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Commentary Potential Enhancement by 3-deazauridine of the Antiviral Activity of Molnupiravir in Patients with COVID-19

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Advances in Infectious Diseases 2023年第2期13卷 210-215页

作者： Richard L. Momparler Département de pharmacologie-Physiologie Université de Montréal and Service de Hématologie/Oncologie Centre de Recherche CHU Sainte-Justine Montréal Québec Canada

Background: Molnupiravir, N4-hydroxycytidine-5’-isopropyl ester, is an oral prodrug of N4-deoxycytidine (NHC), a nucleoside analog, which has in vitro activity against SARS-CoV-2. NHC is phosphorylated in cells to NHC triphosphate (NHC-TP), which is incorporated into viral RNA, leading to epigenetic catastrophe of the viral genome and inhibition of viral replication. The antiviral activity against SARS-CoV-2 is dependent on the number of molecules of NHC-TP incorporated into viral RNA. Clinical studies in patients with COVID-19 showed that treatment with molnupiravir for 5 days decreases the risk of hospitalization and death as compared with placebo. Objective: It should be possible to enhance the antiviral activity of NHC-TP against SARS-CoV-2 by the use of the biochemical modulator, 3-deazauridine (3DU). 3DU is an inhibitor of CTP synthetase. Inhibition of this enzyme results in a reduction in the intracellular pool size of CTP. Since NHC-TP competes with CTP for incorporation into viral RNA in the reaction catalyzed by the SARS-CoV-2 viral RNA-dependent RNA polymerase, the reduction in the level of CTP should result in a significant enhancement of the incorporation of NHC-TP into viral RNA and an enhancement of its antiviral activity. Methods: Analysis of the publications of 3DU and cytosine nucleoside analogues support the hypothesis that 3DU enhances the pharmacological action of the analogues. Results: 3-DU increased the incorporation of 5-azacytidine into RNA and 5-aza-deoxycytidine into DNA of leukemic cells with an enhancement of their antineoplastic action. 3-DU potentiated the antiviral activity against HIV-1 activity by the cytosine nucleoside analogues: 2’-deoxy-3’-thiacytidine (3TC;lamivudine) and 2’,3’-dideoxycytidine (ddC). This anti-HIV-1 activity of 3DU was associated with a reduction in the intracellular pool size of dCTP and increased incorporation of triphosphates of 3TC and ddC into DNA by the HIV-1 reverse transcriptase. The reduction of CTP l

关键词： Molnupiravir N4-Hydroxycytidine-5’-Triphosphate 3-deazauridine COVID-16 Antiviral Therapy

delayed and short course of rapamycin prevents organ rejection after allogeneic liver transplantation in rats

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World Journal of Gastroenterology 2017年第38期23卷 6962-6972页

作者： Salim Hamdani Allan Thiolat Sina Naserian Cynthia Grondin Stéphane Moutereau Anne Hulin Julien Calderaro Philippe Grimbert JoséLaurent Cohen Daniel Azoulay Caroline Pilon Université Paris-Est AP-HP Laboratoire de Biochimie Groupe Hospitalier Henri-Mondor Albert-Chenevier AP-HP Laboratoire de Pharmacologie-Toxicologie Biologiques Groupe Hospitalier Henri-Mondor Albert-Chenevier AP-HP Anatomie et Cytologie Pathologique Groupe Hospitalier Henri-Mondor Albert-Chenevier APHP Service de Chirurgie HPB et Trans-plantation Hépatique Groupe Hospitalier Henri-Mondor Albert-Chenevier department of Hepato-Pancreato-Biliary Surgery and Liver Transplantation Henri Mondor Hospital

AIMTo test whether a delayed and short course of rapamycin would induce immunosuppressive effects following allogeneic orthotopic liver transplantation (OLT) in *** OLTs were performed using Dark Agouti livers transplanted into Lewis recipients, and syngeneic OLTs were performed using the Lewis rat strain. Rapamycin (1 mg/kg per day) was administered by gavage from day 4 to day 11 post-transplantation. Lymphocyte cellular compartments were analyzed by flow cytometry in draining lymph nodes, non-draining lymph nodes and the spleen at days 11 and 42 in rapamycin-treated rats, untreated control rats and syngeneic grafted rats. Skin grafts from Dark agouti or from F344 RT were performed at day 30 on liver grafted rats treated with *** 8-d course of rapamycin treatment initiated 4 d following transplantation resulted in the survival of grafted rats for more than 100 d. In contrast, untreated rats died of liver failure within 13 to 21 d. The analysis of the cellular compartment revealed an increase in two cellular subpopulations, specifically myeloid-derived suppressor cells (MDSCs) and CD8+CD45RClow T cells, without major modifications in the regulatory T cell (Treg) compartment in treated rats in the early stages after grafting. We evaluated the ability of treated rats to reject third-party allogeneic skin grafts to confirm their immune competence. In contrast, when skin was collected from rats syngeneic to the grafted liver, it was not *** results demonstrate that short and delayed rapamycin treatment allows for tolerance in allogeneic OLT. The results also allowed for the identification of the mechanisms of tolerance induced by rapamycin by identifying MDSCs and CD8+CD45RClow T cells as associated with the state of tolerance.

关键词： Myeloid-derived suppressor cells Liver transplantation Rapamycin Regulatory T cells

Hypofractionated Radiation Therapy for the Treatment of Breast Cancer: Experience of National Institute of Oncology, Rabat, Morocco

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Journal of Cancer Therapy 2016年第10期7卷 773-783页

作者： A. S. Koné A. Diakité S. Ahid I. M. Diarra K. Diabaté R. Abouqal Y. Cherrah N. Benjaafar service de Radiothérapie Institut National d’Oncologie de Rabat Rabat Morocco Laboratoire de pharmacologie & Toxicologie Faculté de Médecine et de pharmacie de Rabat Rabat Morocco Laboratoire de Biostatistique de Recherche Clinique et d’Epidémiologie Faculté de Médecine et de pharmacie de Rabat Rabat Morocco

Hypofractionated radiation therapy has proven effective on locoregional control and tolerance in the adjuvant treatment of breast cancer. The aim of this study is to compare the results of hypofractionated radiation therapy versus conventional radiation therapy in terms of local control and tolerance. It was a retrospective study of patients observations collected from January 2007 to december 2008 in department of Radiation Therapy in Institut National d’Oncologie de Rabat. The treatment results were evaluated by the rate of locoregional recurrence, distant recurrence and research of late toxicities. Radiotherapy was delivered using the same technique in both groups, by gamma photons of cobalt 60 with an energy of 1.25 MeV. They were 2 groups: the first group treated with standard dose rate and the second group treated by hypofractionated radiation therapy. The mean age of the patients was 42.8 ± 6.9 years old in the standard group and 43.22 ± 7.2 years old in the hypofractionation group. We noted a predominance of infiltrating ductal carcinoma. The majority of patients were pT2, pN0 and pN1. The majority of patients had radical surgery and chemotherapy with anthracyclines in both groups. We noted a statistically significant difference in the irradiation of chest wall between the standard (89.2%) and hypofractionated group (70.3%), with p = 0.043. The median duration of radiation therapy was statistically different in both groups: 39 days in the standard and 23 days in the hypofractionated group (p 0.001). The local recurrences were statistically identical to 12 and 24 months (p = 0.999). Concerning toxicities, the frequency of adverse event was similar in both groups. Hypofractionated radiation therapy with a total dose of 42 Gy at 2.8 Gy per fraction in 5 fractions weekly is comparable to standard radiotherapy in terms of local control and tolerance and is therefore a very good alternative to standard treatment.

关键词： Hypofractionated Radiation Therapy Breast Cancer Local Control Tolerance

Factors associated with DAA virological treatment failure and resistance-associated substitutions description in HIV/HCV coinfected patients

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World Journal of Hepatology 2018年第11期10卷 856-866页

作者： Dominique Salmon Pascale Trimoulet Camille Gilbert Caroline Solas Eva Lafourcade Julie Chas Lionel Piroth Karine Lacombe Christine Katlama Gilles Peytavin Hugues Aumaitre Laurent Alric Franoois Boué Philippe Morlat Isabelle Poizot-Martin Eric Billaud Eric Rosenthal Alissa Naqvi Patrick Miailhes Firouzé Bani-Sadr Laure Esterle Patrizia Carrieri Franoois Dabis Philippe Sogni Linda Wittkop 无 Assistance Publique des Hopitaux de Paris Hopitaux Universitaires Paris CentreHopital Hotel DieuUnitédes Maladies infectieuses et tropicalesParis 75004France Université Paris descartes Sorbonne Paris CitéParis 75006France Trimoulet CHU de BordeauxHopital PellegrinLaboratoire de VirologieBordeaux 33000France Trimoulet CNRS-UMR 5234Microbiologie fondamentale et PathogénicitéUniversitéde BordeauxBordeaux 3000France Philippe Morlat Laure EsterleFrancois DabisLinda WittkopUniv.BordeauxISPEDInsermBordeaux Population Health Research Centerteam MORPH3EUSUMR 1219CIC-EC 1401Bordeaux F-33000France APHM Hopital La TimoneLaboratoire de Pharmacocinétique et ToxicologieMarseille 13005France Centre Hospitalier Universitaire de Dijon Département d'InfectiologieDijon cedex 21079France INSERM-CIC 1342 Universitéde Bourgogne Dijon 21000France Assistance Publique des Hopitaux de Paris GHUEP site Saint-AntoineServices Maladies infectieuses et tropicalesParis 75011France UniversitéPierre et Marie Curie UMR S1136Institut Pierre Louis d' Epidémiologie et de SantéPubliqueParis 75646France UniversitéParis-Sorbonne Paris 75005France Assistance Publique des Hopitaux de Paris Hopital PitiéSalpêtrière Services Maladies infectieuses et tropicalesParis 75013France Assistance Publique des Hopitaux de Paris Hopital Bichat-Claude BernardLaboratoire de PharmacologieParis 75877France IAME UMR 1137Sorbonne Paris CitéINSERMUniversitéParis DiderotParis 75890France Centre Hospitalier de Perpignan Service Maladies infectieuses et tropicalesPerpignan 66000Franc Centre Hospitalier Universitaire de Toulouse Hopital PurpanService Médecine interne-Pole DigestifToulouse 31300France UMR 152 IRD UniversitéToulouseⅢ Paul SabatierToulouse 31330France Hopital Antoine-Béclère Assistance Publique des Hopitaux de ParisUniversitéParis SudService Médecine interne et immunologieClamart 92140France Centre Hospitalier Universitaire de Bordeaux Service de médecine interneHopital Saint-AndréBordeaux 33000France Uni

AIMTo describe factors associated with treatment failure and frequency of resistance-associated substitutions （RAS）.METHODSHuman immunodefciency virus （HIV）/hepatitis C virus （HCV） coinfected patients starting a first direct-acting antiviral （DAA） regimen before February 2016 and included in the French ANRS CO13 HEPAVIH cohort were eligible. Failure was defned as：（1） non-response [HCV-RNA remained detectable during treatment, at end of treatment （EOT）]; and （2） relapse （HCV-RNA suppressed at EOT but detectable thereafter）. Sequencing analysis was performed to describe prevalence of drug class-specifc RAS. Factors associated with failure were determined using logistic regression *** 559 patients, 77% had suppressed plasmaHIV-RNA 〈 50 copies/mL at DAA treatment initiation41% were cirrhotic, and 68% were HCV treatmentexperienced. Virological treatment failures occurred in22 patients and were mainly relapses （17, 77%） thenundefined failures （3, 14%） and non-responses （29%）. Mean treatment duration was 16 wk overall. Posttreatment NS3, NS5A or NS5B RAS were detected in10/14 patients with samples available for sequencinganalysis. After adjustment for age, sex, ribavirin useHCV genotype and treatment duration, low platelecount was the only factor signifcantly associated with ahigher risk of failure （OR： 6.5; 95%CI： 1.8-22.6）. CONCLUSIONOnly 3.9% HIV-HCV coinfected patients failed DAAregimens and RAS were found in 70% of those failingLow platelet count was independently associated withvirological failure.

关键词： Human immunodeficiency virus Hepatitis C virus Direct-acting antiviral Treatment virological failure Resistant associated mutations

Young footballers, assessed by deep breathing test, have a higher vagal response

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Open Journal of Molecular and Integrative Physiology 2012年第3期2卷 61-64页

作者： Souad Aboudrar Hanane Rkain Leila Errguig Youssouf Radjab Latéfa Oukerraj Abdellatif Azzaoui Azeddine Ibrahimi Leslie Coghlan Mohammed Cherti Halima Benjelloun Taoufiq Dakka Al Akhawayn University School of Science and Engineering Ifrane Morocco Centre de Recherche Epidémiologique et Essais Cliniques (CRECET) Laboratoire de Pharmacologie et de Toxicologie Faculté de Institut National des Sports Moulay Rachid Salé Marocco Laboratoire de Physiologie Faculté de Médecine et de Pharmacie de Rabat Université MohammedⅤSouissi Marocco service de Cardiologie B Faculté de Médecine et de Pharmacie de Rabat Université Mohammed Ⅴ Souissi Marocco Unité d’exploration du Système Nerveux Autonome Service Cardiologie A CHU Ibn Sina Rabat Maroc

Parasympathetic function can be assessed by the deep breathing test (DB) as a simple and reproducible cardiovascular reflex. The aim of this study is to use this test to compare the vagal response of a young footballers group to of age-matched untrained normal subjects. deep breathing test was performed in 2 groups: one of 20 adult young footballers (average age of 19.3 ± 0.6 years), and a second age-matched group of 20 untrained subjects (average age of 19.6 ± 0.6 years). Subjects underwent the DB test after 30 min resting in supine position, and responses were expressed as a percentage of variation of heart rate during the stimulation. Student’s t-test was used to evaluate statistical differences among the two groups for all parameters (vagal response, heart rate, VO2max….) and considering p deep breathing test was significantly higher in the young footballers when compared to the untrained controls (72.6% ± 16.2% vs 55.0% ± 12.8%, respectively, p = 0.03). The basal heart rate was significantly lower in footballers than in the controls group (52.1 ± 7.4 bat/min vs 69.8 ± 14.3 bat/min, p deep breathing allowed us to demonstrate that adult young footballers have a significantly lower basal HR and higher parasympathetic response in comparison to untrained subjects.

关键词： deep Breathing Test Parasympathetic Response Autonomic Nervous System Sudden death Trained Footballers

Over Exposure to Efavirenz Plasma Concentrations among Beninese HIV Patients Treated by A 600 mg Daily Dose

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Journal of Pharmacy and Pharmacology 2017年第9期5卷 628-635页

作者： Allabi Aurel Constant Kiki Mikal Zannou Marcel Onifade El-Fatai Alvarez Jean Claude Laboratoire de pharmacologie et de Toxicologie Facultd des Sciences de la Sant~ Universit~ d'Abomey-Calavi (FSS/UAC)Cotonou 01BP188 Benin Laboratoire National des Stupefiants et de Toxicologie CBRSI Cotonou 01BP188 Benin Centre de Traitement Ambulatoire des PVVIH-CNHU-HKM de Cotonou CNHU-HKM Cotonou 06BP416 Benin service de Pharmacologic et de Toxicologic Centre Hospitalier Universitaire (CHU) Raymond Poincard Garches 92380 France

Therapeutic plasma concentrations of EFV （efavirenz） are between 1,000 ng/mL and 4,000 ng/mL. Concentrations below 1000 ng/mL are associated with higher risk of treatment failure, and concentrations above 4,000 ng/mL are associated with toxicity. The aim of the study was to appreciate EFV plasmas concentrations profile and the association between plasma levels and various characteristics in Beninese patients treated by a 600 mg standard daily-dose. Blood samples were collected and EFV plasma levels were measured by liquid chromatography coupled with mass spectrometry detection in HIV-infected patients receiving EFV in combination with other antiretroviral drugs for at least 14 days. Adverse effects occurring during treatment were collected through a questionnaire. An over-exposure to EFV among Beninese HIV patients were observed, with 46.4% of patients presenting EFV concentration above 4,000 ng/mL, although adverse effects were tolerated indicating that antiretroviral treatment is safe. The measurement of plasma concentration at the steady-state could contribute to early detection of treatment failure and adapt treatment in subjects presenting serious adverse effects within context of therapeutic drug monitoring.

关键词： HIV efavirenz plasma concentrations adverse effects Benin.

Assessment of Air Quality in Brazzaville: Measurement of Some Automobile Pollutants

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Journal of Environmental Protection 2023年第7期14卷 527-537页

作者： Rancia Colombe Diakouka Diambalou Presley Jeanel Ibrahim M’sengui Dzamba Moïse Doria Kaya-Ongoto Ange Antoine Abena Laboratoire National de Santé Publique Service de Bactériologie Brazzaville République du Congo Laboratoire de Biochimie et de pharmacologie Faculté des Sciences de la Santé Université Marien Ngouabi Brazzaville République du Congo Centre National de Transfusion Sanguine Brazzaville République du Congo Faculté des Sciences et Techniques Université Marien NGOUABI (FST UMNG) Brazzaville République du Congo Université Dénis Sassou Nguesso Brazzaville République du Congo

Atmospheric pollution is currently a real public health problem because of its potentially harmful effects on the environment as well as on human health. Several studies conducted in America, Europe, Asia, and Africa have established a significant link between air pollution and cancer, infertility, cardiovascular and respiratory morbidity, and mortality. This study aims to measure some automotive pollutants (CO, CO2, NO2, and SO2) by a selective and colorimetric method using a measurement system on Dräger reagent tubes coupled to a Dräger Accuro sampling pump in order to do a quantitative assessment of air quality in the nine districts of Brazzaville. The results obtained during this study revealed high concentration levels of pollutants (CO, CO2, NO2, SO2), all above the standards recommended by the WHO. The results obtained during this study made it possible to categorise Brazzaville as a polluted city.

关键词： Air Quality Automobile Pollutants Brazzaville

Ribavirin:Past,present and future

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World Journal of Hepatology 2016年第2期8卷 123-130页

作者： Véronique Loustaud-Ratti Marilyne debette-Gratien Jérémie Jacques Sophie Alain Pierre Marquet denisSautereau Annick Rousseau Paul Carrier Fédération Hépatologie CHU Dupuytren87042 LimogesFrance service d’Hépatogastroentérologie CHU Limoges87042 LimogesFrance U850 INSERM Universitéde LimogesCHU Limoges87042 LimogesFrance service de Bactériologie Virologie CHU Limoges87042 LimogesFrance U1092 INSERM Universitéde LimogesCHU Limoges87042 LimogesFrance service de pharmacologie CHU Limoges87042 LimogesFrance

Before the advent of direct acting antiviral agents(DAAs) ribavirin, associated to pegylated-interferon played a crucial role in the treatment of chronic hepatitis C, preventing relapses and breakthroughs. In the present era of new potent DAAs, a place is still devoted to the drug. Ribavirin associated with sofosbuvir alone is efficient in the treatment of most cases of G2 infected patients. All options currently available for the last difficult-to-treat cirrhotic G3 patients contain ribavirin. Reducing treatment duration to 12 wk in G1 or G4 cirrhotic compensated patients is feasible thanks to ribavirin. Retreating patients with acquired anti NS5 A resistance-associated variants using ribavirin-based strategies could be useful. The addition of ribavirin with DAAs combinations however, leads to more frequent but mild adverse events especially in cirrhotic patients. Preliminary data with interferon-free second generation DAAs combinations without ribavirin suggest that future of the drug is jeopardized even in difficult-totreat patients: The optimization of ribavirin dosage according to an early monitoring of blood levels has been suggested to be relevant in double therapy with peginterferon or sofosbuvir but not with very potent combinations of more than two DAAs.

关键词： Ribavirin Hepatitis C Peginterferon Directacting antiviral agents

妊娠晚期接触β肾上腺素能阻滞剂后的新生儿转归

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世界核心医学期刊文摘（儿科学分册） 2005年第10期1卷 37-38页

作者： Cissoko H. Jonville-Béra A.-P. Swortfiguer D. E. Autret-Leca 郭战宏 Ctr. Reg. Pharmacovigilance P. Service de Pharmacologie CHRU 2 boulevard Tonnel lé 37044 Tours Cedex 01 France

Objectives. -To analyse neonatal effects after in utero betablockers exposure and the pertinence of recommendations delivered by our team. Population and met hods. -We report 44 pregnancies exposed to betablockers during the late pregnan cy including the period of delivery about which the Regional Pharmacovigilance C enter of Tours (CRPV) was questionned. Results. -Among the 39 children for whom we know the follow up, 22 had neonatal adverse effects of which 19 could be exp lained by in utero exposure to betablockers i.e. an hypoglycaemia (11 times), a bradycardia (six times), a bradycardia and hypoglycemia (one time) and an hypote nsion (one time). A drug-related effect was retained for eleven newborns (27%) and another etiology could be evoked in the eight others. The risk of neonatal adverse effects seems to increase in newborns exposed to labetalol (5/11), to be taxolol (1/2) or to propranolol (2/6) or when the dose is high. The eight newbor ns who had intrauterine growth retardation were generally more often exposed to atenolol than eutrophic newborns. Four babies had malformations. Conclusions. - Our recommendation was an hospitalization 44 times (100%) to monitor heart rate , blood pressure and glycemia. When the follow-up is known, hospitalization was performed in 88%of the cases. Glycemia, heart rate and blood pressure were mon itored in all the hospitalized children and in three of the five not hospitalize d children. Our recommendation seems particularly justified with regard to hypog lycemia which is often asymptomatic but whose consequences can be severe. Atenol ol often provider of intrauterine growth retardation and labetalol more often at the origin of neonatal adverse effects are probably to avoid during pregnancy.

关键词：妊娠晚期拉贝洛尔 β阻滞剂药物警戒心动过缓普萘洛尔阿替洛尔倍他洛尔监测心率不良反应