Anti-enteroviral triple combination of viral replication inhibitors: activity against coxsackievirus B1 neuroinfection in mice.
BACKGROUND
Chemotherapy is an important tool for controlling enterovirus infections, but clinically effective anti-enterovirus drugs do not currently exist, mainly due to the development of drug resistance. We investigated the combination effects of enterovirus replication inhibitors in order to limit this process. In previous studies, we showed the efficacy of consecutive alternating administration of the triple combinations disoxaril/guanidine/oxoglaucine and pleconaril/guanidine/oxoglaucine against coxsackievirus B1 infection in newborn mice. Drug sensitivity tests of the viral brain isolates showed that these drug combinations prevented the development of drug resistance.


METHODS
In the current study, we replaced guanidine-HCl with enteroviral RNA synthesis inhibitor MDL-860 to test the effect of a new triple combination-pleconaril/MDL-860/oxoglaucine-applied via consecutive alternating administration in newborn mice infected subcutaneously with 20 MLD50of coxsackievirus B1.


RESULTS
The pleconaril/MDL-860/oxoglaucine combination via consecutive alternating administration showed high activity at the 75 mg/kg MDL-860 dose: a protective effect of 50% and a pronounced suppression of brain virus titers. Moreover, along with prevention of drug resistance, a phenomenon of increased drug sensitivity was established. MDL-860 sensitivity in pleconaril/MDL-860/oxoglaucine increased 8.2 times vs. placebo (29 times vs. monotherapy) on day 7 and oxoglaucine sensitivity-4.9 times vs. placebo (by 6.8 times vs. monotherapy) on day 13. As concerns pleconaril, a demonstrable prevention of drug resistance was registered without increase of drug sensitivity. Daily, simultaneous administration of pleconaril/MDL-860/oxoglaucine showed no protective effects and led to a rapid development of drug resistance.


CONCLUSIONS
These results add new support for using consecutive alternating administration treatment courses to achieve clinically effective chemotherapy of enterovirus infections.
1 Department of Virology, The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
Adelina
A
Stoyanova
1 Department of Virology, The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
Ivanka
I
Nikolova
2 Institute of Pharmacy, University of Innsbruck, Innsbruck, Austria.
Gerhard
G
Pürstinger
3 Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Sofia, Bulgaria.
Georgi
G
Dobrikov
3 Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Sofia, Bulgaria.
Vladimir
V
Dimitrov
3 Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Sofia, Bulgaria.
Stefan
S
Philipov
1 Department of Virology, The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
Angel S
AS
Galabov
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001058:Apomorphine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D003384:Coxsackievirus Infections / Q000188:drug therapy*; D024882:Drug Resistance, Viral / Q000187:drug effects; D004359:Drug Therapy, Combination; D029822:Enterovirus B, Human / Q000187:drug effects* / Q000254:growth & development*; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D009570:Nitriles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D010069:Oxadiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D010080:Oxazoles; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D009570:Nitriles; D010069:Oxadiazoles; D010080:Oxazoles; C111587:oxoglaucine; C036426:2-(3,4-dichlorophenoxy)-5-nitrobenzonitrile; C115201:pleconaril; D001058:Apomorphine
Animal model; compounds; drug combination; drug resistance; picornaviridae