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Biomedical subjects

R Plante

Publications and source records attributed to R Plante.

At least 19 recordsLinked to original sources
PubMed1998

beta-Lactam derivatives as inhibitors of human cytomegalovirus protease.

The development of novel monobactam inhibitors of HCMV protease incorporating a carbon side chain at C-4 and a urea function at N-1 is described. Substitution with small groups at the C-3 position of the beta-lactam ring gave an increase in enzymatic activity and in stability; however, a lack of selectivity against other serine proteases was noted. The use of both tri- and tetrasubstituted urea functionalities gave effective inhibitors of HCMV protease. Benzyl substitution of the urea moiety was beneficial, especially when strong electron-withdrawing groups where attached at the para position. Modest antiviral activity was found in a plaque reduction assay.

Animals↗
PubMed1998

Reproductive health and work: different experiences.

Quebec and Denmark passed legislation in 1981 that aims to protect pregnant women and their unborn children from health hazards in the workplace. Finland passed similar legislation in 1991. While these measures have much in common, they are applied in very different ways. Approximately 1% of pregnant working women benefit from a "special maternity leave" in Denmark, compared with 0.1% in Finland, while in Quebec, nearly 40% of working women benefit from preventive reassignment measures during their pregnancies. In this article, we will analyze the reasons for these disparities between rates of utilization in Finland, Denmark, and Quebec in light of the Quebec experience over the last 16 years.

Denmark↗
PubMed1998

Potent beta-lactam inhibitors of human cytomegalovirus protease.

A series of novel monobactam inhibitors of human cytomegalovirus (HCMV) protease has been described that possess a heterocyclic thiomethyl side chain at C-4. Changes to the heterocycle did not significantly change the inhibitory activity of these compounds in an enzymatic assay, although improvements in solubility and cell culture activity were noted. A number of permutations between C-4 substitutions and N-1 derivatives led to the identification of several beta-lactams with antiviral activity in a plaque reduction assay. N-methyl thiotetrazole-containing compounds were found to be the most potent inhibitors in the enzymatic assay.

Antiviral Agents↗
PubMed1997

Peptidomimetic inhibitors of the human cytomegalovirus protease.

The development of peptidomimetic inhibitors of the human cytomegalovirus (HCMV) protease showing sub-micromolar potency in an enzymatic assay is described. Selective substitution of the amino acid residues of these inhibitors led to the identification of tripeptide inhibitors showing improvements in inhibitor potency of 27-fold relative to inhibitor 39 based upon the natural tetrapeptide sequence. Small side chains at P1 were well tolerated by this enzyme, a fact consistent with previous observations. The S2 binding pocket of HCMV protease was very permissive, tolerating lipophilic and basic residues. The substitutions tried at P3 indicated that a small increase in inhibitor potency could be realized by the substitution of a tert-leucine residue for valine. Substitutions of the N-terminal capping group did not significantly affect inhibitor potency. Pentafluoroethyl ketones, alpha,alpha-difluoro-beta-keto amides, phosphonates and alpha-keto amides were all effective substitutions for the activated carbonyl component and gave inhibitors which were selective for HCMV protease. A slight increase in potency was observed by lengthening the P1' residue of the alpha-keto amide series of inhibitors. This position also tolerated a variety of groups making this a potential site for future modifications which could modulate the physicochemical properties of these molecules.

Antiviral Agents↗
PubMed1996

Peptidomimetic inhibitors of herpes simplex virus ribonucleotide reductase with improved in vivo antiviral activity.

We have been investigating the potential of a new class of antiviral compounds. These peptidomimetic derivatives prevent association of the two subunits of herpes simplex virus (HSV) ribonucleotide reductase (RR), an enzyme necessary for efficient replication of viral DNA. The compounds disclosed in this paper build on our previously published work. Structure-activity studies reveal beneficial modifications that result in improved antiviral potency in cell culture in a murine ocular model of HSV-induced keratitis. These modifications include a stereochemically defined (2,6-dimethylcyclohexyl)amino N-terminus, two ketomethylene amide bond isosteres, and a (1-ethylneopentyl)amino C-terminus. These three modifications led to the preparation of BILD 1351, our most potent antiherpetic agent containing a ureido N-terminus. Incorporation of the C-terminal modification into our inhibitor series based on a (phenylpropionyl)valine N-terminus provided BILD 1357, a significantly more potent antiviral compound than our previously published best compound, BILD 1263.

Animals↗
PubMed1996

Ureido-based peptidomimetic inhibitor of herpes simplex virus ribonucleotide reductase: an investigation of inhibitor bioactive conformation.

We have been investigating peptidomimetic inhibitors of herpes simplex virus (HSV) ribonucleotide reductase (RR). These inhibitors bind to the HSV RR large subunit and consequently prevent subunit association and subsequent enzymatic activity. This report introduces a new series of compounds that contain an extra nitrogen (a ureido function) at the inhibitor N-terminus. This nitrogen improves inhibitor binding potency 50-fold over our first published inhibitor series. Evidence supports that this improvement in potency results from a new hydrogen-bonding contact between the inhibitor and the RR large subunit. This report also provides evidence for the bioactive conformation around two important amino acid residues contained in our inhibitors. A tert-butyl group, which contributes 100-fold to inhibitor potency but does not directly bind to the large subunit, favors an extended beta-strand conformation that is prevalent in solution and in the bound state. More significantly, the bioactive conformation around a pyrrolidine-modified asparagine residue, which contributes over 30 000-fold to inhibitor potency, is elucidated through a series of conformationally restricted analogues.

Enzyme Inhibitors↗
PubMed1995

Peptidomimetic inhibitors of herpes simplex virus ribonucleotide reductase: a new class of antiviral agents.

We have been investigating a new class of antiviral compounds effective against herpes simplex virus (HSV) in vitro and in vivo. Antiviral activity results from inhibition of HSV ribonucleotide reductase (RR). The inhibitors are designed as mimics of the RR small subunit C-terminus, a region essential for RR subunit association and consequently enzymatic activity. Inhibition results from specific binding of the inhibitor to the HSV RR large subunit thereby preventing subunit association. This report details the structure--activity studies that lead to the indentification of BILD 1263, a potent inhibitor of HSV RR subunit association (IC50, 0.2 nM) that also inhibits the replication of HSV types 1 and 2 in cell culture (EC50, 3 and 4 microM) and reduces the severity of HSV-1-induced keratitis in a murine ocular model. The discovery of inhibitors with in vitro antiviral results from a combination of improving inhibitor potency in a RR binding assay and modifying inhibitor physicochemical properties. The importance and possible role of the new structural modifications introduced into this inhibitor series is discussed.

Animals↗
PubMed1995

Renal artery aneurysm: treatment with percutaneous placement of a stent-graft.

A stent-graft was placed percutaneously in the right renal artery of a 50-year-old woman with hypertension and a fibromuscular dysplastic lesion consisting of severe stenoses and a 1.5-cm saccular aneurysm with a wide neck. At 1-year follow-up with arteriography, arterial luminal diameter was normal and no aneurysm was depicted. The patient's blood pressure was normal without blood pressure medication.

Aneurysm↗
PubMed1994

A comparison study of the EF-18 agar/Hydrophobic Grid Membrane Filter (HGMF) method and the enzyme linked antibody (ELA)/HGMF method to the HPB standard method in the isolation of Salmonella.

As part of a comparative and collaborative study of rapid methods for the detection of Salmonella and the standard Health Protection Branch (HPB) method, six Federal and Provincial Laboratories compared the EF-18 agar/Hydrophobic Grid Membrane Filters (HGMF) method to the standard HPB method. Two Federal Laboratories also compared the enzyme linked antibody (ELA)/HGMF method (which is a further development of the EF-18 agar/HGMF method) to the standard method. During this study the false-negative rates ranged from 0% to 15% for the standard HPB method, from 5.88% to 43.5% for the EF-18 agar/HGMF method, and from 0% to 10.5% for the ELA/HGMF method. The EF-18 agar/HGMF method did not compare well with the standard HPB method due to the number of false-negatives. Problems with this method resulted from the inability to isolate colonies of Salmonella on the HGMF due to the small colony size, abnormal colony coloration, and overgrowth by competitors. The ELA/HGMF method, however, was shown to be comparable to the standard HPB method. The main advantages of this method are that the antibody-staining step is independent of colony coloration and carbohydrate utilization on the plating media; the ability to detect some unusual strains of Salmonella irrespective of their atypical reactions on the media; and the ELA staining can indicate the presence of Salmonella even when the HGMF is overgrown by competitors. Also, cultural confirmation can proceed simultaneously yet independently of the ELA staining procedure. The data presented here indicate that this method is worth further study.

Bacteriological Techniques↗
PubMed1994

Herpes simplex virus ribonucleotide reductase subunit association inhibitors: the effect and conformation of beta-alkylated aspartic acid derivatives.

Incorporating beta-alkylated aspartic acid derivatives into herpes simplex virus ribonucleotide reductase subunit association inhibitors can improve inhibitor potency up to 50 times over the corresponding inhibitors containing an unsubstituted aspartic acid. A combination of NMR studies, conformational analysis, and molecular mechanics calculations suggests that the beta-alkyl group improves inhibitor potency by favoring the bioactive conformation of the critical aspartic acid carboxyl group. Further support for this hypothesis is provided by a potent conformationally restricted aspartic acid derivative in which the carboxyl group is locked in the putative bioactive conformation.

Alkylation↗
PubMed1991

A comparative study of the 'FDA' and 'USDA' methods for the detection of Listeria monocytogenes in foods.

Nineteen laboratories across Canada took part in a comparative study of the 'FDA' and 'USDA' methods for the detection of Listeria monocytogenes in foods and environmental samples. The results show that the enrichment period of the FDA method can be shortened from 7 to 2 days without substantially reducing the number of positive samples. With a limited number of samples, the USDA method proved to be slightly more efficient in isolating L. monocytogenes than the FDA method. Fraser broth, in principle, proved to be useful as a screening tool but is not very selective. Oxford agar and lithium chloride-phenylethanol-moxalactam medium were better than modified McBride's agar in isolating this microorganism.

Agriculture↗
PubMed1991

Specific inhibition of ribonucleotide reductases by peptides corresponding to the C-terminal of their second subunit.

Previous studies have shown that herpes virus ribonucleotide reductase can be inhibited by a synthetic nonapeptide whose sequence is identical to the C-terminal of the small subunit of the enzyme. This peptide is able to interfere with normal subunit association that takes place through the C-terminal of the small subunit. In this report, we illustrate that inhibition of ribonucleotide reductases by peptides corresponding to the C-terminal of subunit R2 is also observed for the enzyme isolated from Escherichia coli, hamster, and human cells. The nonapeptide corresponding to the bacterial C-terminal sequence was found to inhibit E. coli enzyme with an IC50 of 400 microM, while this peptide had no effect on mammalian ribonucleotide reductase. A corresponding synthetic peptide derived from the C-terminal of the small subunit of the human enzyme inhibited both human and hamster ribonucleotide reductases with IC50 values of 160 and 120 microM, respectively. However, this peptide had no inhibitory activity against the bacterial enzyme. Equivalent peptides derived from herpes virus ribonucleotide reductase had no effect on either the bacterial or mammalian enzymes. Thus, subunit association at the C-terminal of the small subunit appears to be a common feature of ribonucleotide reductases. In addition, the inhibitory phenomenon observed with peptides corresponding to the C-terminal appears not only to be universal, but also specific to the primary sequence of the enzyme.

Acetylation↗
PubMed1991

[Oral health of 15-year-old students living in non-fluoridated public school sectors on l'Ile de Montreal in 1987].

Using data from a cross-sectional survey on 570 fifteen year old students living in non-fluoridated public school sectors on the Island of Montreal in 1987, the effect of terminating the restorative aspect of public dental health care insurance for twelve to fifteen year old students is examined. This study also highlights the level and quality of dental caries treatment on the twelve to fifteen year old group. The main point to be made is that there was an improvement in the DMFT index values of fourteen and fifteen year old students in metropolitan areas. In reality, fourteen year old children had a DMFT index of 6.45 in 1983-1984, while the fifteen year old children in the 06A region (non-fluoridated area) had a DMFT of 6.07 in 1987. Since the metropolitan fluoridated area had been eliminated from the results in 1987, it is quite obvious that the 6.07 result obtained overestimates the actual prevalence of dental caries in the metropolitan area in 1987. On the other hand, the progress which had been recorded between 1977 and 1984 by francophones in relation to anglophones was partially lost in 1987. Furthermore, this study has demonstrated that the prevalence and level of dental caries treatment are highly associated with the language spoken at home and also with the family's socio-economic status.

Adolescent↗
PubMed1989

[The prevalence of malocclusion problems and orthodontic treatment needs in 13 and 14-year old Quebec school children in 1983-1984].

This article details the problems related to occlusion of 13-14 year old Quebec students. The data was derived from a province wide probability sample of 1201 children in 1983-84 using Granger's Orthodontic Treatment Priority Index (TPI). The principal conclusion are: 32% of the children are in Angle's class II; 18% have an overjet of 5 mm and over; 50% have one or more teeth in minor or major displacement; treatment is mandatory or highly desirable for 13.7% and only 2.9% of the students are under treatment. The results are compared to 6 surveys of the same nature.

Adolescent↗
PubMed1988

Blood lead and maximal urinary excretion of delta-aminolevulinic acid.

Reliability and ease of use are certainly the two major qualities of a screening test or medical surveillance in the workplace. The advantages of using a reliable urinary test thus are evident: the sampling is easy, rapid, noninvasive and, therefore, well accepted. Screening tests or medical surveillance can measure the toxic chemical itself, its metabolites or its consequences on metabolism. In this study the relation between blood lead levels--the most commonly used test for screening and surveillance of saturnism--and urinary excretion of delta-aminolevulinic acid (ALA-U) was measured. The original part of this study is that it takes into account the chronobiology of ALA-U excretion. The samples are collected in the afternoon when ALA urinary excretion is at its highest level. Using a 5 mg/g of creatinine level as a threshold to detect blood lead levels equal to or higher than 60 micrograms/dL the test has an 88% sensitivity, a 91% specificity and a 37% positive predictive value. No worker whose blood lead level is equal to or higher than 65 micrograms/dL has been missed. It is suggested that using 5 mg of ALA-U/g of creatinine as a threshold to prescreen workers who should have their blood lead level measured could be useful in workplaces where lead exposure is moderate or low.

Adult↗