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Biomedical subjects

M Frenay

Publications and source records attributed to M Frenay.

At least 55 records · Page 3Linked to original sources
PubMed1991

Improved bioavailability of a new oral preparation of medroxyprogesterone acetate.

Medroxyprogesterone acetate (MPA) is widely used in the hormonal therapy of breast cancer. So far, oral formulations of MPA commercially available present a very low bioavailability, with a less than 10% extent of oral absorption. A new oral preparation of MPA has been recently developed. Based on a pilot study, an open, randomized, crossover trial has been performed on 22 breast and endometrial cancer patients to evaluate the relative bioavailability of this new oral formulation (200-mg sachet, twice daily) as compared with a standard formulation (Farlutal, 500-mg tablet, twice daily). The bioavailability evaluation was mainly based on the area under the curve measured between two administrations at steady state, after 15 days of continuous therapy. Wide interpatient variability of MPA plasma levels after oral MPA administration was confirmed. The MPA plasma levels were higher in patients treated with the new formulation than in patients treated with Farlutal. The relative bioavailability of the new preparation was 3.5 times higher than that of the standard. This new formulation represents a great improvement in the extent of oral absorption of MPA and could lead to better management of hormone-responsive tumors by hormonal therapy.

Administration, Oral↗
PubMed1991

Prognostic value of total cathepsin D in breast tumors. A possible role in selection of chemoresistant patients.

Evaluation of prognostic factors for breast cancers is important for therapeutic decisions both at the time of surgery and during postoperative surveillance. In 1979, H. Rochefort described an induced protein with a molecular weight of 52,000 Daltons identified as procathepsin D. Total cathepsin D (TCD) (52K + 48K + 34K), expressed in pmol/mg protein, can be measured by an immunoradiometric method commercialized by Cis-Biointernational. Total cathepsin D was assayed in 413 breast cancer tumors from patients who underwent surgery between January 1, 1978, and December 31, 1985. Using a cut-off of 35 pmol/mg protein, patients with an elevated level had a significantly poorer survival than those with a low level (p = 0.03). This difference was not found for node-negative patients but was very significant for node-positive patients (p less than 0.008). The survival of node-positive patients with a low total cathepsin level was not statistically different from that of node-negative patients. Analysis of the N+ subgroup of patients who did not receive adjuvant chemotherapy revealed that TCD no longer had any prognostic value, whereas it was still important for the N+ subgroup who received an adjuvant treatment. Cox multivariate analysis of prognostic value for survival placed total cathepsin D in third position, after nodal invasion and progesterone receptor status, for the entire population, and in first position before progesterone receptor status for the node-positive population. The association of a low cathepsin level and positive progesterone receptors characterized the subgroup of patients with the longest survival. TCD levels played the same role for prediction of the outcome of metastasis.(ABSTRACT TRUNCATED AT 250 WORDS)

Breast Neoplasms↗
PubMed1991

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.

Adolescent↗
PubMed1991

Oestrogen and progesterone receptor status in bone biopsy specimens from patients with breast cancer.

Of 16 breast cancer patients with histologically proven, tumour-infiltrating biopsy specimens most had low ER and PR values; the ER and PR contents varied between 0 and 135 and 0 and 44 fmol/mg protein, respectively. With the conventional clinical threshold of 10 fmol/mg protein, 8 specimens (50%) were ER-PR-, 4 (25%) ER-PR+, 3 (19%) ER+PR+ and 1 (6%) ER+PR-. ER levels were significantly lower in the tumoral bone lesion compared with the primary tumour. For 15 patients with negative biopsies and without endocrine treatment, ER and PR concentrations were quantifiable (2 fmol/mg protein or more) in 9 (60%) and 11 cases (73%), respectively. 8 of 9 patients over 55 (89%) were ER+ (2 fmol/mg protein or more). Conversely, for patients under 55, 1 of 6 (17%) was ER+ (P less than 0.001). Results for PR were similar. These data strongly suggest that steroid receptors are present in healthy bone tissue.

Adult↗
PubMed1991

Analysis of tissue platinum distribution in patients with cancer of the oesophagus.

The objective of this work has been to analyse the repartition of platinum (Pt) tissular levels within the tumour (T), the peritumoral adjacent non-tumoral area (P) and distant healthy tissue of the same anatomical zone (H) in oesophagus cancer. Forty-two biopsies (congruent to 5 mg) have been performed under endoscopy and after informed consent in 11 patients (mean age 61 yr, range 43-74) with squamous cell carcinoma of the oesophagus treated by the neoadjuvant chemotherapy protocol including cisplatin (100 mg/m2) and 5-FU (1 g/m2 x 5 days). Biopsies were done 34-36 h after cisplatin. Additional biopsies were obtained for histological controls. Pt was measured by flameless atomic absorption spectrometry. Considering Pt concentration in T, P and H there was no significant accumulation during repeated treatment (3 cycles). For all cycles, mean [S.D.] values (micrograms/g dry tissue) were 2.03 [2.39] for H, 2.75 [2.03] for P and 3.73 [2.3] for T (H vs. T, P = 0.006). In addition, Pt concentrations were found comparable between the upper and lower poles of the tumours (5 patients). Pt concentrations in T did not predict antitumour activity. These data complete the rather limited knowledge on tissular Pt levels in treated patients and suggest a decreasing gradient of Pt concentrations from tumour to healthy tissue in oesophagus cancer.

Adult↗
PubMed1990

In vitro chemosensitivity testing of Fotemustine (S 10036), a new antitumor nitrosourea.

Fotemustine (S 10036) is a new anti-tumor nitrosourea characterized by a phosphonoalanine carrier group coupled to the nitrosourea moiety, which potentially increases the cellular penetration of the drug. Using human tumor cell lines, the activity of S 10036 was compared with that of the more established nitrosoureas BCNU and CCNU. Growth-inhibiting effects were evaluated by the [3H]-thymidine incorporation test. In a panel of 12 human cancer cell lines [melanoma (4), ovary (2), head and neck (3), lung (1), bladder (1), breast (1)], the dose-response curves of S 10036 (0-100 microM) were similar to those obtained with equimolar concentrations of BCNU and CCNU; they indicated a moderately more marked effect for two and an equal effect for six melanoma cell lines with S 10036 as compared with BCNU. Moderate but significant synergistic combinations were obtained when S 10036 (0-80 microM) and CDDP (0-100 microM) or DTIC (250-6,500 microM) were combined in melanoma cell lines. In conclusion, the new nitrosourea S 10036 shows promising activity, particularly against human melanoma cell lines.

Antineoplastic Agents↗
PubMed1990

Steroid receptors in human osteoblast-like cells.

The presence and functions of steroid receptors were evaluated in three human osteosarcoma cell lines (OS1 = SA OS; OS2 = HOS TE 85, and OS3 = MNNG HOS TE 85). The human breast cancer cell line MCF-7 was used as internal control for oestrogen receptors (E2R). High and low affinity sites were characterised. The high affinity sites had a similar dissociation constant in all four cell lines. In contrast, the number of sites per cell was higher in MCF-7 cells. E2 did not significantly modify the number of progesterone receptors (PgR) per cell in any of the osteosarcoma lines. As expected, E2 increased the number of PgR sites per MCF-7 cell. 4-hydroxytamoxifen decreased the growth of MCF-7 cells only. OS1 and OS2 were sensitive only to the highest concentration tested, which produces only non-specific cytotoxic effects. Thus E2R and PgR were found in osteoblast-like cells, but the function of E2R in such cells remains unknown.

Breast Neoplasms↗
PubMed1990

Efficacy and safety of zopiclone and triazolam in the treatment of geriatric insomniacs.

Most studies with zopiclone, a cyclopyrrolone derivative with a short elimination half life (5 h) have compared its hypnotic activity with that of long elimination half life molecules. In this double-blind study in geriatric patients, drugs were administered during 3 weeks and the therapeutic effects of zopiclone at optimal dosage (5 or 7.5 mg) were compared to those of triazolam (0.125 or 0.25 mg). After a 3 day single-blind washout period, placebo responders were excluded and 48 patients were thereafter treated with either placebo (Tétreault et al., 1965), zopiclone or triazolam (Pegram et al., 1980). The initial dosage was increased when indicated at the end of the first week and kept constant thereafter. At the end of the third week of double-blind treatment, a 4 day single-blind placebo washout was performed to assess drug withdrawal effects. Results confirmed the safety and efficacy of both drugs over placebo during active administration. Hypnotic activity was maximal at 7.5 mg of zopiclone and 0.25 mg of triazolam. Drug efficacy was found constant over the 3 week administration both for triazolam and zopiclone. During withdrawal, no true rebound effect was demonstrated but the active drugs were significantly worse than placebo during the first day for sleep onset duration, sleep soundness and quality of sleep. With triazolam some effects persisted up to the third day of withdrawal.

Aged↗
PubMed1990

[Should systematic bone scintigraphy be carried out on breast cancer patients with small tumors?].

Bone metastases are frequent in the evolution of breast cancer. Bone scan is the best method for early detection. At initial presentation the frequency of bone metastases is low, and it is usefulness to recommend this exam except for old people or patients with risks factors. During the follow-up, the utility of repeated bone scan is discussed. For the majority of authors, it may be reserved for symptomatic patients or when biological modifications appeared. The follow-up of these patients must be essentially clinical. This strategy delay the diagnosis of bone metastases of only a few weeks; and it don't seem to affect the prognosis of these patients.

Age Factors↗
PubMed1989

Salivary passage of 5-fluorouracil during continuous infusion.

Plasmatic and salivary concentrations of 5-FU were investigated in ten patients given 5-day continuous infusions of 5-fluorouracil (5-FU) (1 g/m2/day). Measurable concentrations of salivary 5-FU were scattered ranging from 6 to 100 ng/ml. Between individual 5-FU concentrations in saliva and plasma the coefficient of correlation was low. The theoretically predicted ratios of 5-FU concentrations in saliva over those in plasma, calculated as a function of salivary pH, did not correlate with the observed ratios, the majority of which ranged between 0.1 and 0.5. Noteworthy, 8 of 10 patients exhibited a more or less pronounced increase in 5-FU salivary excretion during 5-day continuous i.v. infusions.

Aged↗
PubMed1989

Pharmacokinetics of weekly low dose doxorubicin.

Weekly low dose doxorubicin (WLD-dox) is an interesting alternative to the classical 3 week schedule because of its reduced cardiotoxicity, the major dose-related side-effect. This study characterized the pharmacokinetic behaviour of WLD-dox with particular attention to the effect of treatment duration on the variability of individual pharmacokinetic parameters. Twenty-eight patients with advanced breast cancer were treated by WLD-dox (12 mg/m2 week). Individual pharmacokinetic analyses were performed at the first injection and every month thereafter; residual drug levels were measured every week before injection. Dox and its main metabolite doxol were measured by HPLC and fluorescence. Pharmacokinetic data were available for 51 cycles. The mean concentration-time profile for 25 patients with normal liver function tests fitted well with a two-compartment model: COext (nM) = 2905 +/- 1834; t 1/2 alpha = 0.08 +/- 0.03 h; t 1/2 beta = 10.4 +/- 3.6 h; clearance (1/h) = 55.4 +/- 24.8; Vd (1) = 809 +/- 434. The findings concur with those for classical 3-week dox schedule (45 mg/m2) analysed in six patients as controls. Exceptions were the initial extrapolated concentration and area under curves which were reduced for WLD-dox according to the dose. Dox and/or doxol overexposure was patent in all three patients with elevated pre-treatment serum bilirubin. During treatment, up to 48 WLD-dox administrations, no significant trends were noted for 10 patients in the evolution of initial extrapolated concentration, terminal half-life, total body clearance or the proportion of doxol formed. Residual drug levels were controlled up to 40 WLD-dox administrations (135 samples); in half the cases they comprised between 1 and 20 nM without particular sign of increasing along the treatment course. In this case WLD-dox can be assimilated to a continuous exposure to low drug levels with intermittent pulses thus representing an original pharmacological profile for dox.

Adult↗
PubMed1989

Tamoxifen metabolism: pharmacokinetic and in vitro study.

The qualitative and quantitative importance of tamoxifen (TMX) metabolism in vivo led us to investigate further the metabolic profile of this major anti-oestrogenic drug in a significant group of 81 breast cancer patients and to evaluate the respective in vitro activity of each metabolite. TMX and its four metabolites described until now (NDT, 4-OHT, Y, Z) were measured in blood (HPLC method) at the time of first drug intake and at the steady state. Between these two states, the unchanged drug relative proportion dropped from 65% to 27%. Demethylation was the major metabolic pathway. For 13 clinically evaluable patients, there was no significant difference in the distribution of serum levels of TMX and metabolites as a function of response to treatment. In vitro studies were performed on two human breast cancer cell lines: MCF-7, oestrogen receptor and progesterone receptor positive (ER+, PR+) and CAL-18 B (ER-, PR-). Cytostatic effects were evaluated by the tritiated thymidine incorporation test. TMX and all metabolites were active on these two cell lines, but the 50% inhibitory concentrations (IC50) were 4-250-fold higher in CAL-18 B than in MCF-7, depending on the metabolite considered. For the MCF-7 cells only, the antiproliferating activity was parallel to the relative binding affinity for ER. Moreover, for the MCF-7 cells only, the effects of these drugs were partially reversed by oestradiol (E2), the higher the metabolite affinity for ER, the lower the reversal efficacy. These compounds were tested in mixtures at proportions duplicating those found in patients after initial drug intake (mixture D1), and the steady state (mixture Css). The mixtures were also compared to the equimolar unchanged drug. No differences were seen among these three experimental conditions for either MCF-7 or CAL-18 B. A dose-effect relationship was noted. Overall, TMX and its metabolites exert a dual effect: when concentrations are below a threshold between 2 x 10(-6) and 10(-5) M, the drugs are mainly cytostatic; this effect is related to their affinity for ER. At higher relevant clinical concentrations, a cytotoxic activity is observed and it appears independent of the presence of ER.

Aged↗
PubMed1989

A limited sampling procedure for estimating adriamycin pharmacokinetics in cancer patients.

The aim of this study was to find a procedure allowing estimation of individual pharmacokinetic parameters for adriamycin with minimal cost and disturbance for the patient. Twenty-five patients with breast cancer were treated by short infusion of adriamycin at a dose of 12 mg m-2 week-1 (41 courses). Population characteristics were determined on 15 randomly chosen courses (10 patients, group I) in order to define two optimal sampling times (26 min and 24 h) and to perform Bayesian estimation on the remaining 26 courses (17 patients, group II). For patients of group II, Bayesian estimation (BE) associated with a reduced sub-optimal sampling protocol (20 min and 24 h) was compared with maximum likelihood estimation (MLE), the classical procedure. Regression analysis of clearance values obtained after BE versus MLE indicated a high correlation coefficient (r = 0.969) with the slope (a = 0.991 +/- 0.085) and the intercept (b = 2.271 +/- 4.810) close to 1 and 0 respectively. This original method is thus valid to measure accurately adriamycin clearance; it improves patient comfort and can be used routinely.

Adult↗
PubMed1989

[Results of a phase II study of the combination of cis-platinum and 5-FU in epidermoid or undifferentiated large cell bronchial cancer].

The aim of this study was to test cisplatinum and 5-FU chemotherapy. Thirty-five patients with epidermoid or undifferentiated lung carcinoma were entered in a multicentric phase II trial, in an attempt to further define the activity and toxicity of this association. None of them had been previously treated by chemotherapy. The dosage schedule was cisplatinum 100 mg/m2 D1 and 5-FU 1 g/m2 D1 to D5 every 3 weeks for 3 courses before evaluation. There were CR: 2, PR: 10, for a total response rate of 35%. Median survival was 7 months. Tolerance was acceptable. We conclude that this association can be safely administered, but that the results are not superior to others previously reported. Further studies are required to define the activity of a cisplatinum, 5-FU and radiotherapy association.

Adult↗
PubMed1988

Interim report of phase II study of new nitrosourea S 10036 in disseminated malignant melanoma.

Thirty-three patients with disseminated malignant melanoma were entered in a phase II study of the new nitrosourea S 10036 using a 100-mg/m2 weekly induction schedule for 3-4 consecutive weeks. Patients who responded to this treatment were followed with a maintenance therapy every 3 weeks. Toxic effects were mainly hematological and consisted of delayed thrombocytopenia and leukopenia. Among 30 patients who could be evaluated, eight partial responses were observed (response rate, 26.67%); among seven patients with cerebral metastasis, two partial responses were observed. This multicentric study is currently being continued to confirm this interim report.

Antineoplastic Agents↗
PubMed1988

Dose versus pharmacokinetics for predicting tolerance to 5-day continuous infusion of 5-FU.

This non-randomized study reports pharmaco-clinical data on 5-FU administered by the widely used 5-day continuous infusion schedule to 42 patients with metastatic colorectal cancer; 5-FU was given by hepatic intra-arterial route (h.i.a.) at doses ranging from 800 to 1,450 mg/m2, and by a systemic intravenous route (i.v.) at doses ranging from 650 to 1,300 mg/m2. 5-FU blood levels were available for a total of 179 cycles. Toxicity was dose-dependent during h.i.a. cycles but not during i.v. cycles. For h.i.a. cycles, 1,000 mg/m2/day represented the threshold dose for tolerance. The individual total cycle drug concentration-time product might predict toxicity for both i.v. and h.i.a. cycle when the threshold is set at 30,000 ng/ml.hr. These data may be of practical value for improving the therapeutic index of 5-day continuous treatment by 5-FU given by i.v. or h.i.a. routes.

Adult↗