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Biomedical subjects

C Lucas

Publications and source records attributed to C Lucas.

At least 163 records · Page 9Linked to original sources
PubMed1993

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.

Adult↗
PubMed1993

Activity and unexpected lung toxicity of the sequential administration of two alkylating agents--dacarbazine and fotemustine--in patients with melanoma.

We report the results and discuss the toxicity of clinical trials based on a single concept: the decrease in O6alkyl DNA alkyltransferase (O6AT) resistance mechanism when a chloroethylating agent is used sequentially after a methylating agent. This decrease in O6AT being dose dependent, several increasing doses of dacarbazine (DTIC) have been tested (400 mg/m2 to 1000 mg/m2 every 4 weeks, 3-4 h before fotemustine (100 mg/m2 intravenously every 4 weeks). These results (mean overall response rate 27%) compared with reference regimes, demonstrate that DTIC is able to increase the alkylating power of fotemustine: same range of response rate with only half of the two drug doses compared to an alternated combination, high activity rate especially in lung metastases (10/42 complete responses + 13/42 partial responses), different pattern for haematotoxicity, and occurrence of a new side-effect: acute lung toxicity as adult respiratory distress syndrome (ARDS). This lung toxicity was totally unexpected since several hundreds of patients had been so far treated with fotemustine as single agent or in other combinations with DTIC without any case of acute or delayed lung toxicity. Prophylactic administration of corticoids was not effective and monitoring of the respiratory function was of no predictive value. Due to the additional depleting effects of DTIC on at least two main defence mechanisms--the O6AT system and cytosolic and/or nuclear glutathione--we suppose that the sequence is able to increase the alkylating power of fotemustine to an excessive extent and/or that the detoxication capacity of the cell against DTIC and/or fotemustine metabolites is overwhelmed. Other depletors of the O6AT activity which do not generate metabolites that compete for the same detoxication pathway as the chloroethylnitrosourea (CENU) metabolites should be tested.

Adult↗
PubMed1993

DSM-III-R disorders, social factors and management of school attendance problems in the normal population.

Eighty 13-15-year-old children who failed to attend one of four schools for more than 40% of a term, without good reason, were studied. A systematic schedule (C.A.P.A.) was used in interviewing parents and children. Twenty-five had DSM-III-R Disruptive Behaviour Disorders and 15 had Anxiety/Mood Disorders. Truancy was associated with the former and school refusal with the latter but both often occurred without any Disorder. Fourteen children had neither school refusal nor truancy. Compared to controls, poor attenders came from materially disadvantaged homes. School refusal with anxiety disorders rarely received psychiatric treatment. Non-disturbed absentees were not usually dealt with appropriately.

Absenteeism↗
PubMed1993

The effects of curvature on fluid flow fields in pulmonary artery models: flow visualization studies.

In vitro pulsatile flow visualization studies were conducted to assess the effects of varying radii of curvature of the right ventricular outflow tract (RVOT) and main pulmonary artery (MPA) on the flow fields in the main, right, and left pulmonary arteries of a one month lamb pulmonary artery model. Three glass flow-through models were studied; one with no curvature, one with the correct anatomic curvature, and one with an overaccentuated curvature on the RVOT and MPA. All other geometric parameters were held constant. Pulsatile flow visualization studies were conducted at nine flow conditions; heart rates of 70, 100, and 140 bpm, and cardiac outputs of 1.5, 2.5 and 3.5 l/min with corresponding mean pulmonary pressures of 10, 20, and 30 mmHg. Changes were observed in the pulmonary flow fields as the curvature of the outflow tract, heart rate and mean pulmonary pressure were varied. An increase in vessel curvature led to an increase in the overall radial nature of the flow field as well as flow separation regions which formed faster, originated further downstream, and occupied more of the vessel area. At higher heart rates, the maximum size of the separation regions decreased, while flow separation regions appeared earlier in the cardiac cycle and grew more quickly. Heart rate also affected the initiation of flow reversal; flow reversal occurred later in the cardiac cycle at lower heart rates. Both heart rate and mean pulmonary pressure influenced the stability of the pulmonary flow field and the appearance of coherent structures. In addition, an increase in mean pulmonary pressure increased the magnitude of reverse flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Development of a specific and sensitive two-site enzyme-linked immunosorbent assay for measurement of inhibin-A in serum.

A polyclonal chicken antiserum against purified 32-kilodalton (kDa) recombinant inhibin-A (rh-InhA) and two monoclonal antibodies (mAb) against either rh-InhA (11B5) or 28-kDa recombinant activin-A (rh-ActA; 9A9) were used to develop three sensitive InhA enzyme-linked immunosorbent assays (ELISAs). The sensitivity of an ELISA using affinity-purified chicken anti-rh-InhA (Ck) for both coat and capture (Ck/Ck) averaged 78 +/- 3 pg/ml, while the mAb/Ck ELISAs (11B5/Ck or 9A9/Ck) averaged 100 +/- 6 pg/ml in a 10% serum matrix, with intra-and interassay coefficients of variation of 2-5% and 8-10%, respectively, for all assays. The ELISA formats did not cross-react with purified rh-ActA or recombinant human transforming growth factor-beta 1 or detect any immunoreactive proteins in medium conditioned by cell lines expressing rh-ActA or recombinant human transforming growth factor-beta 1. The Ck/Ck ELISA detected significant amounts of immunoreactivity in medium from cells expressing the free alpha-subunit of inhibin and recombinant inhibin-B (rh-InhB). In contrast, the mAb/Ck ELISAs showed no cross-reactivity to medium conditioned by these two cell lines. All three ELISA formats detected rh-InhA added to either human or rat serum in vitro or serum from rats injected with rhInhA. The Ck/Ck and 9A9/Ck ELISAs successfully quantitated inhibin in sera from patients undergoing ovulation induction and in rats (with or without sc administration of pregnant female serum gonadotropin). The 11B5/Ck ELISA appeared to be specific for the 32-kDa form of inhibin, while the 9A9/Ck ELISA was useful in quantitating inhibin-A in biological fluids, with little cross-reactivity to free alpha-chain or inhibin-B.

Animals↗
PubMed1993

Hormonal study of a human mixed follicular and medullary thyroid carcinoma.

We studied the hormonal secretion of a human mixed follicular and medullary carcinoma. Thyroglobulin (Tg) secretion, especially by large cells and sometimes by small ones, was visualized with immunoenzymatic staining. Calcitonin (CT) was produced by small spindle-shaped cells. Moreover, immunofluorescence double staining performed on the resected thyroid tissue showed the secretion of both Tg and CT in a small number of cells. The cells lost their hormonal secretion after 2 months of culture. Hormonal secretion was modulated by different additives in the medium. Tg secretion was induced when TSH was added to the culture medium; the maximal effect was produced with the addition of 1 mU TSH/ml and 1 microM cortisol, which potentiated the effect of TSH on Tg production. A durable Tg secretion was obtained by embedding the cells in Engelbretch-Hohn-Swarn (EHS) tumour matrix. The CT production was reinduced by the addition of 4 mM Ca2+, 1 microM glucagon and 1 microM cortisol to the culture medium. These findings show that different cells are found in a mixed follicular and medullary carcinoma, some of which can secrete both CT and Tg. They can remain differentiated for a long period after being embedded in EHS tumour matrix with Ca2+ and hormonal components.

Adenocarcinoma, Follicular↗
PubMed1993

Identification and quantitative determination of glutathione-related urinary metabolites of fotemustine, a new anti-cancer agent.

1. Potential sulphur-containing metabolites of the anticancer agent, fotemustine, were synthesized, namely thiodiacetic acid (TDA), S-2-hydroxyethyl N-acetyl-L-cysteine (2-HE-NAC), N-acetyl-L-cysteine (NAC), S-methyl N-acetyl-L-cysteine (M-NAC), S-carboxymethyl-L-cysteine (CM-Cys), S-carboxymethyl N-acetyl-L-cysteine (CM-NAC), their corresponding sulphoxides and sulphones. Their chemical structures and stabilities were confirmed and derivatization methods were developed for their analysis by sulphur-selective g.l.c. (g.l.c.-FPD) and g.l.c.-mass spectrometry. 2. Four methods for isolation of potential metabolites of fotemustine were developed. Quantification of metabolites, derived in various ways was carried out by g.l.c.-atomic emission detection (AED) or g.l.c.-mass spectrometry. 3. Male Wistar rats (n = 4) were given a single i.p. dose of 40 mg/kg fotemustine. Urine excretion of TDA (18.4 +/- 1.9% in 24 h) and TDA sulphoxide (12.0 +/- 1.6% in 24 h) was significant; 32.7 +/- 4.6% of the fotemustine dose was excreted as TDA, and TDA sulphoxide in 48 h. NAC was excreted in rat urine at 1% of the dose. No other potential glutathione-derived metabolites of fotemustine were excreted. 4. Male Wistar rats (n = 4) were also treated i.p. with fotemustine at 5, 20 and 40 mg/kg, to investigate dose dependency and the time course of excretion of TDA. Excretion of TDA in 48 h urine decreased from 32 +/- 2 to 17 +/- 2% dose (mean +/- SD) with increasing dose of fotemustine.

Animals↗
PubMed1993

[Cell culture in thyroid cancers].

The authors studied the diagnostic interest of cell cultures in thyroid tumors. They cultivated 10 tumours (4 papillary carcinomas, 5 medullary carcinomas and 1 sarcoma-looking tumour). In 7 cases, cultures yielded nothing more than pathologic examination. Nonetheless the study allowed to detect a double secretion (calcitonin and thyroglobulin) in 2 medullary carcinomas which turned out to be mixed proliferations. It also detected a production of thyroglobulin by the sarcoma. They think that cell cultures may have a diagnostic interest besides pathologic examination, allowing precise study of secretory features of the tumors.

Adult↗
PubMed1992

Hepatic intra-arterial infusion of fotemustine: pharmacokinetics.

Fotemustine is a new nitrosourea derivative that contains an alpha-aminophosphonic acid and has a short half-life and a high plasma clearance. As myelosuppression occurs as the dose-limiting toxicity, local drug delivery has been investigated in the treatment of liver metastases arising from colorectal cancer. A pharmacokinetic study was undertaken in patients who received either i.v. or hepatic intra-arterial (HIA) infusion of 100 mg/m2 fotemustine so as to estimate the advantage of local chemotherapy, considering the pharmacokinetic differences between the two routes together with the resultant toxicities (when available). Our findings substantiated the hypothesis that a 4-h HIA infusion of foetmustine would result in a lower exposure of healthy tissues to the drug, since the AUC measured in systemic plasma was reduced by approximately 50% following such treatment as compared with i.v. infusion. This reduction in AUC should indicate a manyfold increase in exposure of the liver tumour to the alkylating properties of the drug, since it represents the proportion of the dose that has degraded within the liver. The first-pass liver-extraction ratio of fotemustine given as a 4-h HIA infusion, which ranged from 0.4 to 0.9 as estimated in patients receiving i.v. and HIA infusions in a cross-over study, argues for further investigation of HIA foetemustine infusion for the treatment of liver metastases so as to increase the response rate and decrease the occurrence of major toxic side effects in such patients.

Adenocarcinoma↗
PubMed1992

Binding of a new vinca alkaloid derivative, S12363, to human plasma proteins and platelets. Usefulness of an erythrocyte partitioning technique.

The interactions of S12363 with human plasma proteins have been investigated in vitro by an erythrocyte partitioning technique that allows a quantitative estimation of the plasma and erythrocytes binding. S12363 was 85-95% plasma-bound and 97-98% blood-bound. The main binding protein in plasma was alpha-acid glycoprotein, with a binding constant of 0.6 x 10(6) M-1, accounting for 70% of total S12363 in plasma. Owing to extensive binding to platelets (40-50% of total blood amount), S12363 was mainly distributed in the non plasma blood compartment, with blood-to-plasma concentrations ratio of 1.2-1.4. These results indicate that, in vivo, the fraction of blood S12363 available for tissue diffusion, i.e., the free drug fraction in blood, should depend on both alpha 1-acid glycoprotein concentration in plasma and blood platelet count.

Blood Platelets↗
PubMed1992

Neutralization of multiple laboratory and clinical isolates of human immunodeficiency virus type 1 (HIV-1) by antisera raised against gp120 from the MN isolate of HIV-1.

Vaccines prepared from the envelope glycoprotein, gp120, of the common laboratory isolate of human immunodeficiency virus type 1 (HIV-1) (IIIB/LAV-1) elicit antibodies that neutralize the homologous virus but show little if any cross-neutralizing activity. This may be because the principal neutralizing determinant (PND) of gp120 is highly unusual in the IIIB/LAV-1 strain and is not representative of those found in the majority of field isolates. We have now examined the immunogenicity of recombinant gp120 prepared from the MN strain of HIV-1 (MN-rgp120), whose PND is thought to be representative of approximately 60% of the isolates in North America. Our results show that MN-rgp120 is a potent immunogen and elicits anti-gp120 titers comparable to those found in HIV-1-infected individuals. While both MN-rgp120 and IIIB-rgp120 induced antibodies able to block gp120 binding to CD4, strain-specific and type-common blocking antibodies were detected. Finally, antibodies to MN-rgp120 but not to IIIB-rgp120 were effective in neutralizing a broad range of laboratory and clinical isolates of HIV-1. These studies demonstrate that susceptibility or resistance to neutralization by antibodies to gp120 correlates with the PND sequence and suggest that the problem of antigenic variation may not be insurmountable in the development of an effective AIDS vaccine.

Amino Acid Sequence↗
PubMed1992

Effects of cisplatin on human thyrocytes in monolayer or follicle culture.

Cis-diamminedichloroplatinum (II) (cisplatin) is a widely used anticancer drug which induces many side-effects, but its action on the thyroid gland is still unknown. We have investigated the effects of this drug on human thyrocytes cultured in monolayers or in follicles and stimulated with 200 microU TSH/ml. After 72 h in culture, different concentrations of cisplatin (15, 30 and 75 microM) caused partial or total inhibition of cyclic AMP (cAMP), thyroglobulin (Tg) and tri-iodothyronine (T3) production, whereas thyroxine levels increased in the medium of thyrocytes cultured as follicles. Small doses of the drug did not affect thyrocyte production. Decreases in neutral-red uptake by thyroid cells and in intracellular lactate dehydrogenase, alpha-hydroxybutyryldehydrogenase and creatine phosphokinase activities were induced by 30 and 75 microM cisplatin. These data show that high concentrations of cisplatin had a cytotoxic effect on thyrocytes. Cisplatin also induced inhibition of the production of cAMP, Tg and T3.

Cells, Cultured↗
PubMed1992

Value of early pharmacodynamic and pharmacokinetic investigations with anticancer drugs: data from phase I tolerance studies on a new vinca alkaloid derivative.

1. A novel anticancer vinca alkaloid derivative (I) has been given as an i.v. bolus to cancer patients, using four different dosage regimens with dose levels ranging from 0.04 to 0.84 mg/m2 (equivalent to between 0.12 and 1.35 mg per dose), and the pharmacokinetics determined up to 72 h after dosing. In addition, secondary effects of leukopenia and neutropenia, were related to drug exposure using a sigmoid Emax model. 2. Plasma levels of I declined in a triphasic manner with a terminal half-life of approximately 50 h; most drug elimination (55%) being associated with the terminal phase. 3. Clearance of I was relatively low (245 +/- 160 ml/min) and remained constant with increasing doses. Initial distribution volume was low (approximately 71) but once distribution was complete, it was comparatively high (327 +/- 2121). 4. Both leukopenia and neutropenia were fitted successfully to a sigmoid Emax model showing that these effects were related to the total exposure to the drug. The Hill constant was less than 1, indicating a relatively shallow exposure/response curve and a predictable, graded increase in response with increasing I exposure, rather than a sudden quantal response. 5. Pharmacokinetically, I shows some similarities to other vinca alkaloids in its plasma level decline profile, although there are some notable differences which can be exploited clinically. In addition, the ability to model both leukopenia and neutropenia to the exposure to I, provides a valuable tool in the design of the most appropriate dosage regimen for the drug, as well as for dose adjustment taking into account inter-individual variations.

Adolescent↗
PubMed1992

[Efficacy and tolerance of 2 new percutaneous vena cava filters. A prospective study in 80 patients].

Eighty consecutive patients with an average age of 66.5 +/- 16 years were reviewed 3 and 9 months after implantation of two new percutaneous vena caval filters (Filcard, Cardial) in order to evaluate their efficacy and tolerance. The indications were: a contra-indication to anticoagulants in 19 cases, recurrent pulmonary embolism under anticoagulant therapy in 22 patients, chronic cor pulmonale in 4 patients; finally, in 35 cases, the filter was implanted prophylactically for a "floating" or extensive ilio-caval thrombosis under anticoagulant therapy or in high risk patients: severe cardio-pulmonary failure, malignant disease, massive pulmonary embolism with a contra-indication to fibrinolytic therapy. All implantations were performed by the jugular approach with no local or general complications apart from one pericaval haematoma with a favourable outcome. Cavography and opacification of the renal veins was carried out systematically during implantation. All patients underwent clinical examination, antero-posterior and lateral X rays of the filter, pulmonary scintigraphy, antero-posterior and lateral cavography, a CT scan of the filter, Doppler ultrasonography and rheoplethysmography of the legs 3 months after implantation. At 9 months, clinical examination, abdominal X rays and rheoplethysmography were repeated. There was 100% follow-up at 3 and 9 months. The complications observed at 3 and 9 months were: 5 cases of malposition (6%), 3 recurrent pulmonary emboli (4%), 9 recurrent venous thromboses (13%), 4 vena caval thromboses (5.7%), 7 thrombi caught in the filter (10%), 27 perforations of the vena cava (38%), 3 over 30 degrees tilts of the filter (4%) and 22 migrations (31%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

[Multiple cerebral hemorrhage and amyloid angiopathy of the white matter in a case of Alzheimer's disease].

Amyloid angiopathy is a common pathological finding in Alzheimer's disease. It usually involves leptomeningeal and cortical vessels but spares the white matter. It may cause lobar cerebral hemorrhages at a late stage of the disease. We report a case of Alzheimer's disease at an early stage with diffuse lesions of amyloid angiopathy including some within the white matter, apparently responsible for 2 deep and 1 superficial cerebral hemorrhages.

Alzheimer Disease↗
PubMed1991

Prevention of HIV-1 IIIB infection in chimpanzees by CD4 immunoadhesin.

The first step in infection by the human immunodeficiency virus (HIV) is the specific binding of gp120, the envelope glycoprotein of HIV, to its cellular receptor, CD4. To inhibit this interaction, soluble CD4 analogues that compete for gp120 binding and block HIV infection in vitro have been developed. To determine whether these analogues can protect an uninfected individual from challenge with HIV, we used the chimpanzee model system of cell-free HIV infection. Chimpanzees are readily infected with the IIIB strain of HIV-1, becoming viraemic within about 4-6 weeks of challenge, although they do not develop the profound CD4+ T-cell depletion and immunodeficiency characteristic of HIV infection in humans. CD4 immunoadhesin (CD4-IgG), a chimaeric molecule consisting of the N-terminal two immunoglobulin-like regions of CD4 joined to the Fc region of human IgG1, was selected as the CD4 analogue for testing because it has a longer half-life than CD4, contributed by the IgG Fc portion of the molecule. In humans, this difference results in a 25-fold increased concentration of CD4-IgG in the blood compared with recombinant CD4. Here we report that pretreatment with CD4-IgG can prevent the infection of chimpanzees with HIV-1. The need for a preventative agent is particularly acute in perinatal HIV transmission. As recombinant CD4-IgG, like the parent IgG molecule, efficiently crosses the primate placenta, it may be possible to set up an immune state in a fetus before HIV transfer occurs, thus preventing infection.

Acquired Immunodeficiency Syndrome↗