title: Is the anti-psychotic, 10-(3-(dimethylamino)propyl)phenothiazine (promazine), a potential drug with which to treat SARS infections? Lack of efficacy of promazine on SARS-CoV replication in a mouse model.
abstract: Phenothiazine and derivatives were tested for inhibition of SARS-CoV replication. Phenothiazine slightly inhibited SARS-CoV replication in a neutral red (NR) uptake assay. Adding a propylamino group to give promazine reduced virus yields (VYR assay) with an EC(90)=8.3+/-2.8 microM, but without selectivity. Various substitutions in the basic phenothiazine structure did not promote efficacy. Phenazine ethosulfate was the most potent compound by VYR assay (EC(90)=6.1+/-4.3 microM). All compounds were toxic (IC(50)=6.6-74.5 microM) except for phenoxathiin (IC(50)=858+/-208 microM) and 10-(alpha-diethylamino-propionyl) phenothiazine.HCl (IC(50)=195+/-71.2 microM). Consequently, none were selective inhibitors of SARS-CoV replication (SI values <1-3.3 microM). These data portended the poor efficacy of promazine in a SARS-CoV mouse lung replication model. Intraperitoneal treatment with promazine using a prophylactic (-4h)/therapeutic regimen of 1, 10, or 50mg/(kg day) did not reduce virus lung titers at day 3, yet prolonged virus replication to 14 days. Similar therapeutic promazine doses were not efficacious. Thus, promazine did not affect SARS-CoV replication in vitro or in vivo, nor were any other phenothiazines efficacious in reducing virus replication. Therefore, treating SARS infections with compounds like promazine is not warranted.
authors.affiliation: Institute for Antiviral Research, Utah State University, 5600 Old Main Hill, Logan, UT 84322-5600, USA. dale.barnard@usu.edu
authors.forename: Dale L
authors.initials: DL
authors.lastname: Barnard
authors.forename: Craig W
authors.initials: CW
authors.lastname: Day
authors.forename: Kevin
authors.initials: K
authors.lastname: Bailey
authors.forename: Matthew
authors.initials: M
authors.lastname: Heiner
authors.forename: Robert
authors.initials: R
authors.lastname: Montgomery
authors.forename: Larry
authors.initials: L
authors.lastname: Lauridsen
authors.forename: Kie-Hoon
authors.initials: KH
authors.lastname: Jung
authors.forename: Joseph K-K
authors.initials: JK
authors.lastname: Li
authors.forename: Paul K S
authors.initials: PK
authors.lastname: Chan
authors.forename: Robert W
authors.initials: RW
authors.lastname: Sidwell
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D002470:Cell Survival; D018890:Chemoprevention; D002522:Chlorocebus aethiops; D016207:Cytokines / Q000032:analysis; D005260:Female; D008168:Lung / Q000473:pathology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D009499:Neutral Red / Q000378:metabolism; D010640:Phenothiazines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D045473:Severe acute respiratory syndrome-related coronavirus / Q000187:drug effects*; D045169:Severe Acute Respiratory Syndrome / Q000188:drug therapy / Q000517:prevention & control; D014709:Vero Cells; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; D010640:Phenothiazines; D009499:Neutral Red