ABSTRACT
Up to 85% of the US adult population carries herpes simplex virus type-1 (HSV-1), with a smaller percentage (22%) infected with HSV-2. Herpesviruses can survive in lytic phase, when the viruses are actively replicating, or in latency, when the virus is functionally dormant in ganglia. Among drugs to treat these infections is acyclovir (ACV). ACV exhibits poor oral bioavailability and a short in vivo half-life; only about 10-15% of ingested drug enters the bloodstream and its half-life is about 3 hours. With those disadvantages and the possibility of poor patient compliance, viral replication may not always be suppressed. To abrogate these shortcomings we propose local distribution via sustained drug release. We present a matrix-based antiherpetic ring, composed of poly(ethylene co-vinyl acetate), that releases ACV directly to the vaginal epithelium. A 30-day in vitro drug release trial showed that approximately 135 +/- 20 µg/day of ACV was consistently released. Rings were nontoxic in cell culture and suppressed primary HSV-1 and HSV-2 replication. We expect these data form the basis for novel interventions in human health, where new prophylactics and therapeutics against genital herpes are truly needed.
ABSTRACT
Herpes simplex virus-1 (HSV-1) affects a large portion of the global population and has been shown to cause more severe symptoms in immunocompromised patients. It is in immunocompromised populations that HSV-1 has shown to have higher rates of resistance to the most commonly used antiherpetics, such as acyclovir/valacyclovir/penciclovir/famciclovir. The development of drug resistance has forced research into new antiherpetic therapies, including combination drug therapies. One potential complication of multidrug therapies is the existence of drug-drug interactions; as more drugs are used in the therapy, those interactions tend to become more complicated. This study tested the combination of acyclovir/cidofovir/amenamevir, the last drug being a new antiherpetic that targets the helicase-primase complex to prevent replication of viral DNA, for multidrug intervention. We used the design of experiments (DOE) function in Minitab to analyze the drug-drug interactions in their ability to inhibit growth of HSV-1. The DOE software was unable to detect any significant drug-drug interactions among these three antiherpetics as dosed. This would imply that these drugs could be used in combination to suppress viral replication without synergistic or antagonistic effects. This study shows that this therapy holds potential for further study and that DOE software is a potentially useful tool for determining complex drug-drug interactions.
