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Biomedical subjects

A Pierre

Publications and source records attributed to A Pierre.

At least 37 records · Page 2Linked to original sources
PubMed1999

Electromechanical characterization of myocardial hibernation in a pig model.

BACKGROUND: This study attempted to assess in-vivo electromechanical changes following gradual coronary artery occlusion in a pig ameroid constrictor model using a novel three-dimensional left ventricular mapping system. METHODS AND RESULTS: We measured unipolar and bipolar voltage potentials and local endocardial shortening in the ischemic lateral and non-ischemic anterior zones in animals at rest (n = 9) 5 weeks after the implantation of ameroid constrictors around the left circumflex artery. Echocardiography was used to assess regional contractility (percentage myocardial thickening), and an echo-contrast perfusion study was performed using acoustic densitometry methods. The ischemic lateral zone showed reduced myocardial perfusion at rest (peak intensity; 3.4 +/- 1.7 versus 20.7 +/- 14.8, P = 0.005), impaired mechanical function (percentage wall thickening 22 +/- 19% versus 40 +/- 11%, P = 0.03; local endocardial shortening 2.9 +/- 5.5% versus 11.7 +/- 2.1%, P = 0.002), and preserved electrical activity (unipolar voltage 12.4 +/- 4.7 versus 14.4 +/- 1.9 mV, P = 0.25; bipolar voltage 4.1 +/- 1.1 versus 3.8 +/- 1.5 mV, P = 0.62), compared with the anterior region. CONCLUSIONS: Gradual coronary artery occlusion resulting in regional reduced perfusion and function at rest (i.e. hibernating myocardium) is characterized by preserved electrical activity. An electromechanical left ventricular mapping procedure such as the one described here may be of diagnostic value for identifying the hibernating myocardium.

Animals↗
PubMed1999

Biological and pharmacological characterisation of three models of human ovarian carcinoma established in nude mice: use of the CA125 tumour marker to predict antitumour activity.

In an attempt to improve the relevance of human tumour xenografts to the clinical situation, we have established 3 models of human ovarian carcinoma (IGROV1, A2780 and NIH:OVCAR-3) in nude mice in which progressive peritoneal carcinomatosis resulted in the death of tumour-bearing animals (median survival times: 32, 40 and 64 days, respectively). Histological analyses revealed both common and different characteristics in growth patterns and dissemination profiles. In each case, three stages of the disease were defined (early, intermediate and late). The antitumour activities of adriamycin, cisplatin, cyclophosphamide and paclitaxel were then compared when administered at the early stage where small multifocal tumour nodules were detectable in the peritoneal cavity of the animals. Significant antitumour activities of cisplatin and particularly paclitaxel were noted in terms of increase in survival time of the treated mice (T/C values for IGROV1, A2780 and NIH:OVCAR-3 respectively: 152%, 167%, and 187% for cisplatin and 211%, 179% and >283% for paclitaxel), paclitaxel being curative against the NIH:OVCAR-3 xenograft. These results reflect the high efficacy of these two drugs in the clinic in the treatment of ovarian carcinoma. The clinically used CA125 tumour marker, not detectable in healthy mice, was measured in the serum of mice bearing IGROV1 and NIH:OVCAR-3 tumours. CA125 serum levels increased as a function of time and were well correlated to disease progression. Moreover, treatment with cisplatin and paclitaxel led to significant decreases in these levels of between 58% and 100%. This human serum marker could be used to predict early on the efficacy of chemotherapy in these two models. In conclusion, the three experimental ovarian carcinomas possess several important characteristics of the human disease and may thus be used as a screen to select new antitumour drugs potentially active in this pathology.

Animals↗
PubMed1999

Electromechanical characterization of acute experimental myocardial infarction.

OBJECTIVE: A new cardiac mapping system combines harmless magnetic field energy and tip-deflecting catheters (equipped with location sensors) to obtain real-time 3-dimensional electromechanical maps of the left ventricle endocardial surface without using x-ray fluoroscopy. This experimental study assessed electromechanical changes during acute coronary occlusion and reperfusion in a canine model. METHODS: Group 1 (n = 10) underwent coronary occlusion for 45 minutes followed by reperfusion (n = 6) and group 2 (n = 11) underwent coronary occlusion for 90 minutes. Endocardial peak-to-peak voltage amplitudes and local endocardial shortening values were measured in ischemic and non-ischemic zones at baseline, following coronary occlusion and reperfusion. RESULTS: In ischemic zones, local shortening was significantly reduced during coronary occlusion compared to baseline (Group 1: 4.7 +/- 2.0% at 45 minutes vs. 15.5 +/- 3.4%, p < 0.001, 6.2 +/- 2.1% at 90 minutes vs. 15.5 +/- 3.4%, p < 0.001; Group 2: 5.0 +/- 2.9% at 90 minutes vs. 13.9 +/- 3.3%, p = 0.007). Coronary occlusion caused a significant reduction in voltage potentials in the ischemic area (unipolar voltage at 45 minutes: 32.2 +/- 7.3 mV vs. 36.2 +/- 8.5 mV at baseline, p = 0.03; unipolar voltage at 90 minutes: 30.5 +/- 11.3 mV vs. 38.3 +/- 14.2 mV, p = 0.003; bipolar voltage at 45 minutes: 7.6 +/- 5.5 mV vs. 10.1 +/- 6.0 mV, p < 0.04; bipolar voltage at 90 minutes: 7.6 +/- 4.4 mV vs. 9.8 +/- 6.2 mV, p < 0.02). Voltage amplitudes were no longer reduced during reperfusion (unipolar voltage: 34.3 +/- 10.5 mV vs. 36.2 +/- 8.5 mV, p = 0.26; bipolar voltage: 9.1 +/- 4.5 mV vs. 10.1 +/- 6.0 mV at baseline, p = 0.37), or in non-ischemic regions during either coronary occlusion or reperfusion. CONCLUSIONS: Electromechanical mapping study provides unique insights into acute myocardial infarction and stunning by detection and localization of early electromechanical changes during coronary occlusion and/or reperfusion.

Animals↗
PubMed1997

Synthesis and antitumor activity of the metformin platinum (IV) complex. Crystal structure of the tetrachloro(metformin)platinum (IV) dimethylsulfoxide solvate.

The synthesis of (metformin) tetrachloroplatinum (IV) was investigated (metformin is N,N-dimethylbiguanide). It crystallizes with one dimethylsulfoxide molecule as solvate in the monoclinic system, space group P2(1)/n (No. 14) with Z = 4. The cell dimensions are: a = 13.136(7), b = 9.424(2), c = 14.009(8) A, beta = 111.96(4) degrees, V = 1608.4(2) A3. Of the 4269 independent nonzero reflections collected, 1979 with I > 3 sigma (I) were considered and used in the calculations. The structure was refined to R = 0.043 and wR = 0.045. The platinum coordination is octahedral, built up from four chloride anions and one bidentate chelating ligand via the two imine nitrogen atoms cis position. The distances and angles are typical of six-membered rings that have similar donor atoms. The complex was evaluated in vitro and in vivo on murine P388 leukemia. It was found to be as potent as cis-dichlorodiammine platinum (II), CDDP, in inhibiting the proliferation of the sensitive P388 cells. However the resistant P388/CDDP cells were threefold more sensitive to the compound than to CDDP. The two compounds induced a similar perturbation in the G2+M phases of the cell-cycle. The complex was less active than CDDP in vivo on P388 leukemia when administered i.p. (intra peritoneal) on day 1.

Animals↗
PubMed1996

New purines and purine analogs as modulators of multidrug resistance.

A series of 36 purine and purine analog derivatives have been synthesized and tested for their ability to modulate multidrug resistance in vitro (P388/VCR-20 and KB-A1 cells) and in vivo (P388/VCR leukemia). Compounds were compared to S9788, a triazine derivative which has already shown some activity during phase 1 clinical trials and also a limiting cardiovascular side effect possibly linked to its calcium channel affinity. The fact that active compounds increase adriamycin accumulation in the resistant KB-A1 cells, and not in the sensitive KB-3-1 cells, suggests they act predominantly by inhibiting the P-glycoprotein-catalyzed efflux of cytotoxic agents. No direct relation was found between the affinity for the phenylalkylamine binding site of the calcium channel and in vitro sensitization of resistant cells. In vivo, when administered po in association with vincristine (0.25 mg/kg), five compounds (3, 4, 9, 25, and 26), of very differing calcium channel affinities (Ki from 5 to 560 nM), fully restored (T/V > or = 1.4) the sensitivity of P388/VCR leukemia to vincristine.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Architecture of a gain controller in the pursuit system.

A monkey can pursue faster target oscillations if they appear during ongoing smooth pursuit than if they appear while the monkey is fixating a stationary target. Others have proposed a switch in the pursuit circuit to account for this bistable sensitivity to high frequency targets. It is hypothesized that the switch is closed only during pursuit, permitting the retinal motion signal to pass through the circuit at full gain. Losses in pursuit gain caused by certain cortical lesions do mimic the effect of a switch jammed open. To explore this gain adjustment mechanism further, we measured in monkeys the smooth eye movements in response to a high frequency sinusoidal target (called 'humm') presented under a variety of testing conditions. Pursuit gain measured in response to this humm was not merely bistable. Rather, a graded gain modulation of the pursuit system was possible. Furthermore, the gain adjustment had some directional sensitivity to it, enhancing the response to humm along one axis more than the other. In exploring the factors which gated the gain adjustment, it appeared that the movement of the eyes and not the image motion that occurs during pursuit was paramount for enhancing pursuit gain. Gain was not enhanced by saccadic but only by smooth pursuit tracking movements. Finally, gain could be modulated somewhat by covert signals such as the expectation of future smooth pursuit movements.

Animals↗
PubMed1996

Phosphopeptides interacting with colloidal calcium phosphate isolated by tryptic hydrolysis of bovine casein micelles.

After extended tryptic hydrolysis of large bovine casein micelles, a mineral-rich peptide fraction was recovered by ultracentrifugation. Its mineral part contained 72% of the colloidal Ca and 49% of the colloidal P1 originally present in the native micelle. Colloidal nitrogenous components were also present, amounting to 27% of the original N content. They contained most of the phosphopeptides and 82% of the micellar phosphoseryl residues. These tryptic peptides were characterized by reversed-phase HPLC on-line electrospray ion source-mass spectrometry analysis. Among the peptides produced 14 phosphopeptides were identified: alpha s2-CN(1-24), alpha s2-CN(1-21), alpha s1-CN(43-79), alpha s1-CN(35-79)7P, alpha s1-CN(35-79)8P, alpha s1-CN(37-79), alpha s1-CN(104-119), alpha s1-CN(104-124), beta-CN(1-25), beta-CN(1-28), beta-CN(1-29), beta-CN(30-97), beta-CN(33-97) and beta-CN(29-97). The proportion of the phosphopeptides interacting with colloidal calcium phosphate was correlated with their relative content of phosphoserine residues, since phosphopeptides containing more than four phosphoserine residues were consistently present within this fraction. It also appeared that other types of peptides, some of them hydrophobic in nature, were also partly or completely present within the colloidal fraction, including alpha s1-CN(91-100), alpha s1-CN(152-193), alpha s1-CN(23-34), alpha s1-CN(125-193), alpha s1-CN(125-199), beta-CN(177-209). beta-CN(184-209), beta-CN(114-169) and beta-CN(108-169). Their possible involvement in the micellar backbone is discussed.

Animals↗
PubMed1996

Ablation of the pursuit area in the frontal cortex of the primate degrades foveal but not optokinetic smooth eye movements.

1. Neural pathology which impairs foveal smooth pursuit eye movements typically also degrades optokinetic pursuit of large textures, suggesting that the two kinds of pursuit share a common circuit. This study reports an exception. After sequential bilateral ablation of the pursuit area in the frontal lobe three monkeys displayed degraded pursuit of a small foveal target but performed normally on identical measures of optokinetic pursuit. 2. A related experiment in one subject demonstrated a pursuit deficit when the foveal target moved relative to the background, but not when background and target moved together. The frontal pursuit area may specifically control pursuit of relative motion, and do so by receiving signals primarily from motion detectors in the macular part of the visual field.

Animals↗
PubMed1994

In vivo reversal of multidrug resistance by two new dihydropyridine derivatives, S16317 and S16324.

Two new dihydropyridine derivatives with low calcium channel affinity, S16317 and S16324, were found to fully overcome multidrug resistance in vitro. These two compounds increased doxorubicin cytotoxicity on the human COLO 320DM cell line and completely reversed the vincristine resistance of murine P388/VCR cells. In vivo, S16324 administered p.o. (200 mg/kg on days 1 to 4) or i.p. (50 mg/kg on days 1, 5, 9) in combination with vincristine (i.p.) restored the antitumor activity of vincristine in P388/VCR-bearing mice. S16317 showed a reversing activity when administered p.o., i.v. (days 1 to 4) or i.p. (days 1, 5, 9) at the same dose (25 mg/kg), suggesting a remarkable bioavailability. Moreover, these two compounds potentiated the antitumor activity of vincristine in the sensitive P388 leukemia, increasing the number of long-term survivors. These results suggest that combination chemotherapy using S16317 or S16324 would be effective not only in circumventing multidrug resistance but also in preventing the emergency of a population of resistant tumor cells in sensitive tumors.

Adenocarcinoma↗
PubMed1990

Flow cytometric evaluation of the cell cycle perturbations induced by S12363, a new vinca alkaloid derivative.

L1210 cells treated for 21 hours with S12363, a new vinca alkaloid derivative and the parent compounds (vinblastine, vincristine, vindesine) at equitoxic concentrations were found, by flow cytometry, to be equally accumulated in the G2 + M phase of the cell cycle. The chromatin structure of these cells was then analyzed in order to quantify with high precision the percentage of cells in mitosis. S12363 was found to accumulate, from the first hours of treatment (4-8 hours), and at lower concentrations, a higher percentage of cells in the M phase than the reference drugs. Taking into account previously published studies concerning the characteristics of vinblastine and vincristine uptake, our results are compatible with a facilitated uptake of S12363.

Acridine Orange↗
PubMed1989

Interrelationship between affinity for DNA, cytotoxicity and induction of DNA-breaks in cultured L1210 cells for two series of tricyclic intercalators. Simplified analogues of ellipticine derivatives.

The interrelationship between affinity for DNA, cytotoxicity and induction of single-strand DNA breaks in cultured L1210 cells was studied for 21 compounds belonging to two series of tricyclic intercalators: 1-amino-substituted 4-methyl-5H-pyrido[4,3-b]indoles (gamma CARB) and 1-amino-substituted 4-methyl-5H-pyrido[3',4':4,5]pyrrolo[2,3-c]pyridines (PPP), which are simplified analogues of Ellipticine derivatives obtained by deletion of one cycle. Adriamycin, m-AMSA (4'-(9-acridinylamino) methanesulfon-m-anisidide), PZE (10-[diethylaminopropyl amino]-6-methyl-5H-pyrido[3',4':4,5]-pyrrolo[2,3-g] isoquinoline and RTE [( 1-(3-diethylaminopropylamino)-9-methoxy ellipticine, bimaleate) are used as reference compounds. The intercalation of these compounds into DNA was strongly suggested by three experimental observations: (i) the competitive inhibition of ethidium bromide intercalation, (ii) bathochromic and hypochromic effects on absorption spectra induced by DNA, and (iii) drug-induced increase of the DNA length, measured by viscosimetry. PPP derivatives are generally less cytotoxic and induce DNA breaks less efficiently than the gamma CARB ones, both in terms of maximum breakage frequencies and required drug concentrations. The most active compounds induced SSB in the DNA of L1210 cells, in a bell-shaped manner: the SSB frequency increased, rose to a maximum and then decreased as the drug concentrations increased. The maximum SSB frequencies induced by the most active compounds are of the same order as those of reference compounds Adriamycin and PZE. The structurally important requirements are essentially the same for both DNA breakage activity and cytotoxicity: (i) a N-CH3 in the 5-position, (ii) a CH3 in the 4-position, (iii) a hydroxy in the 8-position and (iv) the presence of an (aminoalkyl)amino side chain with preferentially a 3 carbon unit. There is no direct relationship between DNA affinity in vitro and induction of DNA breaks in cells, although a relatively high affinity seemed to be a necessary condition, since the most active compounds have the highest affinities and compounds having a very low affinity are totally inactive. The close correlation between cytotoxicity and extent of induction of DNA breaks suggests that these breaks may be in fact the lethal lesions responsible for cell death and thereby for the antitumor properties of these tricyclic intercalators.

Alkaloids↗
PubMed1988

Production of protein-associated DNA breaks by 10-[diethylaminopropylamino]-6-methyl-5H-pyrido[3',4':4,5]pyrrolo [2,3-g]isoquinoline in cultured L1210 cells and in isolated nuclei: comparison with other topoisomerase II inhibitors.

10-[3-Diethylaminopropylamino]-6-methyl-5H-pyrido[3',4':4,5] pyrrolo[2,3-g]isoquinoline (PZE) is an ellipticine derivative currently in clinical trials. PZE has been postulated to produce cellular DNA lesions by an uncommon mechanism. PZE-induced DNA damage was further investigated in L1210 cells in culture. PZE was highly cytotoxic for these cells (90% inhibitory concentration = 3.1 microM). The effects of PZE on cellular DNA were studied first by alkaline sucrose sedimentation, in comparison with those of 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA). Like m-AMSA, PZE induced DNA strand breaks which were detected without a proteolytic treatment of the cell lysate. This result rules out the existence of covalent protein bridges sealing DNA termini at the break sites. PZE was less active than m-AMSA. DNA fragmentation was maximum at 5 microM and was lower at higher concentrations. The DNA effects of PZE were also studied by alkaline elution, and compared with those of Adriamycin and m-AMSA. Like Adriamycin, PZE induced single-strand breaks (SSBs) in a bell-shaped manner with respect to drug concentration. The maximum SSB frequency [1784 +/- 370 (SEM) rad equivalents)] was obtained at 16 microM. The kinetics of SSB reversion after drug removal was slower than in the case of m-AMSA. Similar bell-shaped curves were obtained for PZE-induced double-strand breaks and DNA-protein cross-links. PZE induced more double-strand breaks per SSB than did m-AMSA. However, as in the case of m-AMSA, PZE induced equal SSB and DNA-protein cross-link frequencies. These results suggest that PZE induces DNA breaks by inhibiting topoisomerase II as do other antitumor intercalators.

Animals↗
PubMed1987

Physicochemical and pharmacological properties of the antitumor ellipticine derivative 2-(diethylamino-2-ethyl)9-hydroxy ellipticinium-chloride, HCl.

2-(Diethylamino-2-ethyl)9-hydroxyellipticinium-chloride, HCl (DHE), a new congener of the antitumor agent elliptinium acetate (Celiptium) (NMHE), has recently been selected for phase I clinical trials. NMHE has a methyl group at nitrogen 2 on the ellipticine ring while DHE possesses a basic diethylaminoethyl chain at this position. Compared to NMHE, the presence of the diethylaminoethyl side chain results in the following: a significant increase in the lipophilicity of the drug; no significant modification in either the binding constant values to DNA or the ability to intercalate between DNA base pairs; a marked decrease in the unwinding angle value of supercoiled DNA; and no significant change in the alteration of the catalytic activity of topoisomerase II in vitro. DHE appears to act as a simple reversible intercalating agent as shown by the selective mutagenic effect on Salmonella TA 1977 tester strain and by its inability to induce the SOS functions in a sfiA lac fusion containing Escherichia coli strain. From a pharmacological point of view, the presence of the diethylaminoethyl chain results in a 2-fold increase in the cytotoxicity to L1210 cultured cells, a strong increase in the antitumor efficiency on experimental murine tumors such as L1210 and P388 leukemia, B16 melanoma, M 5076 reticulosarcoma, and colon 38 adenocarcinoma, and finally an objective decrease in the acute and subacute toxicity in mice, rat, and macaque. The absence of significant differences in the interaction of NMHE and DHE with their potential targets in vitro leads to the hypothesis that the superiority of DHE in terms of cytotoxicity and antitumor efficiency may be due to an increase in the diffusion across cellular membrane and a more favorable biodistribution in vivo.

Adenocarcinoma↗
PubMed1984

Quantification of SSB protein in E. coli and its variation during RECA protein induction.

Using a two-site immunometric assay (IRMA) we quantified the concentration of single-stranded DNA binding protein (SSB) in several E. coli strains. We found approximately 7,000 monomers of SSB present per bacterium, and this number remained constant throughout the exponential phase of growth. Two ssb- mutants (ssb-1 and ssb-113) are defective in the induction of the S.O.S. pathway. One of the first functions expressed upon induction of the S.O.S. pathway is the amplification of recA protein (RECA), which we monitored by an IRMA assay similar to the one used for SSB quantification. By combining the two assays we determined the level of SSB and RECA in ssb- mutants or in SSB and RECA overproducer strains. We found: a) a normal induction of RECA following UV irradiation of E. coli bacteria overproducing SSB, b) a normal level of SSB in wild type and ssb-1 and ssb-113 mutants either in the absence or in the presence of S.O.S. inducing agents. We confirmed a severe impairment in the induction of RECA in these two mutants after nalidixic acid treatment. Our results suggest that the concentrations of RECA and SSB protein in E. coli are regulated by independent biochemical pathways.

DNA-Binding Proteins↗
PubMed1983

Evaluation of screening tests for the detection of antistreptolysin O antibodies.

The accuracy of two screening tests, one utilizing serum and the other utilizing whole blood, was compared with the accuracy of the conventional macrotitration method for the detection of antistreptolysin O antibodies. Of the 569 specimens tested with the serum screening procedure and the macrotitration method, 235 and 282, respectively, were positive for antistreptolysin O antibodies. Comparative testing of 200 specimens with the peripheral blood screening test and the macrotitration method gave 60.5% by the macrotitration procedure. Discrepant results with both procedures were obtained with specimens having 166 Todd units. The results suggest that these screening procedures can be used to screen specimens for the presence of significant antistreptolysin O antibodies.

Antibodies, Bacterial↗