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J F Marquis

Publications and source records attributed to J F Marquis.

At least 19 recordsLinked to original sources
PubMed2005

Resistance mechanism development to the topoisomerase-I inhibitor Hoechst 33342 by Leishmania donovani.

The bisbenzimidazole compound Hoechst 33342 (Ho342) has been identified as a specific Topoisomerase-I (Topo-I) inhibitor in mammalian cells. More recently, we have reported the ability of Ho342 to target L. donovani Topo-I, leading to parasite growth inhibition in vitro by mechanisms involving DNA breakage and apoptosis-like phenomenon. As the Ho342 lead molecule (2,5'-Bi-1H-benzimidazole) can be used as a starting structure for derivative compounds more effective against Leishmania, defining the Ho342 resistance mechanism(s) in Leishmania represents an important strategic tool. In the present study, we selected resistant parasites to Ho342 (LdRHo.300). While we observed an increase of the Topo-I gene expression correlated by a higher Topo-I DNA relaxation activity, the Topo-I genes (LdTOP1A and LdTOP1B) sequencing did not reveal any mutation for the resistant parasites. Moreover, our results on Ho342 cellular accumulation suggested the presence of a potential energy-dependent Ho342 transporter in the wild-type parasite, and that an alteration of this transporter has occurred in LdRHo.300, leading to an altered drug accumulation. Collectively, Ho342 resistance characterization provided results supporting that the resistance developed by LdRHo.300 involves complex mechanisms, most likely dominated by an altered drug accumulation, providing new insight in the Ho342 resistance mechanisms.

Animals↗
PubMed2003

Consequence of Hoechst 33342-mediated Leishmania DNA topoisomerase-I inhibition on parasite replication.

This study reports that inhibition of Leishmania Topo-I with the minor groove-binding ligands (MGBLs) Hoechst 33342 (Ho342) blocks parasite growth in culture by mechanisms involving DNA breakage. While Ho342 inhibited the replication of several species of Leishmania in a dose- and time-dependent manner, Ho258 was not effective. Cytofluorometric analysis suggested that superior effectiveness of Ho342 over Ho258 was attributed to Leishmania parasites being more permeable toward Ho342. This observation was supported by the ability of both Ho342 and Ho258 to block the relaxation of supercoiled pBR322 DNA by Leishmania Topo-I. The Ho342 specificity toward L. donovani Topo-I was reinforced by the observation that increased Topo-I gene expression and Topo-I activity in Leishmania was paralleled by augmented resistance for this compound. Furthermore, the capacity of NaCl treatment to reverse MGBL-mediated DNA break suggests that Ho342 targetted Topo-I. Moreover, we observed that Ho342-inducible arrest of Leishmania growth was accompanied by G1 arrest and induction of cell death that closely resembles apoptosis. Taken together, our results suggest that MGBL compounds show promise as Topo-I inhibitors against Leishmania infection.

Animals↗
PubMed2001

Stenting versus thrombolysis in acute myocardial infarction trial (STAT).

OBJECTIVES: We sought to directly compare primary stenting with accelerated tissue plasminogen activator (t-PA) in patients presenting with acute ST-elevation myocardial infarction (AMI). BACKGROUND: Thrombolysis remains the standard therapy for AMI. However, at some institutions primary angioplasty is favored. Randomized trials have shown that primary angioplasty is equal or superior to thrombolysis, while recent studies demonstrate that stent implantation improves the results of primary angioplasty. METHODS: Patients presenting with AMI were randomly assigned to primary stenting (n = 62) or accelerated t-PA (n = 61). The primary end point was the composite of death, reinfarction, stroke or repeat target vessel revascularization (TVR) for ischemia at six months. RESULTS: The primary end point was significantly reduced in the stent group compared with the accelerated t-PA group, 24.2% versus 55.7% (p < 0.001). The event rates for other outcomes in the stent group versus the t-PA group were as follows: mortality: 4.8% versus 3.3% (p = 1.00); reinfarction: 6.5% versus 16.4% (p = 0.096); stroke: 1.6% versus 4.9% (p = 0.36); recurrent unstable ischemia: 9.7% versus 26.2% (p = 0.03) and repeat TVR for ischemia: 14.5% versus 49.2% (p < 0.001). The median length of the initial hospitalization was four days in the stent group and seven days in the t-PA group (p < 0.001). CONCLUSIONS: Compared with accelerated t-PA, primary stenting reduces death, reinfarction, stroke or repeat TVR for ischemia. In centers where facilities and experienced interventionists are available, primary stenting offers an attractive alternative to thrombolysis.

Aged↗
PubMed2001

Treatment of visceral leishmaniasis with sterically stabilized liposomes containing camptothecin.

The efficacy of 20(S)-camptothecin (CPT), free and incorporated into sterically stabilized liposomes, has been investigated in vitro against Leishmania donovani promastigotes and in vivo in a murine model of visceral leishmaniasis. Incubation of L. donovani promastigotes with free or liposomal CPT inhibited the growth of parasites in a dose-dependent manner. Tissue distribution studies revealed that the intraperitoneal administration of liposomal CPT was efficient for the delivery of high drug levels to the liver and spleen. Treatment of infected mice with intraperitoneal injections of free and liposomal CPT significantly reduced the parasite loads in the livers by 43 and 55%, respectively, compared with the loads for untreated controls. However, both treatments caused normochromic anemia and neutropenia.

Animals↗
PubMed2000

Peroxovanadium-mediated protection against murine leishmaniasis: role of the modulation of nitric oxide.

The phosphotyrosine phosphatase inhibitor bpV(phen) has the ability to markedly decrease the progression of leishmaniasis in vivo. Here, we have identified the mechanisms that are responsible for this protective effect. We report that two potent peroxovanadium (pV) compounds, bpV(phen) and bpV(pic), control progression of leishmaniasis in a similar manner by modulating NO-dependent microbicidal action. We observed that their injection can rapidly and transiently induce the expression of inducible NO synthase (iNOS) in livers of mice and enhance circulating nitrate levels. Treatment of mice with bpV(phen) or bpV(pic) completely controlled progression of leishmaniasis in an NO-dependent manner, since inhibition of iNOS with aminoguanidine completely reversed this pV-mediated protection. This NO-dependent pV-mediated protection was further demonstrated by the incapacity of bpV(phen)-treated Nramp-/-, iNOS-/- mutant mice to control Leishmania major infection. Using an air pouch model, we showed that bpV(phen) can strongly modulate secretion of L. major-induced pro-inflammatory molecules and neutrophil recruitment. In addition, we observed that bpV(phen) per se can strongly induce the expression of Th1 type cytokines over Th2 in spleens of animals. Overall, this study has allowed us to establish the in vivo functional and immunological events involved in pV-mediated protective mechanism against leishmaniasis and that NO plays a pivotal role in this process.

Animals↗
PubMed2000

Reactivation of coagulation after stopping infusions of recombinant hirudin and unfractionated heparin in unstable angina and myocardial infarction without ST elevation: results of a randomized trial. OASIS Pilot Study Investigators. Organization to Assess Strategies for Ischemic++ Syndromes.

AIMS: To compare effects of heparin and hirudin on biochemical markers of coagulation. METHODS AND RESULTS: Patients (n=395) with unstable angina or myocardial infarction without ST elevation were randomized to a 72-h infusion of one of three regimens: unfractionated heparin (bolus of 5000 IU followed by an infusion of 1200 IU. h(-1)), low-dose hirudin (HBW 023; 0.2 mg. kg(-1)bolus followed by 0.10 mg. kg(-1). h(-1)) or medium-dose hirudin (0.4 mg. kg(-1)bolus followed by 0.15 mg. kg(-1). h(-1)). Infusions were adjusted to maintain an activated partial thromboplastin time of between 60-100 s. Activated partial thromboplastin time, prothrombin fragment 1.2 (F1.2), thrombin antithrombin III complex and D-dimer were measured before, during and after the infusion. Median activated partial thromboplastin time was similar in the two groups early on, but was significantly lower in the heparin group than in the combined hirudin group 48 h after starting the infusion (53 s and 75 s, respectively;P<0.001), and 6 h after stopping (31 s and 46 s, respectively;P<0.001). Median F1.2 levels were not significantly different between the groups during the infusion. Median thrombin antithrombin III levels in the heparin and hirudin groups were 2.8 microg. l(-1)and 2.3 microg. l(-1), respectively, at 6 h (P<0.001), and 3.0 microg. l(-1)and 2.3 microg. l(-1), respectively, at 48 h (P<0.001). Median D-dimer levels were 320 ng. ml(-1)and 260 ng. ml(-1)48 h after starting the infusion in the heparin and hirudin groups, respectively (P<0.001), and 415 ng. ml(-1)and 280 ng. ml(-1), respectively (P<0.001) 6 h after stopping. D-dimer levels were significantly elevated above baseline values in both groups 24-48 h after stopping the infusions. CONCLUSIONS: The greater reduction of thrombin antithrombin III and D-dimer during the hirudin infusion supports the hypothesis that hirudin is a more potent antithrombin agent than heparin. Increased D-dimer levels after stopping heparin or hirudin suggest that there is an ongoing pro-coagulant state. These results point to the greater efficacy of hirudin in preventing early clinical events (death, myocardial infarction and refractory ischaemia) compared with heparin that have been observed in large randomized trials. Persistent activation of coagulation afterstopping infusions in our study suggests that a longer course of antithrombotic treatment may be needed to pacify the thrombus.

Angina, Unstable↗
PubMed1999

Primary stenting versus balloon angioplasty in occluded coronary arteries: the Total Occlusion Study of Canada (TOSCA).

BACKGROUND: Balloon angioplasty (PTCA) of occluded coronary arteries is limited by high rates of restenosis and reocclusion. Although stenting improves results in anatomically simple occlusions, its effect on patency and clinical outcome in a broadly selected population with occluded coronary arteries is unknown. METHODS AND RESULTS: Eighteen centers randomized 410 patients with nonacute native coronary occlusions to PTCA or primary stenting with the heparin-coated Palmaz-Schatz stent. The primary end point, failure of sustained patency, was determined at 6-month angiography. Repeat target-vessel revascularization, adverse cardiovascular events, and angiographic restenosis (>50% diameter stenosis) constituted secondary end points. Sixty percent of patients had occlusions of >6 weeks' duration, baseline flow was TIMI grade 0 in 64%, and median treated segment length was 30.5 mm. With 95.6% angiographic follow-up, primary stenting resulted in a 44% reduction in failed patency (10.9% versus 19.5%, P=0.024) and a 45% reduction in clinically driven target-vessel revascularization at 6 months (15.4% versus 8.4%, P=0.03). The incidence of adverse cardiovascular events was similar for both strategies (PTCA, 23.6%; stent, 23.3%; P=NS). Stenting resulted in a larger mean 6-month minimum lumen dimension (1.48 versus 1.23 mm, P<0.01) and a reduced binary restenosis rate (55% versus 70%, P<0.01). CONCLUSIONS: Primary stenting of broadly selected nonacute coronary occlusions is superior to PTCA alone, improving late patency and reducing restenosis and target-vessel revascularization.

Adolescent↗
PubMed1999

Characterization of a Leishmania donovani gene encoding a protein that closely resembles a type IB topoisomerase.

In order to clone the gene encoding a type I DNA topoisomerase from Leishmania donovani, a PCR-amplified DNA fragment obtained with degenerate oligodeoxyribonucleotides was used to screen a genomic library from this parasite. An open reading frame of 1905 bases encoding a putative protein of 635 amino acid residues was isolated. A substantial part of the protein shares a significant degree of homology with the sequence of other known members of the IB topoisomerase family, in a highly conserved region of these enzymes termed the core domain. However, homology is completely lost after this conserved central core. Moreover, no conventional active tyrosine site could be identified. In fact, the protein expressed in Escherichia coli did not show any relaxation activity in vitro and was unable to complement a mutant deficient in topoisomerase I activity. The results of Southern blot experiments strongly suggested that the cloned gene was not a pseudogene. Northern analysis revealed that the gene was transcribed in its full length and also excluded the possibility that some form of splicing is necessary to produce a mature messenger. Furthermore, our results indicate that the gene is preferentially expressed in actively growing L.donovani promastigotes and that it is also expressed in other kinetoplastid parasites.

Amino Acid Sequence↗
PubMed1999

Predictors of long-term outcome after stent implantation in a saphenous vein graft.

Stenting of saphenous vein graft (SVG) lesions is associated with significant clinical events at late follow-up. We sought to determine predictors of clinical outcome after this procedure. One hundred twenty-eight balloon-expandable stents were implanted in the SVGs of 106 patients. Baseline clinical and angiographic characteristics were analyzed. All grafts, including those not stented, were scored for extent of disease involving the luminal surface of the graft, and for the presence of low profile lesions (< 50% graft stenosis) and/or high profile lesions (> or = 50% graft stenosis). The in-hospital success rate was 98.1%. Before discharge, no patient died, required bypass surgery, or had repeat angioplasty of the same graft. Follow-up was obtained on all the patients. At a median of 18 months, 15% had died, 17% had experienced myocardial infarction, 20% had required repeat bypass surgery, and 37% needed repeat angioplasty to either the same site or a different lesion. Event-free survival was recorded in only 44% of the patients. The cumulative Kaplan-Meier survival at 2.4 years was 78.7%. Using the Cox proportional hazards model, predictors of survival were the absence of a high profile lesion in any nonstented patent graft (p = 0.004), and the use of lipid-lowering agents at follow-up (p = 0.01). Stenting SVG lesions can be performed with a high degree of procedural success, but at long-term follow-up there is a high rate of cardiac events. The absence of a high profile lesion in any nonstented patent graft is the strongest predictor of survival.

Angioplasty, Balloon, Coronary↗
PubMed1999

Successful surgical endarterectomy of a stented coronary artery.

An occlusion in this 61-year-old male's distal right coronary artery was initially successfully opened with balloon angioplasty and three "half" Palmaz-Schatz stents (Johnson and Johnson International Systems, Warren, NJ). Subsequent occlusion of the RCA occurred and prompted bypass grafting 2 years later. An extensive manual surgical endarterectomy removed the stents, demonstrating the technical feasibility of surgically removing failed stents in accessible coronary arteries.

Angioplasty, Balloon, Coronary↗
PubMed1998

Late clinical and angiographic follow-up after stenting in evolving and recent myocardial infarction.

OBJECTIVES: This study sought to assess the late clinical and angiographic outcomes of patients who received stents within the first week of acute myocardial infarction (AMI). BACKGROUND: Recent studies have demonstrated that stenting of the infarct-related artery is a useful adjunct to balloon angioplasty in patients with AMI. However, there are limited data on the late clinical and angiographic outcomes of these patients. METHODS: Between January 1994 and September 1995, 32 patients at our institution underwent stenting of the infarct-related artery within 1 week of AMI: 13 within 14 hours (evolving group) and 19 between days 2 and 7 (recent AMI group). Late clinical follow-up was obtained on all survivors. Quantitative angiographic measurements were recorded on the stented segments before stenting, immediately after stenting, and on the follow-up angiograms. RESULTS: At 13.1+/-6.4 months from the time of stenting, three patients died and three required repeat angioplasty, but no patient had reinfarction or required bypass surgery. At follow-up 26 (81%) of 32 patients remained free of major cardiac events; of these, 24 (92%) were free of angina. Repeat angiography performed at 10.8+/-7.5 months in 26 (87%) of 30 discharged patients showed that all infarct-related arteries were patent and the restenosis rate was low: 22% in the 13 patients with evolving AMI (<14 hours) and 12% in the 19 patients with recent AMI (days 2 through 7). CONCLUSION: In this study stenting of the infarct-related artery in patients with evolving and recent AMI was associated with a favorable late clinical outcome. Patency of the infarct-related artery was well maintained, and the restenosis rate was low.

Angioplasty, Balloon, Coronary↗
PubMed1998

An open design, multicentre, randomized trial of percutaneous transluminal coronary angioplasty versus stenting, with a heparin-coated stent, of totally occluded coronary arteries: rationale, trial design and baseline patient characteristics. Total Occlusion Study of Canada (TOSCA) Investigators.

BACKGROUND: Percutaneous transluminal coronary angioplasty (PTCA) of totally occluded coronary arteries is performed in a variety of clinical settings and for a variety of indications. Most commonly it is performed for relief of symptoms of myocardial ischemia. Studies have also suggested that PTCA of occluded arteries beyond the acute phase of myocardial infarction may improve left ventricular function even in the absence of objective evidence of ischemia. One of the major limitations of total occlusion PTCA is a high rate of reocclusion, reported to be as high as 40%. Recently, small studies have suggested that stenting may improve the long term outcome after PTCA of total coronary occlusions. OBJECTIVES: To determine in a prospective, randomized trial whether long term patency and clinical outcome following successful PTCA of a totally occluded coronary can be improved by the use of of a heparin-coated stent. PATIENTS AND METHODS: Subjects were randomly assigned to one of two strategies once the guide wire had crossed the occluded segment of the target artery: PTCA alone, or PTCA followed by insertion of Palmaz-Shatz heparin-coated stent(s). Randomization was stratified according to duration of the coronary occlusion: six weeks or less, and more than six weeks. The primary end-point is failure of sustained patency (Thrombolysis in Myocardial Infarction [TIMI] flow grade less than 3) at six months. Secondary end-points are change in minimal luminal diameter, target vessel revascularization at one year, cardiovascular events at one year, and change in global and regional left ventricular function. BASELINE CHARACTERISTICS: All 410 patients have been randomly assigned to the PTCA alone (n = 208) or PTCA plus stent (n = 202) group. Mean age was 58 +/- 11 years and 18% were female. Prior myocardial infarction had been documented in 67% of patients. The duration of occlusion was six weeks or less in 40% and more than six weeks in 60% of patients. In 64% of patients TIMI flow was grade 0 and in 36% it was grade 1. STUDY IMPLICATIONS: The trial will demonstrate whether the use of a heparin-bonded stent can improve long term patency and clinical outcome in patients undergoing clinically indicated PTCA of totally occluded coronary arteries. If a significant reduction in reocclusion and clinical events is demonstrated, the Total Occlusion Study of Canada (TOSCA) would offer a more effective long term revascularization strategy in future trials testing the open artery hypothesis.

Aged↗
PubMed1998

Coronary stenting in unstable angina: early and late clinical outcomes.

OBJECTIVE: To examine the procedural and long term success of coronary stenting in patients presenting with unstable angina and the effect of warfarin on the clinical outcome of these high risk patients. DESIGN: A nonrandomized, retrospective analysis of patients presenting with unstable angina. SETTING: A tertiary care, Canadian university-affiliated teaching hospital. PATIENTS: Of 1250 patients who underwent percutaneous transluminal coronary angioplasty between January 1994 and June 1995, 365 underwent coronary stenting. The study population consisted of the 156 patients presenting with unstable angina who underwent coronary stenting. Patients with Canadian Cardiovascular Society class IV and postinfarction angina were included. INTERVENTIONS: Stent delivery by standard techniques to the target lesion was successful in all patients. At discharge, 88 patients were prescribed warfarin, ticlopidine and acetylsalicylic acid (ASA); the remaining 68 patients received only ticlopidine and ASA. Late clinical outcomes were assessed by telephone interview. RESULTS: The overall procedural success rate was 96%. One patient died in hospital (0.6%). Other events were abrupt closure (1.9%), myocardial infarction (1.9%) and urgent bypass surgery (1.9%). During follow-up, target vessel reintervention was needed in 19.6% of patients. Early and late clinical outcomes did not differ significantly between anticoagulated patients and those treated with antiplatelet agents alone, but anticoagulated patients had a significantly longer hospital stay. CONCLUSIONS: Coronary stenting in patients with unstable angina was associated with excellent procedural success and favourable late clinical outcomes. Warfarin added no apparent additional clinical benefit to antiplatelet agents in this high risk population.

Angina, Unstable↗
PubMed1996

Fish oils and low-molecular-weight heparin for the reduction of restenosis after percutaneous transluminal coronary angioplasty. The EMPAR Study.

BACKGROUND: Percutaneous transluminal coronary angioplasty (PTCA) is complicated by restenosis within 6 months in > 40% of patients. Theoretical, animal experimental, and human epidemiological and clinical trial findings have suggested that fish oils (n-3) might reduce restenosis. Low-molecular-weight heparin (LMWH) has reduced cellular proliferation and restenosis in several experimental systems. METHODS AND RESULTS: We randomized 814 patients to fish oils (5.4 g n-3 fatty acids) or placebo a median of 6 days before PTCA and continued for 18 weeks. At the time of sheath removal, 653 patients with at least one successfully dilated lesion were randomized to LMWH (30 mg SC BID) or control for 6 weeks in a 2 x 2 factorial design. Follow-up with quantitative coronary angiography (QCA; target, 18 weeks) was interpretable on 96% of these patients. Restenosis rates per patient were for n-3, 46.5%; placebo, 44.7%; LMWH, 45.8%; and control, 45.4%. Restenosis rates per lesion were for n-3, 39.7%; placebo, 38.7%; LMWH, 38%; and control, 40.4%. At follow-up QCA, mean minimal lumen diameters were (mm) for n-3, 1.12; placebo, 1.10; LMWH, 1.12; and control, 1.10. Fifteen percent of patients permanently discontinued n-3/placebo before study completion, and 21% of patients discontinued LMWH early. There were no significant differences in the occurrences of ischemic events. Bleeding was more common with LMWH, usually was mild, and led to early discontinuation of study medication in only 0.9% of patients. Gastrointestinal side effects were more common in patients receiving n-3 than placebo. CONCLUSIONS: There is no evidence for a clinically important reduction of PTCA restenosis in this trial by either n-3 or LMWH. Evaluation of the results for n-3 in the context of previously published data on the reduction of PTCA restenosis indicates that n-3 is not efficacious and that further trials are unwarranted.

Adult↗
PubMed1996

Platelet membrane receptor glycoprotein IIb/IIIa antagonism in unstable angina. The Canadian Lamifiban Study.

BACKGROUND: Ligand binding to the platelet membrane receptor glycoprotein (GP) IIb/IIIa, the final and obligatory step to platelet aggregation, can now be inhibited by pharmacological agents. This study was designed to evaluate the potential of lamifiban, a novel nonpeptide antagonist of GP IIb/IIIa, for the management of unstable angina. METHODS AND RESULTS: In a prospective, dose-ranging, double-blind study, 365 patients with unstable angina were randomized to an infusion of 1, 2, 4, or 5 micrograms/min of lamifiban or of placebo. Treatment was administered for 72 to 120 hours. Outcome events were measured during the infusion period and after 1 month. Concomitant aspirin was administered to all patients and heparin to 28% of patients. Lamifiban, all doses combined, reduced the risk of death, nonfatal myocardial infarction, or the need for an urgent revascularization during the infusion period from 8.1% to 3.3% (P = .04). The rates were 2.5%, 4.9%, 3.3%, and 2.4% with increasing doses. At 1 month, death or nonfatal infarction occurred in 8.1% of patients with placebo and in 2.5% of patients with the two high doses (P = .03). The highest dose of lamifiban additionally prevented the need for an urgent intervention. Lamifiban dose-dependently inhibited platelet aggregation. Bleeding times were significantly prolonged with platelet inhibition of > 80%. Major (but neither life-threatening nor intracranial) bleedings occurred in 0.8% of patients with placebo and 2.9% with lamifiban. CONCLUSIONS: The nonpeptide GP IIb/IIIa antagonist lamifiban protected patients with unstable angina from severe ischemic events during a 3- to 5-day infusion and reduced the incidence of death and infarction at 1 month, suggesting considerable promise for this new therapeutic approach.

Acetates↗