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: Dale L Barnard, Craig W Day, Kevin Bailey, Matthew Heiner, Robert Montgomery, Larry Lauridsen, Kie-Hoon Jung, Joseph K-K Li, Paul K S Chan, Robert W Sidwell
• Journal: Antiviral research (Antiviral Res) Vol. 79 Issue 2 Pg. 105-13 (Aug 2008) ISSN: 0166-3542 [Print] Netherlands
• PMID: 18423639 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antiviral Agents
• Cytokines
• Phenothiazines
• Neutral Red

Topics

• Animals
• Antiviral Agents (administration & dosage, pharmacology, therapeutic use, toxicity)
• Cell Survival
• Chemoprevention
• Chlorocebus aethiops
• Cytokines (analysis)
• Female
• Lung (pathology, virology)
• Mice
• Mice, Inbred BALB C
• Molecular Structure
• Neutral Red (metabolism)
• Phenothiazines (administration & dosage, pharmacology, therapeutic use, toxicity)
• Severe acute respiratory syndrome-related coronavirus (drug effects)
• Severe Acute Respiratory Syndrome (drug therapy, prevention & control)
• Vero Cells
• Virus Replication