested that daunorubicin sequestration in Golgi vesicles could be modulated at concentrations that do not significantly increase daunorubicin cellular concentration. Using immunofluorescence and reverse transcription-polymerase chain reaction analyses, multidrug resistance-associated protein, major vault lung-resistance protein, and anthracycline-resistance associated protein were not found to be implicated. CONCLUSIONS: Synergistic combinations of S9788 and PSC833 might offer alternative ways to decrease the toxicity generated by high-dose Pgp-blockers without altering the efficacy of the resistance modulation.

Complete remission seven years after treatment for metastatic malignant melanoma.

BACKGROUND: In this study, the authors identified seven-year survivors after completion of the French multicenter Phase II trial of fotemustine for the treatment of metastatic malignant melanoma. METHODS: One hundred sixty-nine patients with metastatic malignant melanoma were included in this Phase II study. One hundred fifty-three patient records were evaluable with an overall response rate of 24.2%. RESULTS: Five of these patients are alive and in complete remission. One patient had a complete response after fotemustine administration and then relapsed. One patient had a partial response. Three patients had stable disease. These five patients underwent surgery for relapse or residual disease and subsequently achieved durable complete remission. CONCLUSIONS: Long term survival may be the outcome after surgical resection of residual metastatic melanoma after chemotherapy.

Fotemustine combined with procarbazine in recurrent malignant gliomas: a phase I study with evaluation of lymphocyte 06-alkylguanine-DNA alkyltransferase activity.

The aims of this phase I study in patients with recurrent malignant gliomas were to determine the maximum tolerated dose (MTD) and toxicity profile of fotemustine when combined with a fixed dose of procarbazine (PCZ), and to evaluate the extent of O6-alkylguanine-DNA alkyltransferase (ATase) depletion in circulating lymphocytes during treatment. Sixteen patients received an induction cycle consisting of 100 mg/day oral PCZ for 12 consecutive days and a 1-h intravenous infusion of fotemustine given 4 h after PCZ on days 5 and 12 at escalated doses (50, 75, 100 and 125 mg/m2/day). After a 6-week rest period, a maximum of 4 maintenance cycles (PCZ 300 mg/day, 4 days; fotemustine, day 4) was given every 4 weeks. ATase activity was measured on days 1, 5 and 12 over 4 h after PCZ intake. Fifteen patients had previously received at least one nitrosourea-based chemotherapy, associated with PCZ in 12 cases. The MTD of fotemustine was 125 mg/m2 (days 5 and 12) with myelosuppression as the dose limiting toxicity (DLT). At this dose level, half of patients experienced grade 3 anemia, neutropenia or thrombopenia. No extra-hematological DLT was observed. No significant depletion of ATase activity by PCZ was evidenced. One partial response and 7 stable diseases were obtained leading to a disease control rate of 50%. The median times to progression and survival were 2.6 and 9.7 months, respectively. This combined regimen of PCZ and fotemustine was well tolerated with a good disease control rate in heavily pretreated glioma patients and merits further investigation in phase II studies.

Time-schedule dependency of S 16020, a new topoisomerase II inhibitor.

S 16020 is a new olivacine derivative which has been shown to intercalate into DNA and to stabilize the cleavable complex formed by DNA and purified topoisomerase II. The aim of the present study was to estimate the impact of time exposure on the in vitro activity of S 16020. This was done on seven cancer cell lines of human origin (head and neck, kidney, and ovary). Doxorubicin was used as a reference drug. The cytotoxic activity of S 16020 remained stable during at least 3 h. A loss of activity of about 30% was apparent after 6 or 24 h preincubation. This relative loss of activity reached about 50% after 72 h preincubation. Considering all tested cell lines, the average IC50 decrease was 89+/-8% for S 16020 with incubation times between 1 and 72 h. An exposure index (El) was calculated to evaluate the effect of time on the cytotoxic efficacy. The reference time was 1 h exposure. The El values were corrected to take into account the loss of drug activity. For the majority of cell lines EI values were greater than 1 for both drugs, particularly after a 6 h exposure time. This means that, in this case as compared to the shorter exposure (1 h), increasing time has a relative detrimental effect on drug efficacy. For the two cancer cell lines of ovarian origin, El values remained close to 1 for both drugs whatever the total exposure time. This means that, in this case, time and concentration have symmetrical effects on cell survival. The pharmacological information provided by the present study may be useful in designing future clinical trials on this potentially interesting new topoisomerase II inhibitor. As a consequence of these data, 1 and 3 h drug administration schedules are currently tested during phase I trials.