Acyclovir toxicity

The antiviral mechanism of action of acyclovir has been reviewed (72). Acyclovir is converted to the monophosphate in herpes vims-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], which in turn is phosphorylated to the triphosphate by unidentified cellular en2ymes. 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 vimses 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. 

Recently, however, there have been a number of encouraging developments in the field of antiviral therapy. For example, acycloguanosine (acyclovir see Chapter 5) has been shown to be non-toxic to host cells while specifically inhibiting the replication of herpes vimses. Successfiil clinical trials have led to the introduction of this dmg for the treatment of a variety of herpetic conditions. 

Foscarnet, cidofovir, and trifuridine have been administered in acyclovir-resistant patients.30 These agents are usually reserved for use after other agents have failed because of their associated toxicities. 

Ethonium and Decametaximun have shown rather high toxicity at both methods of testing whereas Zovirax (Acyclovir), E-aminocapronic acid, Ambenum and Sodium Aceminatum had a hypo toxicity at their influence on cells monolayer, and Colpoda steinii infusorians culture. 

The adverse effects of valacyclovir and acyclovir are similar. Toxicity is generally minimal, consisting largely of headache, nausea, and diarrhea. Less frequently observed are skin rash, fatigue, fever, hair loss, and depression. Reversible renal dysfunction (azotemia) and neurotoxicity (tremor, seizure, delirium) are dose-Umiting toxicides of intravenous acyclovir. Adequate hydration and slow drug infusion can minimize the risk of renal toxicity. 

The potential for drug interactions, particularly with other drugs that are actively secreted by the proximal tubules, should be considered. Probenecid has been shown to inhibit the renal clearance of acyclovir. Cyclosporine and other nephrotoxic agents may increase the risk of renal toxicity of acyclovir. 

Foscarnet should not be used in combination with drugs that cause renal toxicity (e.g., acyclovir, aminoglycosides, amphotericin B, NSAIDs). Abnormal renal function has been noted when foscarnet is used with ritonavir or ritonavir and saquinavir. Pentamidine may increase the risk of nephrotoxicity, hypocalcemia, and... 

Acyclovir (9.9) shows a unique specificity and lack of toxicity in HSV-1, HSV-2, and varicella (chickenpox, shingles) viral infections. A guanine derivative, acyclovir lacks the pentose of similar compounds and is phosphorylated at the alcoholic OH by the viral thymidylate kinase only. Consequently, it is not activated in uninfected cells additionally. 

Oral famciclovir is generally well tolerated, although headache, diarrhea, and nausea may occur. As with acyclovir, testicular toxicity has been demonstrated in animals receiving repeated doses. However, men receiving daily famciclovir (250 mg every 12 hours) for 18 weeks had no changes in sperm morphology or motility. The incidence of mammary adenocarcinoma was increased in female rats receiving famciclovir for 2 years. 

Gastrointestinal complaints (eg, nausea, diarrhea, vomiting, flatulence) are the most common adverse effects but rarely require discontinuation of therapy. Other potential adverse effects include headache and asthenia. Tenofbvir-associated proximal renal tubulopathy causes excessive renal phosphate and calcium losses and 1-hydroxylation defects of vitamin D, and preclinical studies in several animal species have demonstrated bone toxicity (eg, osteomalacia). Monitoring of bone mineral density should be considered with long-term use in those with risk factors for or with known osteoporosis, as well as in children. Reduction of renal function over time, as well as cases of acute renal failure and Fanconi s syndrome, have been reported in patients receiving tenofovir alone or in combination with emtricitabine. For this reason, tenofovir should be used with caution in patients at risk for renal dysfunction. Tenofovir may compete with other drugs that are actively secreted by the kidneys, such as cidofovir, acyclovir, and ganciclovir. 

Acyclovir is generally well tolerated. Nausea, diarrhea, and headache have occasionally been reported. Intravenous infusion may be associated with reversible renal dysfunction due to crystalline nephropathy or neurologic toxicity (eg, tremors, delirium, seizures) however, these are uncommon with adequate hydration and avoidance of rapid infusion rates. Chronic daily suppressive use of acyclovir for more than 10 years has not been associated with untoward effects. High doses of acyclovir cause testicular atrophy in rats, but there has been no evidence of teratogenicity to date in a cumulative registry and no effect on sperm production was demonstrated in a placebo-controlled trial of patients receiving daily chronic acyclovir. 

Oral famciclovir is generally well tolerated, although headache, diarrhea, and nausea may occur. As with acyclovir, testicular toxicity has been demonstrated in animals receiving repeated doses. 

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... 

Acyclovir Topical available outside of the United States. Zovirax Tablets, oral—400 mg, 800 mg capsule, oral—200 mg suspension, oral—200 mg/5 ml injectable— 50 mg/ml generic also available Topical acyclovir is similar in efficacy to idoxuridine, vidarabine, and trifluridine but less toxic to the eye. 

Acyclovir is less toxic to the ocular surface than idoxuridine, vidarabine, and trifluridine (Tabery, Grant). 

Hakimelahi has reported a novel strategy for the synthesis of N -purine acyclic nucleosides, in which the key step involves the reaction of [2-(p-methoxyphenyloxy)ethoxyl]methyl chloride and iV -tritylated nucleobases, followed by concomitant self-detritylation. 7-[(2-Hydroxyethoxy)methyl] guanine was phosphorylated by both HSV- and Vero-cell thymidine kinases to yield (92), and was found to have more potent cellular toxicity than acyclovir, while the adenine parent was phosphorylated by neither kinase. In addition, the N -adenine acyclic nucleoside phosphonate (93) was synthesised by alkylation of adenine with 3-bromopropionitrile to yield AT -(cyanoethyl)adenine, which upon... 

In an in vivo animal study, at doses not causing crystalluria or tissue crystal deposition, short term exposure to acyclovir caused increased renal vasoconstriction and an associated fall in renal blood flow and single nephron plasma flow [22]. Longer-term treatment resulted in a fall in glomerular ultrafiltration coefficient. Thus, it is not clear whether the pathogenesis of acyclovir-induced AKI in humans reflects an obstructive nephropathy from intratubular precipitation of acyclovir, a hemodynamic response, or a type of toxic, immunologic, or hypersensitivity reaction. It is also possible that more than one process may be involved. 

The most important risk factors for acyclovir nephrotoxicity are intravascular volume contraction, preexisting kidney desease, and the use of a high-dose, rapid bolus intravenous infusion [7] Nephrotoxicity with oral acyclovir has been reported only rarely [23] The main non-renal toxicities of acyclovir are gastrointestinal and neurologic side effects, which primarily occur in patients on high-dose intravenous acyclovir. As acyclovir is primarily cleared by the kidney, lower intravenous doses and even oral administration can lead to neurotoxicity in patients with decreased kidney function from either CKD or AKI [15,17, 24, 25]. 

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]... 

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. 

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