Herpes viruses acyclovir

Acyclovir [9-(2-hydroxyethoxymethyl)guanine] (ACV) is clinically useful in the treatment of infections caused by several members of the herpes virus (e.g., herpes simplex, varicella zoster and Epstein-Barr virus [2,38,39]). An enzyme coded for by the virus phosphorylates ACV to a monophosphate intermediate. This species in turn undergoes further phosphorylation to a triphosphate with the aid of normal cell enzymes. Then, ACV triphosphate inhibits the herpes virus DNA... 

Aciclovir (acyclovir) was one of the first effective selective antiviral agents. It is a guanine derivative of value in treating herpes viruses, though it does not eradicate them, and is only useful if drug treatment is started at the onset of infection. 

Acyclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against human herpes viruses. 

It is an acyclic guanosine analog which require triphosphorylation for activation prior to inhibition of viral DNA polymerase. It is active against cytomegalovirus (CMV), varicellazoster virus, Epstein-Barr virus and human herpes virus-8. It is almost 100 times more potent than acyclovir against CMV. 

Acyclovir is useful in the treatment of herpes. Oral herpes is caused by the herpes simplex virus 1 (HSV-1), and genital herpes is caused by the herpes simplex virus 2 (HSV-2). More than 90 percent of the world s population is infected with the oral herpes virus, though there are many infected people who do not exhibit symptoms. Genital herpes is the most prevalent nondurable sexually transmitted disease. In the United States, there are about 30 million people infected with HSV-2 and an estimated 200,000 to 500,000 new cases each year. 

Acyclovir, 9-(2-hydroxyethoxymethyl)guanine (103), exemplifies a further modification of a guanine nucleoside in which part of the furanose ring has been eliminated. It is phosphorylated in herpes infected cells to a greater extent than in normal cells, and the triphosphate inhibits viral DNA polymerase. It is active against herpes virus both in vitro and in vivo. 

Viruses other than HIV may be treated by blocking the action of nucleotide polymerases. Acyclovir (Zovirax, 6.56) and famciclovir (Famvir, 6.57) are used against various herpes viruses (Figure 6.22). Cidofovir (Vistide, 6.58) is active against cytomegaloviral retinitis in patients who are infected with HIV. Ribavirin (Rebetol, 6.59) is approved for use against hepatitis C virus. 

Vidarabine [vye DARE a been] arabinofuranosyl adenine, ara-A, adenine arabinoside) is one of the most effective of the nucleoside analogs and is also the least toxic. However, it has been supplanted clinically by acyclovir, which is more efficacious and safe. Although vidarabine is active against herpes simplex virus type 1 (HSV-1), HSV-2, and varicella-zoster virus (VZV), its use is limited to treatment of immunocompromised patients with herpes simplex keratitis or encephalitis, or VZV infections. Vidarabine, an adenosine analog, is converted in the cell to its 5 -triphosphate analog (ara-ATP), which is postulated to inhibit viral DNA synthesis. Some resistant herpes virus... 

Systemic antiviral therapy promotes resolution of HZO skin lesions and reduces the incidence and severity of dendriform keratopathy, anterior uveitis, and stromal keratitis by decreasing the rate of virus replication. All patients with acute HZO should receive antiviral therapy with the goal of minimizing ocular complications. Acyclovir, valacyclovir, and femciclovir are FDA approved for management of herpes zoster. Acyclovir usually is administered orally in dosages of 800 mg five times per day far 7 days. Valacyclovir has better bioavailability when taken orally and can be used with a recommended dosage of 1 g three times a day for 7 days. Famciclovir, which has bioavailability similar to valacyclovir, has an increased half-life and also has the advantage of less frequent administration than acyclovir 500 mg three times a day for 7 days. 

Acyclovir selectively inhibits viral DNA synthesis. It is preferentially activated in virally infected cells. Cellular uptake and initial phosphorylation are facilitated by the herpes virus thymidine kinase. The affinity of acyclovir for HSV... 

Famciclovir is rapidly converted to penciclovir in intestinal and liver tissue after oral administration. More than half of an oral dose of famciclovir is excreted in the urine as unchanged penciclovir. The plasma elimination half-life of penciclovir is about 2h, similar to that of acyclovir however, the intracellular half-life of penciclovir in herpes virus-infected cells is considerably longer than that of acyclovir. 

Ganciclovir is an acyclic guanine nucleotide analog with a structure similar to acyclovir but with an additional hydroxymethyl group on the acyclic side chain. It is inhibitory to all herpes viruses but is especially active against cytomegalovirus. 

Acyclovir is an effective emti-herpes virus drug. 

Keywords Encephalitis Herpes simplex virus type 1 Varicella zoster virus Cytomegalovirus West Nile virus Acyclovir Valacyclovir Ganciclovir Cidofovir Famciclovir Foscamet Latencyneurological disorders Fifecycle... 

Cidofovir is an acyclic nucleotide analogue of the monophosphate of cytosine. When phosphoiylated by host cellular enzymes, the active compound cidofovir diphosphate has broad activity against the herpes viruses, including CMV, HSV 1 and 2, VZV, Epstein-Barr virus, and the BK polyomavirus. Cidofovir has primarily been used in the treatment of CMV retinitis in patients who have failed treatment with ganciclovir or foscarnet and in acyclovir-resistant herpes simplex infections. More recently, there is also a growing experience with the use of this medication in kidney transplant patients who have BK virus-associated nephropathy [31], although this interest has been dampened by significant toxicity and only modest clinical activity [32]... 

Selby PJ, Powles RE, Jameson B, Kay HEM, Watson JG, Thornton R, Morgenstern G, Clink HM. Parenteral acyclovir therapy for herpes virus infections Inman. Lancet 1979 2 1267-1270. 

Chemically stable analogues of acyclovir (26) have been synthesised in an attempt to attain appreciable activity against herpes virus type-1 while allowing their cellular internalisation and bypassing the intracellular activation of acyclovir to its triphosphate derivative required for activity. These compounds are bio-isosteres of acyclovir monophosphate and diphosphate, but are devoid of any appreciable antiviral activity on both HSV-1 and HIV-1. 

Acyclovir is the drug of choice for herpes simplex encephalitis. In patients with normal renal function, acyclovir is usually administered as 10 mg/kg intravenously every 8 hours for 2 to 3 weeks. Herpes virus resistance to acyclovir has been reported with increasing incidence, particularly from immunocompromised patients with prior or chronic exposures to acyclovir. The alternative treatment for acyclovir-resistant herpes simplex virus is foscarnet. The major toxicity of foscarnet is renal impairment, and doses must be individualized for renal function. The dose for patients with normal renal function is 40 mg/kg infused over 1 hour every 8 to 12 hours for 2 to 3 weeks. Ensuring adequate hydration is imperative. In addition, patients receiving foscarnet should be monitored for seizures related to alterations in plasma electrolyte levels. 

The antiviral mechanism of action of acyclovir has been reviewed (72). Acyclovir is converted to the monophosphate in herpes virus-infected cells (but only to a limited extent in uninfected cells) by viral-induced thymidine kinase. It is then further phosphorylated by host cell guanosine monophosphate (GMP) kinase to acyclovir diphosphate [66341-17-1]y which in turn is phosphorylated to the triphosphate by unidentified cellular enzymes. Acyclovir triphosphate [66341 -18-2] inhibits HSV-1 viral DNA polymerase but not cellular DNA polymerase. As a result, acyclovir is 300 to 3000 times more toxic to herpes viruses in an HSV-infected cell than to the cell itself. Studies have shown that a once-daily dose of acyclovir is effective in prevention of recurrent HSV-2 genital herpes (1). HCMV, on the other hand, is relatively uninhibited by acyclovir. 

Vidarabine is a purine nucleoside analogue active against herpes viruses, influenza viruses, and some RNA viruses. Use of vidarabine for treatment of herpes simplex and varicella-zoster infections has largely been supplanted by acyclovir because of the superior efficacy, fewer adverse effects, and easier administration of the latter agent. Vidarabine has been associated with significant gastrointestinal, neurologic, and hematopoietic toxicities. Patients with renal insuffi-... 

Fluoroidoaracystosine (FIAC, Fig. 7-16) is a potent and selective inhibitor of herpes viruses. Like acyclovir and BVDU, it, too, must be phosphorylated by viral thymidine kinase to act. Its selectivity toward the viral enzyme is several thousand times higher so that it is active against HSV-1 and -2 and herpes zoster virus (HZV) with a good therapeutic index. Clinical studies seem promising. 

---