19 results on '"Rhéaume M"'
Search Results
2. Diagnostic et prise en charge des vascularites primitives du système nerveux central : évaluation des pratiques par un sondage international
- Author
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Nehme, A., primary, Lanthier, S., additional, Boulanger, M., additional, Aouba, A., additional, Cacoub, P., additional, Jayne, D., additional, Makhzoum, J.P., additional, Pagnoux, C., additional, Rhéaume, M., additional, Samson, M., additional, Terrier, B., additional, Touzé, E., additional, and De Boysson, H., additional
- Published
- 2022
- Full Text
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3. Short-term exposure of umbilical cord blood CD34+ cells to human platelet lysate and cytokines enhances engraftment
- Author
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Rhéaume, M., primary, Tremblay, T., additional, Paré, I., additional, Rouleau, P., additional, and Loubaki, L., additional
- Published
- 2021
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4. LO63: Evaluation of epinephrine secondary effects in a Canadian emergency department anaphylaxis adult cohort
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Gabrielli, S., primary, Ben-Shoshan, M., additional, Lachance, A., additional, Rhéaume, M., additional, Londei-Leduc, L., additional, Goldman, R., additional, Chan, E., additional, Upton, J., additional, Hochstadter, E., additional, Bretholz, A., additional, O'Keefe, A., additional, Chu, D., additional, and Morris, J., additional
- Published
- 2020
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5. Pars plana vitrectomy through the Boston Keratoprosthesis type 1
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Harissi-Dagher, M, primary, Durr, G M, additional, Biernacki, K, additional, Sebag, M, additional, and Rhéaume, M-A, additional
- Published
- 2013
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6. Diagnosis and management of adult primary angiitis of the central nervous system: an international survey on current practices.
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Nehme A, Lanthier S, Boulanger M, Aouba A, Cacoub P, Jayne D, Makhzoum JP, Pagnoux C, Rhéaume M, Terrier B, Touzé E, and de Boysson H
- Subjects
- Humans, Adult, Immunosuppressive Agents therapeutic use, Cyclophosphamide, Glucocorticoids, Vasculitis, Central Nervous System diagnosis, Vasculitis, Central Nervous System drug therapy
- Abstract
Background: Primary angiitis of the central nervous system (PACNS) is a rare disease, for which no validated guidelines exist. We report the findings of a survey on the clinical practice of physicians who manage adults with PACNS., Methods: An online survey was distributed through neurology, internal medicine, and rheumatology societies in Canada and Europe. Participants who were directly involved as treating physicians for at least two adult patients with PACNS were eligible for the survey., Results: Ninety-six physicians completed the survey. Most participants were neurologists (n = 38, 40%), internists (n = 34, 35%) or rheumatologists (n = 22, 23%). Participants obtained a CNS biopsy in a median of 25% (IQR: 5-50%) of suspected PACNS cases. When determining the degree to which eight scenarios justified a CNS biopsy, participants achieved fair inter-rater agreement (Gwet's AC
2 0.30, 95% CI 0.23-0.41). For induction therapy, 81 (84%) participants reported using glucocorticoids and cyclophosphamide in > 50% of patients. After obtaining remission, 85 (89%) participants systematically introduced or maintained immunosuppressive therapy. Glucocorticoids were prescribed for a median of 12 months. Maintenance therapy with another immunosuppressant was continued for a median of 24 months. In patients who achieved remission, we explored how eight scenarios with different imaging and CSF results supported an increase in treatment. Inter-rater agreement was substantial if the patient was symptomatic (0.66, 95% CI 0.58-0.80) and moderate (0.50, 95% CI 0.45-0.60) if asymptomatic., Conclusion: This survey illustrates current real-world management of PACNS and emphasizes several areas for which physicians still lack study-based evidence and/or clinical practice guidelines., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)- Published
- 2023
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7. Colour Doppler ultrasound and the giant cell arteritis probability score for the diagnosis of giant cell arteritis: a Canadian single-centre experience.
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Zarka F, Rhéaume M, Belhocine M, Goulet M, Febrer G, Mansour AM, Troyanov Y, Starnino T, Meunier RS, Chagnon I, Routhier N, Bénard V, Ducharme-Bénard S, Ross C, and Makhzoum JP
- Abstract
Objectives: The aim was to compare the accuracy of colour Doppler ultrasonography (CDUS) and temporal artery biopsy (TAB) to establish the final diagnosis of GCA and to determine how the GCA probability score (GCAPS) performs as a risk stratification tool., Methods: Descriptive statistics were performed on a retrospective cohort of patients referred to our vasculitis referral centre between 1 July 2017 and 1 October 2020 for suspected GCA. CDUS, TAB, centre-specific TAB (vasculitis centre vs referring hospitals) and GCAPS were compared against the final diagnosis of GCA as determined by a GCA expert; CDUS was also compared with TAB results., Results: Data from 198 patients were included: 60 patients with GCA and 138 patients without GCA. Sixty-two patients had a TAB. Using the final diagnosis by a GCA expert as a reference, the sensitivity, specificity, positive predictive value and negative predictive value were 93.3%, 98.5%, 96.6% and 97.1% for CDUS and 69.2%, 100%, 100% and 81.8% for TAB, respectively. The false-negative rate was 6.7% for CDUS and 30.8% for TAB. False-negative TAB mostly occurred when performed in referring hospitals (57.1%) as opposed to our vasculitis centre (21.1%). With a cut-off at 9.5 points, sensitivity for GCAPS was 98.3% and specificity 74.3%., Conclusion: CDUS of the temporal and axillary arteries showed a high sensitivity and specificity and helped to diagnose GCA in patients with negative TAB. We validated that GCAPS is a useful clinical tool, with a score of <9.5 making the diagnosis of GCA improbable., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)
- Published
- 2021
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8. Verrucous plane xanthomas secondary to lipoprotein X dyslipidemia in the context of cholestatic fulminant hepatitis: A case report.
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Dang J, Lim D, Watters K, Simard O, Doyon K, Rhéaume M, and Mereniuk A
- Abstract
Cutaneous xanthomas are the result of dermal deposition of lipid, mostly caused by disorders of lipid metabolism. Less commonly, they occur in the setting of cholestatic liver disease, leading to accumulation of lipoprotein X, a rare form of dyslipidemia that does not respond well to conventional treatments. We describe an atypical presentation of sudden diffuse xanthomas secondary to lipoprotein X dyslipidemia in the context of cholestatic fulminant hepatitis caused by trimethoprim-sulfamethoxazole hypersensitivity. Histopathology was also atypical and showed an unusual verrucous appearance consisting of overlying epidermal hyperplasia with hyperkeratosis. Our patient had significant improvement, after normalization of her lipid panel under cholestyramine and 13 sessions of apheresis, with topical corticosteroids offering some relief. This rare case shows the importance of recognizing atypical presentations of xanthomas, particularly when they do not respond to conventional dyslipidemia treatments., Competing Interests: Author Note: Darosa Lim is now affiliated to Division of Dermatology, Department of Medicine, Hôpital du Sacré-Cœur de Montréal, Montreal, QC, Canada. Alexandra Mereniuk is now affiliated to Division of Dermatology, Department of Medicine, Université de Montréal, Montreal, QC, Canada. Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)
- Published
- 2021
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9. Characterization of visual manifestations and identification of risk factors for permanent vision loss in patients with giant cell arteritis.
- Author
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Baalbaki H, Jalaledin D, Lachance C, Febrer G, Rhéaume M, and Makhzoum JP
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- Blindness epidemiology, Blindness etiology, Humans, Retrospective Studies, Risk Factors, Vision Disorders epidemiology, Vision Disorders etiology, Giant Cell Arteritis complications, Giant Cell Arteritis epidemiology
- Abstract
Background/purpose: Permanent vision loss (PVL) is a feared complication and a leading cause of morbidity in giant cell arteritis (GCA). The objective of this study is to describe visual manifestations and identify risk factors of ocular involvement in GCA., Methods: A retrospective database from a single vasculitis referral center was used. Descriptive statistics comparing patients with and without ocular involvement were performed., Results: One hundred patients with GCA were included. Visual symptoms were present in 53% of patients at diagnosis and included blurred vision (30%), diplopia (16%), amaurosis fugax (14%), and blindness (19%). Out of 19 patients with blindness, 16 did not recover and had PVL. Patients with PVL were older (79.2 ± 6.7 vs 74.2 ± 7.6 years; p = 0.008) and more likely to have coronary artery disease (31% vs 10%; p = 0.018). However, they were less likely to have other cranial symptoms (81% vs 96%; p = 0.019), mainly headaches (64% vs 92%; p = 0.003). Risk factors associated with an abnormal ophthalmologic examination were the same as for PVL, but patients were also more likely to have diabetes (29% vs 7%; p = 0.040) and less likely to have constitutional symptoms (53% vs 80%; p = 0.033)., Conclusion: Patients with GCA and ocular involvement were more likely to have baseline diabetes and atherosclerosis. A predisposing vascular vulnerability might therefore increase the risk of ocular involvement. Key points • Most patients with GCA and complete vision loss at presentation will not recover and evolve to have permanent vision loss. • A GCA patient with visual manifestations at presentation has more baseline vascular risk factors (diabetes, atherosclerosis) than patients without ocular involvement. • Patients with GCA and visual manifestations have fewer constitutional symptoms and lower inflammatory markers than patients without ocular involvement., (© 2021. International League of Associations for Rheumatology (ILAR).)
- Published
- 2021
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10. CanVasc Consensus Recommendations for the Management of Antineutrophil Cytoplasm Antibody-associated Vasculitis: 2020 Update.
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Mendel A, Ennis D, Go E, Bakowsky V, Baldwin C, Benseler SM, Cabral DA, Carette S, Clements-Baker M, Clifford AH, Cohen Tervaert JW, Cox G, Dehghan N, Dipchand C, Dhindsa N, Famorca L, Fifi-Mah A, Garner S, Girard LP, Lessard C, Liang P, Noone D, Makhzoum JP, Milman N, Pineau CA, Reich HN, Rhéaume M, Robinson DB, Rumsey DG, Towheed TE, Trudeau J, Twilt M, Yacyshyn E, Yeung RSM, Barra LB, Khalidi N, and Pagnoux C
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- Antibodies, Antineutrophil Cytoplasmic, Canada, Consensus, Cytoplasm, Humans, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis drug therapy
- Abstract
Objective: In 2015, the Canadian Vasculitis Research Network (CanVasc) created recommendations for the management of antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) in Canada. The current update aims to revise existing recommendations and create additional recommendations, as needed, based on a review of new available evidence., Methods: A needs assessment survey of CanVasc members informed questions for an updated systematic literature review (publications spanning May 2014 to September 2019) using Medline, Embase, and Cochrane. New and revised recommendations were developed and categorized according to the level of evidence and strength of each recommendation. The CanVasc working group used a 2-step modified Delphi procedure to reach > 80% consensus on the inclusion, wording, and grading of each new and revised recommendation., Results: Eleven new and 16 revised recommendations were created and 12 original (2015) recommendations were retained. New and revised recommendations are discussed in detail within this document. Five original recommendations were removed, of which 4 were incorporated into the explanatory text. The supplementary material for practical use was revised to reflect the updated recommendations., Conclusion: The 2020 updated recommendations provide rheumatologists, nephrologists, and other specialists caring for patients with AAV in Canada with new management guidance, based on current evidence and consensus from Canadian experts., (Copyright © 2021 by the Journal of Rheumatology.)
- Published
- 2021
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11. Estimating the Change in Renal Function During the First Year of Therapy in ANCA-Associated Vasculitis.
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Lepeytre F, Royal V, Lavoie PL, Bollée G, Gougeon F, Beauchemin S, Rhéaume M, Brachemi S, Laurin LP, and Troyanov S
- Abstract
Introduction: Studies in antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) consistently show that the months following diagnosis have the greatest impact on the long-term renal function. Yet, it remains uncertain how much early gain should be expected with treatment. We sought to determine the factors associated with the change in glomerular filtration rate (GFR) throughout the first year., Methods: We retrospectively reviewed patients from 3 university hospitals who received treatments. We assessed the proportions of glomeruli with crescents, with global sclerosis, the AAV glomerulonephritis classification, the severity of chronic vascular and tubulo-interstitial disease, and the presence of acute tubular injury (ATI). We used repeated-measures analyses of variance (ANOVAs) to determine factors associated with the change in GFR throughout the first year., Results: There were 162 individuals with AAV identified, 96 with a valid renal biopsy and 82 with at least 12 months of follow-up. The initial GFR of 30 ± 25 ml/min per 1.73 m
2 rose by 15 ± 20 during the first year. The severity of pathology findings, myeloperoxidase positivity, and those with kidney- and lung-limited disease presented with a lower GFR. Younger patients with a lower initial GFR and the presence of ATI correlated with a greater increase in GFR by 12 months. A higher proportion of crescents did not predict the change in GFR, contrary to global glomerulosclerosis, where each 10% increase added a loss of 2.7 ± 1.3 ml/min per 1.73 m2 per year ( P = 0.03). These factors remained independent of each other., Conclusion: Multiple factors influence renal recovery during the first year of therapy. Estimating the change in GFR early on will help identify and reassess outliers.- Published
- 2019
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12. A Simplified Approach to Extravascular Lung Water Assessment Using Point-of-Care Ultrasound in Patients with End-Stage Chronic Renal Failure Undergoing Hemodialysis.
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Beaubien-Souligny W, Rhéaume M, Blondin MC, El-Barnachawy S, Fortier A, Éthier J, Legault L, and Denault AY
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- Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Ultrasonography, Kidney Failure, Chronic diagnostic imaging, Kidney Failure, Chronic metabolism, Kidney Failure, Chronic therapy, Lung diagnostic imaging, Lung metabolism, Point-of-Care Systems, Renal Dialysis, Water metabolism
- Abstract
Background: Fluid overload leading to pulmonary congestion is an important issue in patients undergoing hemodialysis. This study aimed to determine if a simplified method of extravascular lung water assessment using ultrasound provided clinically relevant information., Methods: This prospective study recruited 47 patients from a single hemodialysis center. Pulmonary ultrasound was performed before and after 2 hemodialysis sessions in 28 regions on the thorax. The B-line score was defined as the percentage regions where B-lines were present., Results: When B-lines were detected before hemodialysis, a significant relationship was found between fluid removal and the change in B-line score. Patients with a B-line score of ≥21.4% (4th quartile) after the second hemodialysis session were more likely to be hospitalized for pulmonary edema or acute coronary syndrome., Conclusions: A simplified pulmonary assessment using ultrasound provides relevant information about pulmonary congestion in hemodialysis patients and identifies patients at risk of hospitalization for heart-related problems., (© 2017 S. Karger AG, Basel.)
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- 2018
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13. Reply.
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Rhéaume M, Pagnoux C, and Khalidi NA
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- Arteries, Humans, Magnetic Resonance Imaging, Scalp, Giant Cell Arteritis, Temporal Arteries
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- 2017
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14. High-Resolution Magnetic Resonance Imaging of Scalp Arteries for the Diagnosis of Giant Cell Arteritis: Results of a Prospective Cohort Study.
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Rhéaume M, Rebello R, Pagnoux C, Carette S, Clements-Baker M, Cohen-Hallaleh V, Doucette-Preville D, Stanley Jackson B, Salama Sargious Salama S, Ioannidis G, and Khalidi NA
- Subjects
- Aged, Biopsy, Cohort Studies, Female, Humans, Male, Prospective Studies, Arteries diagnostic imaging, Giant Cell Arteritis diagnostic imaging, Giant Cell Arteritis pathology, Magnetic Resonance Imaging methods, Scalp blood supply
- Abstract
Objective: To examine the concordance between high-resolution magnetic resonance imaging (MRI) of the scalp arteries and temporal artery biopsy for the diagnosis of giant cell arteritis (GCA)., Methods: We conducted a prospective cohort study of patients with suspected GCA. Participants underwent high-field 3T MRI of the scalp arteries followed by temporal artery biopsy. Arterial wall thickness and enhancement on multiplanar postcontrast T1-weighted spin-echo images were graded according to a published severity scale (range 0-3). MRI findings were compared with temporal artery biopsy results and the American College of Rheumatology (ACR) criteria for GCA., Results: One hundred seventy-one patients were included in the study. Temporal artery biopsy findings were positive in 31 patients (18.1%), and MRI findings were abnormal in 60 patients (35.1%). ACR criteria were met in 137 patients (80.1%). With temporal artery biopsy as the reference test, MRI had a sensitivity of 93.6% (95% confidence interval [95% CI] 78.6-99.2) and a specificity of 77.9% (95% CI 70.1-84.4). The corresponding negative predictive value of MRI was 98.2% (95% CI 93.6-99.8) and positive predictive value was 48.3% (95% CI 35.2-61.6)., Conclusion: In patients with suspected GCA, normal findings on scalp artery MRI are very strongly associated with negative temporal artery biopsy findings. This suggests that MRI could be used as the initial diagnostic procedure in GCA, with temporal artery biopsy being reserved for patients with abnormal MRI findings., (© 2016, American College of Rheumatology.)
- Published
- 2017
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15. Pregnancy-Related Venous Thromboembolism Risk in Asymptomatic Women With Antithrombin Deficiency: A Systematic Review.
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Rhéaume M, Weber F, Durand M, and Mahone M
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- Adult, Case-Control Studies, Female, Humans, Odds Ratio, Pregnancy, Pregnancy Complications, Cardiovascular prevention & control, Retrospective Studies, Risk Factors, Venous Thromboembolism prevention & control, Antithrombin III Deficiency complications, Asymptomatic Diseases, Pregnancy Complications, Cardiovascular etiology, Venous Thromboembolism etiology
- Abstract
Objective: To evaluate the risk of pregnancy-associated venous thromboembolism in women with asymptomatic antithrombin deficiency., Data Sources: The search was performed on MEDLINE (Ovid and PubMed databases) for the period 1966 to June 2012 and ClinicalTrials.gov as of December 15, 2015., Methods of Study Selection: A systematic review including randomized controlled trials, cohort studies, and case-control studies was conducted. Selection criteria included objectively diagnosed venous thromboembolism or venous thromboembolism treated with 3 months of anticoagulation before the availability of objective testing. The study population consisted of pregnant women with asymptomatic antithrombin deficiency., Tabulation, Integration, and Results: Seven publications were included in the review. No randomized controlled trials were identified. The best available data consist of three retrospective cohort studies and four case-control studies. Pooled results from case-control studies yielded an estimated odds ratio for venous thromboembolism of 6.09 (95% confidence interval 1.58-23.43). No pooled estimates could be obtained for cohort studies. Data on use of thromboprophylaxis were scarce., Conclusion: Despite the small number of patients included, and the variation in study designs, pooled results from case-control studies show a significant association between asymptomatic antithrombin deficiency and pregnancy-associated venous thromboembolism. Thromboprophylaxis during pregnancy and postpartum should be considered in these women.
- Published
- 2016
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16. The liver partition coefficient-corrected inhibitory quotient and the pharmacokinetic-pharmacodynamic relationship of directly acting anti-hepatitis C virus agents in humans.
- Author
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Duan J, Bolger G, Garneau M, Amad M, Batonga J, Montpetit H, Otis F, Jutras M, Lapeyre N, Rhéaume M, Kukolj G, White PW, Bethell RC, and Cordingley MG
- Subjects
- Animals, Cells, Cultured, Digoxin pharmacokinetics, Doxorubicin pharmacokinetics, Hepatocytes virology, Humans, Imipramine pharmacokinetics, Male, Mice, Quinidine pharmacokinetics, Rats, Rats, Sprague-Dawley, Verapamil pharmacokinetics, Antiviral Agents pharmacokinetics, Hepacivirus drug effects, Liver metabolism
- Abstract
Pharmacokinetic-pharmacodynamic (PK-PD) data analyses from early hepatitis C virus (HCV) clinical trials failed to show a good correlation between the plasma inhibitory quotient (IQ) and antiviral activity of different classes of directly acting antiviral agents (DAAs). The present study explored whether use of the liver partition coefficient-corrected IQ (LCIQ) could improve the PK-PD relationship. Animal liver partition coefficients (Kp(liver)) were calculated from liver to plasma exposure ratios. In vitro hepatocyte partition coefficients (Kp(hep)) were determined by the ratio of cellular to medium drug concentrations. Human Kp(liver) was predicted using an in vitro-in vivo proportionality method: the species-averaged animal Kp(liver) multiplied by the ratio of human Kp(hep) over those in animals. LCIQ was calculated using the IQ multiplied by the predicted human Kp(liver). Our results demonstrated that the in vitro-in vivo proportionality approach provided the best human Kp(liver) prediction, with prediction errors of <45% for all 5 benchmark drugs evaluated (doxorubicin, verapamil, digoxin, quinidine, and imipramine). Plasma IQ values correlated poorly (r(2) of 0.48) with maximum viral load reduction and led to a corresponding 50% effective dose (ED(50)) IQ of 42, with a 95% confidence interval (CI) of 0.1 to 148534. In contrast, the LCIQ-maximum VLR relationship fit into a typical sigmoidal curve with an r(2) value of 0.95 and an ED(50) LCIQ of 121, with a 95% CI of 83 to 177. The present study provides a novel human Kp(liver) prediction model, and the LCIQ correlated well with the viral load reductions observed in short-term HCV monotherapy of different DAAs and provides a valuable tool to guide HCV drug discovery.
- Published
- 2012
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17. Cross-species absorption, metabolism, distribution and pharmacokinetics of BI 201335, a potent HCV genotype 1 NS3/4A protease inhibitor.
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Duan J, Yong CL, Garneau M, Amad M, Bolger G, De Marte J, Montpetit H, Otis F, Jutras M, Rhéaume M, White PW, Llinàs-Brunet M, Bethell RC, and Cordingley MG
- Subjects
- Absorption, Aminoisobutyric Acids, Animals, Biological Availability, Caco-2 Cells, Dogs, Drug Evaluation, Preclinical, Hepacivirus enzymology, Humans, Leucine analogs & derivatives, Macaca mulatta, Male, Microsomes, Liver, Oligopeptides chemistry, Proline analogs & derivatives, Quinolines, Rats, Rats, Sprague-Dawley, Thiazoles chemistry, Tissue Distribution, Antiviral Agents pharmacokinetics, Oligopeptides pharmacokinetics, Protease Inhibitors pharmacokinetics, Thiazoles pharmacokinetics, Viral Nonstructural Proteins antagonists & inhibitors
- Abstract
The present study describes the cross-species absorption, metabolism, distribution and pharmacokinetics of BI 201335, a potent HCV protease inhibitor currently in phase III clinical trials. BI 201335 showed a good Caco-II permeability (8.7 × 10(-6) cm/sec) and in vitro metabolic stability (predicted hepatic clearence (CL(hep)) <19% Q(h) in all species tested). Single dose PK revealed a clearance of 17, 3.0 and 2.6 mL/min/kg in rat, monkey and dog respectively, with a corresponding oral bioavailability of 29.1, 25.5 and 35.6%. Comparative plasma and liver PK profile in rodents showed a high liver Kp in the rat (42-fold), suggesting high target tissue distribution. Simple allometry based on animal PK predicted a human oral CL/F of 168 mL/min, within two-fold of the observed value (118 mL/min) at 240 mg in healthy volunteers. Allometry of volume of distribution generated a low exponent of 0.59, and a much lower predicted Vss/F (5-fold less than observed). Several different approaches of Vss/F prediction were evaluated and compared with the value observed in human. The averaged Vss/F from preclinical animals provides the best estimation of the observed human value (169 L vs. 175 L). Corresponding human "effective" t(1/2) values were also compared. The predicted human t(1/2) based on the CL from allometry with metabolic corrections and the averaged animal Vss represented the best estimation of the clinical data (12.1 vs. 17.2 hr). The present study demonstrated that the good preclinical ADMEPK profile of BI 201335 is consistent with that observed in the clinic. While preclinical data accurately predicted the human CL, the prediction of human Vss seems to be more challenging. The averaged Vss/F from all tested preclinical animals provided the best prediction of human Vss and the resulting "effective" t(1/2).
- Published
- 2012
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18. Structure-activity study on a novel series of macrocyclic inhibitors of the hepatitis C virus NS3 protease leading to the discovery of BILN 2061.
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Llinàs-Brunet M, Bailey MD, Bolger G, Brochu C, Faucher AM, Ferland JM, Garneau M, Ghiro E, Gorys V, Grand-Maître C, Halmos T, Lapeyre-Paquette N, Liard F, Poirier M, Rhéaume M, Tsantrizos YS, and Lamarre D
- Subjects
- Administration, Oral, Animals, Antiviral Agents chemistry, Antiviral Agents pharmacology, Biological Availability, Carbamates chemistry, Carbamates pharmacology, Heterocyclic Compounds chemistry, Heterocyclic Compounds pharmacology, Injections, Intravenous, Proline chemistry, Protease Inhibitors chemistry, Protease Inhibitors pharmacology, Rats, Structure-Activity Relationship, Antiviral Agents chemical synthesis, Carbamates chemical synthesis, Hepacivirus enzymology, Heterocyclic Compounds chemical synthesis, Protease Inhibitors chemical synthesis, Viral Nonstructural Proteins antagonists & inhibitors
- Abstract
From the discovery of competitive hexapeptide inhibitors, potent and selective HCV NS3 protease macrocyclic inhibitors have been identified. Structure-activity relationship studies were performed focusing on optimizing the N-terminal carbamate and the aromatic substituent on the (4R)-hydroxyproline moiety. Inhibitors meeting the potency criteria in the cell-based assay and with improved oral bioavailability in rats were identified. BILN 2061 was selected as the best compound, the first NS3 protease inhibitor reported with antiviral activity in man.
- Published
- 2004
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19. Acute murine cytomegalovirus infection: a model for determining antiviral activity against CMV induced hepatitis.
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Bolger G, Lapeyre N, Rhéaume M, Kibler P, Bousquet C, Garneau M, and Cordingley M
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- Alanine Transaminase blood, Alanine Transaminase metabolism, Animals, Aspartate Aminotransferases blood, Aspartate Aminotransferases metabolism, Body Weight, Cidofovir, Cytomegalovirus Infections pathology, Cytomegalovirus Infections virology, Cytosine therapeutic use, Female, Hepatitis, Viral, Animal pathology, Hepatitis, Viral, Animal virology, Herpesviridae Infections drug therapy, Herpesviridae Infections pathology, Herpesviridae Infections virology, Liver virology, Mice, Mice, Inbred BALB C, Muromegalovirus drug effects, Virus Replication drug effects, Antiviral Agents therapeutic use, Cytomegalovirus Infections drug therapy, Cytosine analogs & derivatives, Disease Models, Animal, Ganciclovir therapeutic use, Hepatitis, Viral, Animal drug therapy, Muromegalovirus physiology, Organophosphonates, Organophosphorus Compounds therapeutic use
- Abstract
Acute intraperitoneal infection of weanling BALB/c mice with murine cytomegalovirus (MCMV) resulted in an inoculum titer-dependent weight loss, mortality and elevation of plasma transaminases (ALT: alanine transaminase and AST: aspartate transaminase). Three days post infection (p.i.) with 10(4.85) plaque forming units (pfu) there was 90% mortality with a mean death day p.i. of 4.1 +/- 0.2. Plasma levels of ALT and AST were elevated 24- and 15-fold, respectively. Organ titers of virus (log10 pfu/g tissue) were 6.16 in the liver, 6.05 in the spleen, 4.0-4.7 in the lung, heart, kidney and intestine and undetectable in the muscle and brain. Organ concentrations (units/g wet-weight) of ALT were highest in the liver, whilst for AST the highest levels were found in the heart. The concentrations of ALT but not AST were reduced (35-55%) in the infected liver; the concentrations of ALT and AST were not changed in other infected organs. There were excellent correlations (r > 0.95) between viral titers in the liver, increases of plasma ALT and depletion of liver ALT. HPMPC and ganciclovir administered either p.o. or s.c. reduced mortality, increases in plasma transaminases and viral burdens in the liver and prevented depletion of liver ALT. HPMPC was approximately 10-fold more potent than ganciclovir. These results strongly suggest that intraperitoneal infection of the BALB/c mouse with MCMV represents an animal model of CMV hepatitis that can be monitored by measuring plasma ALT.
- Published
- 1999
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