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Biomedical subjects

C Lucas

Publications and source records attributed to C Lucas.

At least 19 recordsLinked to original sources
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↗
PubMed1991

Transforming growth factor beta 1 (TGF-beta 1) induced neutrophil recruitment to synovial tissues: implications for TGF-beta-driven synovial inflammation and hyperplasia.

We have studied the consequences of introducing human recombinant transforming growth factor beta 1 (hrTGF-beta 1) into synovial tissue of the rat, to begin to better understand the significance of the fact that biologically active TGF-beta is found in human arthritic synovial effusions. Within 4-6 h after the intra-articular injection of 1 microgram of hrTGF-beta 1 into rat knee joints, extensive recruitment of polymorphonuclear leukocytes (PMNs) was observed. Cytochemistry and high resolution histological techniques were used to quantitate the influx of PMNs, which peaked 6 h post-injection. In a Boyden chamber assay, hrTGF-beta 1 at 1-10 fg/ml elicited a chemotactic response from PMNs greater in magnitude than that evoked by FMLP, establishing that TGF-beta 1 is an effective chemotactic agent for PMNs in vitro as well as in vivo. That PMNs may represent an important source of TGF-beta in inflammatory infiltrates was strongly suggested by a demonstration that stored TGF-beta 1 was secreted during phorbol myristate acetate-stimulated degranulation in vitro. Acid/ethanol extracts of human PMNs assayed by ELISA contained an average of 355 ng of TGF/beta 1 per 10(9) cells potentially available for secretion during degranulation of PMNs. [3H]Thymidine incorporation in vivo and autoradiography of tissue sections revealed that widespread cell proliferation was triggered by TGF-beta 1 injection. Synovial lining cells and cells located deep within the subsynovial connective tissue were identified as sources of at least some of the new cells that contribute to TGF-beta 1-induced hyperplasia. Our results demonstrate that TGF-beta is capable of exerting pathogenic effects on synovial tissue and that PMNs may represent a significant source of the TGF-beta present in synovial effusions.

Animals↗
PubMed1991

TGF-beta: a possible autocrine immune regulator.

TGF-beta is a potent regulator of immune functions both in vitro and in vivo. The majority of studies have examined changes in immune functions after the addition of TGF-beta that had been previously activated by acid treatment. Peripheral blood mononuclear cells (PBMC) and tumour cells can each produce latent TGF-beta. The role of endogenously produced latent TGF-beta as an autocrine or paracrine regulator of immune functions has not been extensively studied. Monoclonal antibody (mAb) 4A11 was used to detect and neutralize the activity of endogenous TGF-beta 1 produced during lymphocyte activation. We demonstrate that PBMC, after stimulation with interleukin 2 or phytohaemagglutinin-P/12-O-tetradecanoylphorbol 13-acetate, secrete significant quantities of latent TGF-beta 1. Addition of neutralizing mAbs specific for TGF-beta 1 enhances the proliferative response of the PBMC. CHO cell lines engineered to produce latent TGF-beta 1 were poor stimulators of cytotoxic T lymphocyte generation in vitro and significantly suppress natural killer cell activity in nu/nu mice. We conclude that mechanisms exist in vitro and in vivo to convert latent TGF-beta into an active form which can then regulate immune functions in an autocrine/paracrine manner. The possible role of latent TGF-beta produced by tumour cells in immune surveillance is discussed.

Animals↗
PubMed1991

Pharmacokinetics of fotemustine and BCNU in plasma, liver and tumor tissue of rats bearing two lines of Walker 256 carcinoma.

The plasma and tissue pharmacokinetics of fotemustine (diethyl-1-[3-(2-chlorethyl)-3-nitrosoureido]-ethylphosphonate+ ++) and BCNU (1,3-bis-[2-chlorethyl]-1-nitrosourea) were investigated in healthy control rats and in animals bearing either the nitrosourea-sensitive line A (W256/A) or the nitrosourea-resistant line B (W256/B) of Walker 256 carcinoma. The antitumor activities of these nitrosoureas were similar following i.v. doses ranging from 10 to 40 mg/kg. For both drugs, the survival of tumor-bearing rats was lower in the W256/B than in the sensitive W256/A line. Some sex differences were observed, female rats being more responsive than males to both drugs. Nitrosourea concentrations were assayed in plasma and tissues by differential pulse polarography so as to assess whether the pharmacokinetics could explain the differences in antitumor activity. The antineoplastic effects of fotemustine seemed to be influenced by its pharmacokinetics. The plasma AUC of the intact nitrosourea was higher in females than in males. Fotemustine was cleared 2-5 times more slowly than BCNU from tumor tissue, and its clearance was higher in W256/B- than in W256/A-bearing rats. This suggests that the antitumor activity in the responsive line might partly be due to longer exposure of the growing tumor to the drug. The distribution volume of both nitrosoureas in plasma was higher in tumor-bearing animals than in healthy controls, indicating that the tumor tissue probably constitutes an additional distribution space.

Animals↗
PubMed1991

The measurement of staphylococcal protein A by ELISA in immunoglobulin preparations.

Chicken antibodies were used to develop an ELISA for the quantitation of parts-per-million levels of protein A in the purification of immunoglobulins or immunoglobulin-like molecules. Quantitation of protein A in the presence of excess human or murine immunoglobulins in this assay was compared with that obtained in ELISAs developed with rabbit antibodies specific either to protein A or to other molecules. Experiments demonstrate that protein A is bound to the immunoglobulins being purified and that this binding affects subsequent recognition by the antibodies used for the assay. Because of these effects and because fragments of protein A might not be detected in assays which rely on Fc binding of protein A, chicken antibodies that bind protein A specifically are an advantage for the quantitation of this protein by ELISA. In addition, comparison of the effect of different types of immunoglobulins on the protein A standard curve suggests that alternatives to including the immunoglobulin under purification with the standards can be utilized.

Animals↗
PubMed1991

A new method to select stimulus strength after cardiomyoplasty.

At present, there is no technique available for the determination of optimal stimulus strength in patients after cardiomyoplasty. To stimulate the latissimus dorsi (LD) muscle, we implanted Itrel stimulators in two goats and cardiomyostimulators in three goats following the routine cardiomyoplasty procedure. During the following 3 months, these LD muscles were conditioned at 2.5-4.0 volts (V). After conditioning, LD muscle shortening was measured on x-ray films using the distance between two stimulation electrodes as references. LD muscle shortening increased rapidly at higher stimulus strength and reached 13% +/- 2% at 2.0 V. Shortening was calculated in one patient at 4, 6, and 9 weeks following surgery. The increase in the number of pulses per burst (2, 3, and 6, respectively) had a positive effect on muscle shortening between the two stimulation electrodes (10%, 14%, and 20%, respectively). Also, muscle shortening was measured between two clips attached to the distal part of the LD muscle. Muscle shortening in the area wrapped around the left ventricle was 15% after 9 weeks. In a second patient, shortening between the electrodes was 16% at 14 months after surgery, and distal muscle shortening was 11%. We concluded that optimal stimulation after cardiomyoplasty could be detected more accurately by measurement of LD muscle shortening using the stimulation electrodes or surgical clips as markers.

Animals↗
PubMed1991

Pharmacokinetic profile of fotemustine in rat plasma by electrochemical detection.

1. A differential pulse polarographic (DDP) assay of diethyl-1-[3-(2-chloroethyl)-3-nitrosoureido] ethylphosphonate (fotemustine) was developed to determine the kinetics of this nitrosourea in plasma, brain, liver, lung and kidney. The optimized polarographic determination, previously applied to BCNU and CCNU, attained a limit of detection of 0.3 micrograms fotemustine/ml plasma and 1 microgram/g in other tissues; the calibration curve in electrolyte or in plasma was linear between 0.5 and 100 micrograms/ml. 2. The choice of electrolyte, the effects of pH, temperature, light, and the stability of fotemustine in samples were investigated. Recovery of fotemustine was 76-90% from lung greater than kidney greater than plasma greater than brain greater than liver; the variability coefficients were low (4.0-7.3%). Tissue samples could be stored for 20 days at -20 degrees C without loss of the compound. 3. Plasma kinetics of fotemustine and BCNU given to male rats at therapeutic doses (20 mg/kg i.v.) fitted a bi-exponential equation. Two minutes after injection plasma, levels of unchanged nitrosoureas were 15 and 11 micrograms/ml respectively. Fotemustine could be measured (0.92 microgram/ml) for 3 h, while BCNU could not be detected after 60 min. Unchanged fotemustine was cleared from the blood stream 3-5 times more slowly than BCNU.

Animals↗
PubMed1991

Metabolism of the chloroethylnitrosoureas.

1. The chemical degradation and metabolism of the 2-chloroethylnitrosoureas (CENUSs) have been critically reviewed with the objective of gaining a better understanding of factors that could aid in the design of new, more effective, anticancer drugs. 2. The CENUs are chemically unstable under normal physiological conditions and can rapidly degrade to give a variety of reactive intermediates capable of carbamoylating proteins and/or alkylating both proteins and DNA. 3. Carbamoylation is thought to make a minimal contribution to the cytotoxic effect of the CENUs, although it may be involved in some of the unwanted side-effects. It would seem desirable, therefore, to design new CENUs with low carbamoylating activity. 4. The main action of the CENUs is by alkylation of DNA via a chloroethyldiazo-hydroxide intermediate. Chloroethylation is important, as opposed to hydroxyethylation, since the former leads to inter-strand DNA cross-linking via an intramolecular rearrangement with the removal of chloride. It is this inter-strand cross-linking which prevents subsequent DNA repair and loss of cytotoxicity. 5. Metabolism usually, although not exclusively, leads to deactivation of the CENUs either by dechlorination or denitrosation of the molecule, generally with the former being the dominant route. These reactions occur very rapidly, and before chemical degradation can take place, and can be an important determinant in the final cytotoxicity. Moreover, both these pathways involve the cytochrome P-450 system and can be induced with phenobarbital.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗