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Biomedical subjects

G Gosselin

Publications and source records attributed to G Gosselin.

At least 91 records · Page 5Linked to original sources
PubMed1995

[Coronary angioplasty in cardiac transplantation].

Coronary artery disease is a common complication of cardiac transplantation threatening long-term survival and its management is not well defined. Percutaneous transluminal coronary angioplasty has been proposed as a palliative and exceptional technique in some patients with limited lesions. Of 145 patients undergoing cardiac transplantation between April 1983 and January 1994, 7 underwent 10 coronary angioplasty procedures. The majority was performed in asymptomatic patients, 4 for angigraphic abnormalities alone and 3 for documented painless ischaemia. Primary angiographic success was obtained in 90% (9 out of 10) of lesions. Complication included one acute occlusion and one arteriovenous fistula. Three patients died, 1, 8 and 10 months after angioplasty. After an average of 24 months' follow-up, 3 (out of 7) patients had no cardiac events (myocardial infarction, second angioplasty, second transplantation or death). A multicentre prospective controlled trial is necessary to assess the impact of this procedure on graft and patient survival.

Adult↗
PubMed1994

Equal inhibition of the replication of human immunodeficiency virus in human T-cell culture by ddA bis(SATE)phosphotriester and 3'-azido-2',3'-dideoxythymidine.

It is shown that ddA bis(SATE)phosphotriester is one of the most potent anti-HIV agents in cell culture. Compared with the parent nucleoside, ddA, an increase of 3 orders of magnitude was observed in the EC50, which makes this compound as active as AZT. This can be tentatively explained if one considers that direct ddAMP intracellular delivery shunts the well established ddA/ddI metabolism pathway.

Antiviral Agents↗
PubMed1994

Predictive factors of restenosis after multivessel percutaneous transluminal coronary angioplasty.

To evaluate the rate and predictive factors of restenosis after multivessel percutaneous transluminal coronary angioplasty (PTCA), 122 consecutive patients with multivessel PTCA performed in the same setting were included in a prospective study. Systematic angiographic control at 6 months was performed in 112 patients (92%). Restenosis (increase > 20% and stenosis > 50%) was found in 62 patients (55%) and 82 of 254 segments (32%) were dilated. Statistical analysis identified the number of successfully dilated segments as the only predictor of restenosis by patient (2.4 +/- 0.7 vs 2.0 +/- 0.7; p < 0.03), and the greater degree of residual stenosis as the only predictor of restenosis by lesion (30 +/- 14% vs 23 +/- 12%; p < 0.005). Twenty-two of 62 restenosed patients (35%) were asymptomatic (group 1). Baseline clinical and angiographic characteristics of these patients were similar to those with symptomatic restenosis (n = 40; group 2) and without restenosis (n = 50; group 3). Repeat revascularization for restenosis was used only in symptomatic patients (re-PTCA in 36; bypass surgery in 4). After a mean follow-up of 75 +/- 24 months, clinical status, and rates of cardiac death and myocardial infarction were similar in the 3 groups. Medical care was similar in groups 1 and 3, and higher in group 2. However, the rate of repeat revascularization for progression of disease was similar in the 3 groups (29%). In conclusion, restenosis is a frequent event after multivessel PTCA and is strongly related to the number of successfully dilated segments.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Tolerability of enalapril initiation by patients with left ventricular dysfunction: results of the medication challenge phase of the Studies of Left Ventricular Dysfunction.

Although converting-enzyme inhibitors are useful for the treatment of congestive heart failure (CHF), there are concerns about adverse reactions especially on initiation of therapy. In the Studies of Left Ventricular Dysfunction, enalapril, 2.5 mg twice per day was given on an open-label outpatient basis for 7 days (mean 6.1, range 2 to 7, and median 7) as a prerandomization drug challenge to 7487 patients with left ventricular dysfunction (ejection fraction < or = 0.35). Four hundred forty-four (5.93%) patients reported side effects, including symptoms attributed to hypotension (in 166 patients [2.2%]). The majority (346 [77.9%] of 444 and 129 [77.7%] of 166 with symptoms attributed to hypotension) of patients who reported side effects were willing to participate in the study and to continue receiving enalapril. Thus only 98 (1.3%) of 7487 patients (0.5% because of symptoms attributed to hypotension) were not willing to continue because of side effects. Women and patients of CHF class III or IV were more likely to report side effects. In conclusion, enalapril is well tolerated by patients with left ventricular dysfunction; treatment can be initiated on an outpatient basis in the majority of patients.

Enalapril↗
PubMed1994

Inhibition of human immunodeficiency virus type 1 reverse transcriptase by the 5'-triphosphate beta enantiomers of cytidine analogs.

(-)-beta-L-2',3'-Dideoxycytidine (L-ddC) and (-)-beta-L-2',3'-dideoxy-5-fluorocytidine (L-FddC) have been reported to be potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) in vitro. In the present study, the 5'-triphosphates of L-ddC (L-ddCTP) and L-FddC (L-FddCTP) were demonstrated to competitively inhibit HIV-1 reverse transcriptase (RT), with inhibition constants (KiS) of 2 and 1.6 microM, respectively, when a poly(rI).oligo(dC)10-15 template primer was used; in comparison Ki values for beta-D-2',3'-dideoxycytidine 5'-triphosphate (D-ddCTP) and beta-D-2',3'-dideoxy-5-fluorocytidine 5'-triphosphate (D-FddCTP) were 1.1 and 1.4 microM, respectively. Use of the mutant RT at position 184 (substitution of methionine to valine [M184V]), which is associated with resistance to beta-L-2',3'-dideoxy-3'-thiacytidine (3TC) and beta-L-2',3'-dideoxy-5-fluoro-3'-thiacytidine (FTC), resulted in significant increases (50- to 60-fold) in Ki values for L-ddCTP and L-FddCTP, whereas the elevation in Ki values for D-ddCTP and D-FddCTP was moderate (2-fold). L-ddCTP and L-FddCTP did not inhibit human DNA polymerases alpha and beta up to 100 microM. In contrast, D-ddCTP and D-FddCTP inhibited human DNA polymerase beta, with Ki values of 0.5 and 2.5 microM, respectively. By using sequencing analysis, L-ddCTP and L-FddCTP exhibited DNA chain-terminating activities toward the parental HIV-1 RT, whereas they were not a substrate for the mutant M184V HIV-1 RT.L-ddC and L-FddC did not inhibit the mitochondrial DNA content of human cells up to a concentration of 10 microM, whereas D-ddC and D-FddC decreased the mitochondrial DNA content by 90% at concentrations of 1 and 10 microM, respectively. All of these results suggest that further development of L-ddC, and L-FddC in particular, is warranted as a possible anti-HIV candidate.

Antiviral Agents↗
PubMed1994

Anti-human immunodeficiency virus activities of the beta-L enantiomer of 2',3'-dideoxycytidine and its 5-fluoro derivative in vitro.

The L enantiomer of 2',3'-dideoxycytidine (DDC) was recently shown to inhibit selectively human immunodeficiency virus type 1 (HIV-1) in vitro. In the current study, the potent anti-HIV activity of L-DDC was confirmed and extended to several HIV-1 and HIV-2 strains in various cell culture systems, including primary human lymphocytes and macrophages. Furthermore, its 5-fluoro congener, beta-L-2',3'-dideoxy-5-fluorocytidine (L-FDDC), was found to have more potent anti-HIV activity and a higher therapeutic index in acutely infected human peripheral blood mononuclear cells. These compounds had no marked activity against HIV-1 isolates resistant to the oxathiolane pyrimidine nucleosides (-)-beta-L-2',3'-dideoxy-5-fluoro-3'-thiacytidine [(-)-FTC] and (-)-beta-L-2',3'-dideoxy-3'-thiacytidine, but 3'-azido-3'-deoxythymidine (AZT)-resistant viruses were susceptible to L-DDC and L-FDDC. Cytotoxicity studies with human myeloid progenitor cells indicated that L-DDC and L-FDDC had median inhibitory concentrations comparable to those of AZT, DDC, and FDDC, but L-DDC and L-FDDC were significantly less toxic than AZT, DDC, and FDDC when erythroid progenitor cells were used. L-FDDC had the highest selectivity indices (6,000 and 9,000 for erythroid and myeloid progenitor cells, respectively) of all the compounds evaluated. Further preclinical development of L-FDDC is warranted in order to determine its potential usefulness in the treatment of HIV infections.

Antiviral Agents↗
PubMed1994

Pure nucleoside enantiomers of beta-2',3'-dideoxycytidine analogs are selective inhibitors of hepatitis B virus in vitro.

(-)-beta-L-2',3'-Dideoxycytidine (beta-L-DDC), (+)-beta-D-2',3'-dideoxycytidine (beta-D-DDC), (-)-beta-L-2',3'-dideoxy-5-fluorocytidine (beta-L-FDDC), (-)-beta-L-2',3'-dideoxy-5-fluoro-3'-thiacytidine (beta-L-FTC), and (+)-beta-D-1,3-dioxolane-5-fluorocytidine (beta-D-FDOC) were evaluated for their anti-hepatitis B virus (anti-HBV) activities in HBV-transfected human liver cells (2.2.15). The order of decreasing potency for the compounds at the 90% effect level was beta-D-FDOC > beta-L-FTC > beta-L-FDDC approximately beta-L-DDC >> beta-D-DDC. Inhibition of HBV in transfected liver cells by the cytosine nucleosides was selective. The beta-L-nucleoside-5'-triphosphates were consistently more potent inhibitors of woodchuck hepatitis virus DNA polymerase than the corresponding natural beta-D-enantiomers.

Antiviral Agents↗
PubMed1994

[Electron microscopic comparison of the antithrombotic potential of 2 low osmolality iodine contrast media in percutaneous transluminal coronary angioplasty].

The antithrombogenic potentials of two low osmolality iodine contrast media, ioxaglate (Iox), an ionic product, and iopamidol (Iop), a non-ionic product, were compared in a multicentre, randomised, double-blind study in 64 patients undergoing percutaneous transluminal coronary angioplasty (PTCA) by scanning electron microscopy for the presence of thrombotic material on the guiding catheter (GC) and guide wires (GW). The procedure was strictly standardised: stable angina, type A coronary lesions; aspirin administration (at least 300 mg the day before and on the day of angioplasty); heparinisation (10000 IU at the beginning of the procedure); same GCs (Marathon Baxter 8F), same GWs (Veriflex USCI 0.014). The tips of the catheters and guide wires were scanned by an electronic microscope in a double-blind protocol. The scores for the number of erythrocytes (RBCs), platelets (PLs) and constituted thrombi (THi) were; thickness scored from 0 to 3, the % surface covered and an index of volume combining these two parameters. The clinical and angiographic characteristics of the 2 groups were strictly comparable. The time that the GCs and GWs were in the circulation were 30.0 +/- 2.3 vs 32.6 +/- 3.0 minutes for the former, and 18.6 +/- 1.8 vs 17.1 +/- 1.4 minutes for the later in the Iox and Iop groups, respectively (NS). An angiographic filling defect was not observed in any of the patients in the Iox group and in 4 patients (13%) in the Iop group (NS). The number of thrombotic elements observed on the GCs (RBCs, PLs, THi) was negligible in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Angioplasty, Balloon, Coronary↗
PubMed1994

Enantiomeric 2',3'-dideoxycytidine derivatives are potent human immunodeficiency virus inhibitors in cell cultures.

2',3'-dideoxy-beta-L-cytidine (beta-L-DDC) and its 5-fluoro derivative (beta-L-5-F-DDC) have been stereospecifically synthesized by a multi-step reaction sequence from L-xylose and their anti-HIV properties examined. Among these two L-enantiomers, the hitherto unknown beta-L-5-F-DDC emerged as a potent anti-HIV-1 and HIV-2 compound in different cell culture systems, with selectivity indices similar or superior to those of the currently licensed drug DDC which has the natural beta-D configuration.

Cells, Cultured↗
PubMed1994

Psoralen--lexitropsin hybrids: DNA sequence selectivity of photoinduced cross-linking from MPE footprinting and exonuclease III stop assay, and mode of binding from electric linear dichroism.

The properties of certain hybrids 3 and 5 bearing a photoactivatable psoralen group attached to DNA sequence recognizing lexitropsin carriers have been examined. The hybrids bind to poly(dA-dT) with Kapp of 2.8 and 0.9 x 10(7) M-1, i.e. greater than or equal to that of netropsin (Kapp = 1.0 x 10(7) M-1), indicating that the psoralen moiety may contribute to binding in the case of 5. Photoinduced cross-linking of DNA by 3 and 5, while efficient, is less so than that of individual psoralens and reaches a maximum at a ligand to DNA base pair ratio (r) of 0.2. Complementary strand methidium-propyl-EDTA (MPE).Fe(II) footprinting demonstrated that, in the dark, the sequence preferential recognition of hybrids 3 and 5 is dominated by the lexitropsin moiety. Examination of 360 nm photoinduced DNA cross-linking by the hybrids 3 and 5 was carried out using an exonuclease III stop assay. This revealed that > 95% of the DNA remained double stranded, indicating that 3 and 5 generate primarily biadducts at AT-rich sequences. This assay also located individual monoadduct sites, some of which are remote from the dominant cross-linked sites. When the samples were exposed to 254 nm UV light before loading onto the gel to reverse the photoproducts, the pattern of the exonuclease III stop bands was not altered significantly compared with the experiment without 254 nm irradiation. It is concluded that these termination sites include both mono- and biadducts. Electric linear dichroism examination of the DNA complexes of hybrids 3 and 5 (without light activation) provides evidence that the lexitropsin portion binds in the minor groove, while the psoralen portion intercalates in a suitably located site for subsequent photoinduced cross-linking.

Antineoplastic Agents↗
PubMed1993

Inhibition of HIV-1 replication in cultured cells with phosphorylated dideoxyuridine derivatives encapsulated in immunoliposomes.

Among the 2',3'-dideoxynucleoside 5'-triphosphates containing a physiological base, 2',3'-dideoxyuridine 5'-triphosphate (ddUTP) has been reported to be among the most powerful inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (RT) in cell-free systems. However, in contrast to other dideoxynucleosides, 2',3'-dideoxyuridine (ddU) is inactive in treatment of HIV-infected cells in culture, since it is a poor substrate for cellular nucleoside kinases. This problem cannot be overcome by the use of phosphorylated ddU because such compounds are unable to cross cell membranes. To promote entry and thus bypass the limiting steps of intracellular phosphorylation, we have encapsulated mono- and tri-phosphorylated ddU in liposomes coupled to monoclonal antibodies (immunoliposomes). We investigated antiviral effects in two human T cell lines (MT-4, CEM). We observed that ddU nucleotides remain phosphorylated for several weeks after encapsulation in immunoliposomes, and potent antiviral activity is obtained when these drugs are delivered into infected cells by cell-specific antibodies (ED50 < or = 1 microM on CEM). In contrast, no inhibition was observed with non-targeted liposomes containing phosphorylated ddU, or with empty liposomes, whether targeted or not.

Antiviral Agents↗
PubMed1993

5'-Hydrogenphosphonates of anti-HIV nucleoside analogues revisited: controversial mode of action.

The monomeric and symmetrical dimeric 5'-hydrogenphosphonate derivatives of AZT were prepared and evaluated for their inhibitory properties against HIV-1 in several cell lines. The synthesis of the compounds was achieved by reaction of AZT with in situ prepared phosphorus tris(imidazolide) or with phosphonic acid in the presence of pivaloyl chloride. The two title compounds showed in vitro anti-HIV activity similar to (but not better than) that of AZT in three cell lines which were not deficient in thymidine kinase. On the other hand they were inactive in CEM-TK- cells. Pharmacokinetic studies in several media corroborate the assumption that these compounds must not be considered as 'true antiviral agents', but that they act by releasing their nucleoside entity.

Cell Line↗
PubMed1993

Intracellular delivery of nucleoside monophosphates through a reductase-mediated activation process.

On the basis of three different models (namely: ddU, AZT and PMEA), mononucleotide phosphotriester derivatives were designed to be able to liberate the corresponding monophosphate (or phosphonate) inside the cell through a reductase-mediated activation process. It was demonstrated that the use of bis[S-(2-hydroxyethylsulfidyl)-2-thioethyl] esters of ddUMP (11), AZTMP (12) and PMEA (17) resulted in intracellular delivery of the parent monophosphate (or phosphonate). This point was corroborated by observation of an anti-HIV effect of, 11 in various cell lines, for 12 in CEM TK- cells and by the enhanced activity observed for 17. Furthermore, the reported decomposition data in cell extracts fully confirm the validity of this approach and show unambiguously the potential for intracellular reductase-mediated activation of the starting drug.

Adenine↗
PubMed1992

Binding properties and DNA sequence-specific recognition of two bithiazole-linked netropsin hybrid molecules.

We report the DNA binding properties of two hybrid molecules which result from the combination of the DNA sequence-specific minor groove ligand netropsin with the bithiazole moiety of the antitumor drug bleomycin. The drug-DNA interaction has been investigated by means of electric linear dichroism (ELD) spectroscopy and DNase I footprinting. In compound 1 the two moieties are linked by a flexible aliphatic tether while in compound 2 the two aromatic ring systems are directly coupled by a rigid peptide bond. The results are consistent with a model in which the netropsin moiety of compound 1 resides in the minor groove of DNA and where the appended bithiazole moiety is projected away from the DNA groove. This monocationic hybrid compound has a weak affinity for DNA and shows a strict preference for A and T stretches. ELD measurements indicate that in the presence of DNA compound 2 has an orientation typical of a minor groove binder. Similar orientation angles were measured for netropsin and compound 2. This ligand which has a biscationic nature tightly binds to DNA (Ka = 6.3 x 10(5) M-1) and is mainly an AT-specific groove binder. But, depending on the nature of the sequence flanking the AT site first targeted by its netropsin moiety, the bithiazole moiety of 2 can accommodate various types of nucleotide motifs with the exception of homooligomeric sequences. As evidenced by footprinting data, the bithiazole group of bleomycin acts as a DNA recognition element, offering opportunities to recognize GC bp-containing DNA sequences with apparently a preference (although not absolute) for a pyrimidine-G-pyrimidine motif. Thus, the bithiazole unit of bleomycin provides an additional anchor for DNA binding and is also capable of specifically recognizing particular DNA sequences when it is appended to a strongly sequence selective groove binding entity. Finally, a model which schematizes the binding of compound 2 to the sequence 5'-TATGC is proposed. This model readily explains the experimentally observed specificity of this netropsin-bithiazole conjugate.

Base Sequence↗
PubMed1991

Bis(pyrrolecarboxamide) linked to intercalating chromophore oxazolopyridocarbazole (OPC): selective binding to DNA and polynucleotides.

We have investigated some properties related to interaction with DNA and recognition of AT-rich sequences of netropsin-oxazolopyridocarbazole (Net-OPC) (Mrani et al., 1990), which is a hybrid groove-binder-intercalator. The hybrid molecule Net-OPC binds to poly[d(A-T)] at two different sites with Kapp values close to 7 x 10(6) and 6 x 10(8) M-1 (100 mM NaCl, pH 7.0). Data obtained from melting experiments are in agreement with these values and indicate that Net-OPC displays a higher binding constant to poly[d(A-T)] than does netropsin. On the basis of viscometric and energy transfer data, the binding of Net-OPC to poly[d(A-T)] is suggested to involve both intercalation and external binding of the OPC chromophore. In contrast, on poly[d(G-C)], Net-OPC binds to a single type of site composed of two base pairs in which the OPC chromophore appears to be mainly intercalated. The binding constant of Net-OPC to poly[d(G-C)] was found to be about 350-fold lower than that of the high-affinity binding site in poly[d(A-T)]. As evidenced by footprinting data, Net-OPC selectively recognizes TTAA and CTT sequences and strongly protects the 10-bp AT-rich DNA region 3'-TTAAGAACTT-5' containing the EcoRI site. The binding of Net-OPC to this sequence results in a strong and selective inhibition of the activity of the restriction endonuclease EcoRI on the plasmid pBR322 as substrate. The extent of inhibition of the rate constant of the first strand break catalyzed by the enzyme is about 100-fold higher than the one observed in the presence of netropsin under similar experimental conditions.

Base Sequence↗
PubMed1991

Long-term angiographic follow-up after angioplasty of venous coronary bypass grafts.

From April 1981 to June 1987, 57 patients underwent venous coronary bypass graft percutaneous angioplasty and had a minimal follow-up of 18 months. The procedure was elective for 28 patients, urgent for 19, and was considered as an emergency for 10. A total of 64 grafts were dilated that had been bypassed 58 +/- 48 months previously (range 2 to 184 months); lesions were located on the aortic anastomosis in 12 grafts, on the body in 38, and on the coronary anastomosis in 14. Technical success was 95.3% (61 of 64) per lesion; clinical success was 84.4% (54 of 64) per lesion and 82.5% (47 of 57) per patient. Thrombotic complications with images of a lacunar defect occurred in 11 grafts (17.2%). Predictive factors for these complications were: age of grafts 38.5% for greater than 60 month grafts versus 2.6% for less than 60 month grafts (p less than 0.01); site of lesion, body lesion 28.9% versus anastomosis none (p less than 0.01); type of lesion, concentric and short 6% versus other 29% (p less than 0.05); and recent fibrinolysis in 66% versus 10.6% (p less than 0.05). Long-term follow-up is available in the 47 successful patients and the three limited non-Q wave myocardial infarction patients. Two patients died at 13 and 17 months. Long-term angiographic follow-up is available in 45 of 48 patients or 94%. At the end of the study, 35 of 57 (61.4%) venous bypass grafts in 32 patients (64%) were patent after one or more percutaneous transluminal angioplasties.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiography↗
PubMed1991

Accelerated coronary atherosclerosis after cardiac transplantation: major threat to long-term survival.

Accelerated coronary atherosclerosis (ACA) has been documented at autopsy and was noted at coronary angiography in seven patients, 11 to 48 months after cardiac transplantation. To delineate the importance of this problem, the risk factors and the therapeutic approaches in 7 patients who had ACA after heart transplantation were compared with those in 28 patients free of ACA at annual coronary angiography. Ischemic cardiomyopathy was the preoperative diagnosis in all but one patient in the ACA group. The age of the transplant recipients, total myocardial ischemic times and arterial blood pressures at follow-up were similar in both groups. Donor age averaged 31 +/- 3 years in the ACA group and 22 +/- 1 years in patients free of ACA. Preoperative cholesterol, triglyceride and high-density lipoprotein levels were lower in ACA-free patients and the low-density lipoprotein level was higher. At the last follow-up visit, serum lipid levels were similar in both groups. The incidence of acute rejection and of infection was slightly, but not significantly, higher in patients with ACA. The actuarial survival of ACA patients 4 years after transplantation was 30% +/- 20% compared with 100% for patients free of ACA (p less than 0.01). Actuarial rates of freedom from ACA and from death due to ACA were 73% +/- 11% and 81% +/- 11% respectively. Stepwise discriminant analysis showed that older donors and higher pretransplant triglyceride levels were independently related to the development of ACA after cardiac transplantation. In conclusion ACA remains an important cause of late death after heart transplantation. Although therapeutic measures are limited, prevention should focus on strict control of serum lipid levels after transplantation.

Adult↗