Combination therapy with antiviral agents

Dose adjustment for combination therapy with saquinavir For serious toxicities that may be associated with saquinavir mesylate, the drug should be interrupted. Saquinavir mesylate at doses less than 1,000 mg with ritonavir 100 mg twice daily are not recommended since lower doses have not shown antiviral activity. For recipients of combination therapy with saquinavir mesylate and ritonavir, dose adjustments may be necessary. These adjustments should be based on the known toxicity profile of the individual agent and the pharmacokinetic interaction between saquinavir and the coadministered drug. Health care providers should refer the complete monographs for these drugs for comprehensive dose adjustment recommendations and drug-associated adverse reactions of nucleoside analogues. 

Foscamet is an antiviral agent that inhibits replication of all known herpes viruses, including cytomegalovirus (CMV), herpes simplex virus types 1 and 2 (HSV-1, HSV-2), human herpes virus 6 (HHV-6), Epstein-Barr virus (EBV) and varicella-zoster virus (VZV). It is indicated in the treatment of CMV retinitis in patients with AIDS treatment of acyclovir-resistant mucocutaneous HSV infections in immunocompromised patients and as combination therapy with ganciclovir for patients who have relapsed after monotherapy with either drug. 

It may be possible to increase the utility of our resources to treat influenza virus infection through combinations of antiviral agents with different modes of action (discussed in Cinatl et al. 2007a De Clercq and Neyts 2007). The sialidase inhibitors, for example, may be able to be used in conjunction with the adamantane-based M2 ion channel inhibitors (Govorkova et al. 2004 Ilyushina et al. 2006), with Ribavirin (Smee et al. 2002) or with non-influenza virus specific therapeutics such as anti-inflammatory drugs (Carter 2007). Combination therapy may also reduce the potential of resistance development (Ilyushina et al. 2006). 

Severe infection such as gonococcal conjunctivitis requires systemic therapy, which may be used in conjunction with topical agents. Treatment of viral infections often is directed at relieving patient symptoms, because specific antiviral agents do not currently exist in most cases. Chlamydial disease requires systemic therapy frequently combined with adjunctive topical therapy. 

Ribavirin 67 (Figure 4.19) is an antiviral agent used in combination with a-2p interferon to treat hepatitis C [97, 98]. Although this therapy is effective against the hepatitis C virus, it has several side effects [99]. To improve the pharmacokinehc profile and reduce side effects, a ribavirin prodrug was considered for development by Schering-Plough. The alanine ester of ribavirin 68 showed improved bioavailability and reduced side effects in preclinical evaluation. The synthesis of 68 required the... 

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