NUCLEOTIDE ANALOGS

5 Jun

The  derivatives of nucleosides that are  monophosphorylated belong to the nucleotide analogs. Those with antiviral properties include cidofovir, adefovir, and  tenofovir. Tenofovir is  used to treat HIV infection and  is discussed in Chapter 2, page 62.

Phosphorylation of nucleosides occurs  within the  cyto- plasm of cells that are  beginning mitotic division. The synthe- sis of bases that contribute to DNA chain elongation is limited by  the  inclusion of nucleotide analogs. Mitochondrial DNA- polymerase may  also be affected.

Cidofovir

Introduction

Cidofovir has  received much attention as a therapy for many viral diseases (Fig. 3.21). Although preemptive antiviral ther- apy for CMV infection following allogenic stem cell transplan- tation is recommended as an effective strategy for preventing CMV  disease, some  studies do  not  support this hypothesis (211).  Cidofovir is considered an  option for the  treatment of acyclovir-resistant  HSV  although it has   not  been   FDA- approved for  this purpose. However, there is  an  increasing need  for  additional therapies as  more  herpes viral strains

become  acyclovir-resistant.  Cidofovir shows  promise as  a ther- apy  against TK-deficient strains  of HSV.  As the  first acyclic phosphonate nucleotide approved for use  in the  United States, cidofovir  can  be  used to  treat CMV retinitis inpatients with AIDS.  AIDS  patients treated with cidofovir  for CMV retinitis often report an improvement in AIDS-related Kaposi’s sarcoma.

Cidofovir is the  most  effective anti-orthopoxvirus  agent currently under preclinical investigation (212). Other diseases for which cidofovir  is used include VZV, CMV, HPV,  polyoma viruses, adenoviruses, and  other poxviruses (213).  Cidofovir shows  efficiency against  JC  virus in  vitro  (214).  Cidofovir is considered to be the second-line therapy for CMV disease after the  first antiviral failed (215).  Anogenital warts respond to cidofovir  topical gel (216).

Mechanism of Action

Cidofovir is  considered to  be  an  acyclic  phosphonate nucle- otide. Cidofovir is similar to foscarnet in that it does not require thymidine kinase for  phophorylation (Fig.  3.22).  To become activated, the  drug is  phosphorylated by  cellular kinase to cidofovir  diphosphate  (217–219), which makes it effective against TK-deficient strains of HSV. HHV-8  replication is sen- sitive to  cidofovir. Although  cidofovir  is  poorly  absorbed by mouth, aerosolized cidofovir  may help  create a barrier against aerosolized virus infections. Cidofovir acts  as a chain termina- tor for viral DNA polymerase. After intracellular phosphoryla- tion  to a diphosphate form, activity occurs  at the  3′ end  of the viral DNA with termination at the  end  of two sequences.

Clinical  Studies and  Reports that  Support the  Use of Cidofovir

Several studies document the  treatment of acyclovir-resistant and  normal strains of HSV with topical cidofovir. Representa- tive  studies are  highlighted in Table 3.19  (213,215,220–251). The FDA did not approve the  use of cidofovir  gel for acyclovir- resistant herpesvirus infection due to a lack of sufficient phase- three data (229). However, the  manufacturer has  reported suc- cessful treatment  of HSV  with compounded cidofovir  cream (230).  Cidofovir delays the  progression of CMV  retinitis in

patients with AIDS (220–224). The  use  of cidofovir  alone may not change the  course of progressive multifocal leukoencepha- lopathy in non-HIV-positive patients (249).

Cidofovir has  shown to  be  effective against  HHV-8  (in vitro). HAART therapy usually benefits KS lesions, but  a case report indicates cidofovir  treatment may  be considered for the control of KS lesions and  to reduce HHV-8  replication (250).

Treatment

Genital warts and  common warts can  be effectively treated with cidofovir, although it is  not  currently FDA-approved for  this purpose. Table 3.20  highlights other treatments. Dosages may  vary  with little effect  on toxicity. For  patients receiving 3 mg/kg  vs 5 mg/kg  of cidofovir, the  only toxic con- dition deemed significant (p < 0.04) was  an increase in base- line   creatinine. Other  conditions included nausea  and vomiting. Cidofovir must be used with caution if combined with other known nephrotoxic drugs or  used concomitant with cyclosporin (215).

Adverse Effects

A number of side  effects  have been  reported with the  use  of cidofovir  (211–251).

With  HSV:

Pain. Pruritus.

Skin changes. May cause localized fibrosis if cidofovir  is injected.

Ulcerations.

Erythema. Some  HPV  (condylomata acuminata)  HIV- positive patients experience transient  erythema from cidofovir  use  with no long-term side  effects  (248).

Neutropenia.

Nephrotoxicity. Occurs as  serum creatinine levels  rise to 1.5–2  times normal. Some  patients develop tubular toxicity. Pretreatment with intravenous normal saline and  probenecid is  mandatory to  decrease the  risk of nephotoxicity.

Metabolic acidosis. Ocular hypotony. Uveitis. (250).

Special Considerations

Probenecid. Probenecid can  be  used with intravenous normal saline to reduct the risk of nephrotoxicity (213). Other nephrotoxic  agents. Concomitant use  is  con-

traindicated.

Cidofovir gel availability. Compounding of the  drug is expensive.

Smallpox vaccination study. Currently, smallpox vac- cinations are  being  tested. Should volunteers develop complications of vaccinia, cidofovir  will be the  drug of choice  for antiviral therapy.

Adefovir

Introduction

Adefovir  dipivoxil is a diester prodrug of adefovir with specific activity against the  human hepatitis B virus (HBV). Adefovir was  approved in  September 2002.  Those  who  take the  oral drug have experienced improved liver  histology and  have a

Fig. 3.23 Associated names, structure, and  applicability of adefovir dipivoxil.

reduced serum HBV DNA concentration if they were  infected with the  precore mutant strain of the  virus (252). With  precore mutant HBV,  the  virus’  ability to  produce “e” antigen is destroyed by the  viral genome. Precore mutant virus is associ- ated with more  severe liver  disease and  is  more  commonly found  in  Asian and  Mediterranean countries. The  wild  type also  responds favorably to  adefovir. Brand name, chemical structure, and  antiviral uses of adefovir are  shown in Fig. 3.23.

Mechanisms of Action

Adefovir  is a nucleotide analog of adenosine monophosphate that is acyclic. Nucleotide analogs block HBV DNA polymere- ase,  the  enzyme involved in correct replication of the  virus in cells. Adefovir  is actually adefovir dipivoxil, a diester prodrug of adefovir. Adefovir  is phosphorylated to the  active metabo- lite,  adefovir diphosphate,  by  host   cellular kinases. The diphosphate form  inhibits the  reverse transcriptase of the DNA  polymerase by  competing with the  normal DNA  sub- strate, deoxyadenosine triphosphate. Once  the  adefovir com- pound is  incorporated into  the  viral DNA,  the  DNA  chain ceases to elongate. This  mechanism is shown in Fig. 3.24.

Studies to Support the  use  of Adefovir

A variety of studies were  performed on  adefovir before  the

FDA gave  approval, and  are  shown in Table 3.21 (252–255).

Treatment

Adefovir  is administered as an oral tablet. Each table contains

10 mg of adefovir dipivoxil and  a number of inactive ingredi- ents. In laboratory studies, 0.2–0.25 µM of adefovir achieved a

50% reduction in viral DNA synthesis. Adefovir  is excreted by glomular filtration and  active tubular  secretion by  the  kid- neys. The  potential for CYP 450 interactions with adefovir as a inhibitor or substrates with other medicinal products is neg- ligible  given the  renal elimination of adefovir. Adefovir  may be taken without regard to food.

Adverse Events

In  initial clinical trials, a  number of adverse events were reported, such  as  asthenia, headache, abdominal pain, nau- sea,  flatulence, diarrhea, and  dyspepsia. However the  reports between those receiving adefovir and  the placebo were not sig- nificantly different. Pre-  and  post-liver transplant  patients reported some  additional concerns that may  be important on

a case-by-case basis: changes in serum creatinine and  serum phosphorus, pruritus and  rash, abnormal liver  functions, and some  respiratory complications.

Discontinuation of adefovir treatment. Once patients who  have been  on adefovir or other anti-HBV therapy discontinue therapy, severe acute exacerbation of hepa- titis has  occurred. Monitoring of hepatic function of pa- tients who  discontinue anti-HBV therapy  should continue over  time. Resumption of anti-HBV therapy may  be needed if alanine aminotransferase (ALT) lev- els  rise  significantly. Patients with poor  liver  function (hepatitis or cirrhosis) may be at higher risk. Deaths have occurred, so patients should be closely monitored.

Nephrotoxicity. Patients with normal renal function have a low risk of nephrotoxicity. However, for patients with or at risk of renal dysfunction, chronic administration of the standard dosage of adefovir may cause nephrotoxicity.

Coadministration with nephrotoxic agents. Coad- ministration of cyclosporine, tacrolimus, aminoglyco- sides, vancomycin, and  non-steroidal anti-inflammatory drugs with adefovir may  increase the  chances that nephrotoxicity may  occur.

Coadministration with ibuprofen. Ibuprofen at a dosage of 800  mg  three times /day  increased adefovir exposure by 23% although the  significance of this ob- servation is unknown.

Pregnancy. No  adequate or  well-controlled studies on pregnant  women have been  conducted. Fetal malfor- mations occurred in pregnant rats when administered doses  38  times human systemic exposure, although there is no indication that this would  be predictive of human response. Adefovir  should be  administered to pregnant women only after careful consideration of the risks and  benefits and  only if clearly needed.

Pediatric and geriatric use. Insufficient studies have been  done  to establish safety and  effectiveness.

Overdosage. Doses of adefovir of 500 mg daily for 2 weeks and  250  mg  daily  for  12  weeks have been  associated

with gastrointestinal side  effects. In  case  of overdose, the  patient should be monitored for evidence of toxicity and  standard supportive treatment used, as necessary.

HIV. For those with HIV, adefovir may  interfere with the efficacy  of usual HIV  medications. Patients  should have an HIV test prior to administration of adefovir.

Lactic acidosis. Nucleoside analog medications, such  as adefovir, may  cause a  build-up of acid  in  the  blood called lactic acidosis, which should be treated as a med- ical  emergency. Symptoms of lactic acidosis are  weak- ness or  tiredness, unusual  muscle pain, trouble breathing, stomach pain with nausea and  vomiting, cold  extremities, dizziness or  light-headedness, or  a fast  or irregular heartbeat.

Special Considerations

Renal impairment. Patients with moderately or severely impaired renal function or undergoing dialysis for end- stage renal disease may  experience decreased half-life and  clearance rates for adefovir. The  dosing interval of adefovir may  need  to be adjusted for these patients.

Hepatic impairment. In non-chronic HBV patients, the pharmacokinetics remains the  same in  patients with moderate and  severe hepatic impairment compared with unimpaired patients. No change in dosage is an- ticipated for these patients.

ANTISENSE DRUGS

Antisense oligonucleotides containing locked  (poorly  binding) nucleic acids  are  a  new  class  of therapeutic agents for viral infections, cancer, inflammatory, and  cardiovascular diseases. Some  drawbacks of antisense  drugs include low-binding to active sites and  toxic side  effects  (256).  Oligonucleotides may be inhibitors of HIV (257).  It still  remains a challenge for oli- gonucleotides to provide efficient and  specific  antisense activ- ity  with reduced toxicity.  Fomivirsen is  an  example of an antisense drug.

Fig. 3.25 Associated names, structure, and  applicability of fomivirsen.

Fomivirsen

Introduction

Fomivirsen, an  antisense drug, is the  first in  this group to be  FDA-approved. Patients  who  have CMV  retinitis as  a result of their AIDS infection may be treated with fomivirsen, particularly if they have a contraindication to, or an intolerance for, other CMV retinitis treatments (Fig. 3.25).  Fomivirsen is effective when certain CMV strains are  known to be ganciclo- vir, foscarnet, and  cidofovir  resistant.

Mechanism of Action

Fomivirsen is  a  DNA  analogue that complements a  unique sequence of nucleotides with the  mRNA  of CMV. Formivirsen is a single-stranded antisense oligonucleotide (Fig. 3.26). This region of mRNA  is responsible for the  regulation of viral gene expression that is necessary to produce infectious CMV. As the CMV genetic material begins to reproduce, messenger RNA is used to encode  a specific  protein. Fomivirsen is a complemen- tary (antisense) sequence that binds to the  messenger  RNA sequences and  prohibits the  development of new  CMV  pro- teins. Because it is more  specific  to CMV, fomivirsen produces few side  effects. Because fomivirsen interferes with CMV rep- lication, CMV may  not  be able  to develop resistance as it has to ganciclovir and  other antivirals.

Clinical  Studies and  Reports of Fomivirsen Usage

Most clinical studies have involved the use of fomivirsen in the treatment of CMV retinitis (258–260) (Table 3.22).

Treatment

Treatment for CMV-retinitis is shown in Table 3.23.

Adverse Effects

In  AIDS  patients, pigmentary retinopathy, alterations in  the electro-retinogram, rings of over-or under-pigmented  retinal epithelium around the cornea (bull’s-eye maculopathy), and  cat- aracts have been  reported. Other common adverse effects  are:

Ocular inflammation. Vitreitis and/or iritis may  occur.

Intraocular pressure. Elevation of  intraocular  pres- sure occurs  in 10–20%  of cases.

Special Considerations

Fomivirsen has  a narrow therapeutic index. It can cause toxic effects  in some patients when the  same dose is safe for others. Widespread retinal epithelial charge can occur, causing severe peripheral loss (261,262).

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