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OTHER ANTIVIRALS AND MEDICATIONS

5 Jun

Foscarnet

Introduction

Foscarnet is used for the  treatment of CMV retinitis in immu- nosuppressed patients (187). Forcarnet also has  emerged as a replacement for  acyclovir for  herpes simplex infections that have become  acyclovir-resistant (389). Approved for use by the FDA,  foscarnet is  an  organic analog of inorganic pyrophos- phate (Fig. 3.41). The unique mechanism of foscarnet makes it more  effective against TK-negative viral strains. In  addition, foscarnet has  efficacy  against VZV strains that are  acyclovir resistant although this use  of foscarnet is not  FDA-approved. Other possible applications of foscarnet include HIV  and HHV-8  (213,390–393).

Fig. 3.41 Associated names, structure, and  applicability of foscarnet.

Mechanism of Action

As an  organic analog of inorganic pyrophosphate, foscarnet inhibits viral DNA polymerase by blocking its  pyrophosphate binding site  (Fig.  3.42).  Foscarnet also  inhibits HIV  reverse transcriptase in  the  same manner. The  nucleotide triphos- phates are  unable to cleave  from the  pyrophosphate and  there is  inhibition of further  primer-template extension (392).

Another asset of foscarnet is that it does not require phospho- rylation by viral thymidine kinase (TK) for intracellular acti- vation. This  makes foscarnet effective against  TK-negative viral strains.

Clinical  Studies and  Reports that Support the Use of Foscarnet

A diverse number of clinical studies and reports support the use of foscarnet as  a  major replacement therapy when acyclovir- resistant strains of specific  viruses are  present (186,211,

391–405) (Table 3.40).

Treatment

Currently, foscarnet is administered intravenously (Table 3.41) or  by  injection. Foscarnet does  not  cure  CMV  retinitis, but may  help  in  preventing a worsening of symptoms. Foscarnet must be  administered regularly as  it works best  when the blood  titer does  not  vary. Foscarnet has  been  used for  CMV infections in the  lungs, esophagus, and  intestines and  for VZV infections that do not respond to acyclovir.

Adverse Effects

Anemia. Foscarnet may  cause or worsen anemia, dehy- dration, or kidney disease. Sores or ulcers in the  mouth or throat are  rare.

Most common side effects. Some  of the  more  common effects  may  not  need  medical attention  and  may  go away as the  body adjusts to foscarnet. These include:

Abdominal or stomach pain. Anxiety.

Confusion. Dizziness.

Loss of appetite. Nausea and vomiting.

Unusual tiredness or weakness. Headache.

Anemia without neutropenia.

Electrolytic imbalances. Patients may  experience in- creased thirst and  a change in frequency of urination. Foscarnet may  cause genital ulcerations. Washing the genitals after urination may decrease the extent of this problem.

Nausea and vomiting. Headache.

Central nervous system disturbances. Convulsions, muscle twitching, and  tremors are  less  common.

Renal dysfunction. Renal dysfunction is  usually re- versible provided there is  frequent monitoring of se- rum creatinine levels  and  adequate hydration.

Renal toxicity. Risk  of renal toxicity is increased when other nephrotoxic medications are  concurrently admin- istered. Dose adjustments should be made if changes in renal function occur.

Tingling, pain, or   numbness. A  tingling  sensation around the  mouth or  pain or  numbness in  hands or feet  while  receiving medication may  indicate a drop  in normal calcium levels.

Special Considerations

Foscarnet-resistance. Six  patients with AIDS  have been  reported to have foscarnet-resistant HSV. Five  of these cases had  been  previously treated with foscarnet (391,392). Some  of these cases responded to acyclovir, but there are reports of resistance to both acyclovir and foscarnet (406).

Monotherapy failure with foscarnet or ganciclovir.

Combination therapy of both  foscarnet and  ganciclovir is indicated.

Aminoglycoside antibiotics coadministration. Coad- ministration of foscarnet with aminoglycoside antibiot- ics increases the  risk of renal toxicity.

Amphotericin B coadministration. Coadministration with foscarnet increases the  risk of renal toxicity.

Other drug contraindications or  dosage concerns:

•  Carmustine;

•  Cisplatin;

• Combination pain medicine containing acetaminophen and  aspirin or  other salicylates (with large amounts taken regularly);

• Cyclosporine;

• Deferoxamine (with long-term use);

• Gold salts (medicine for arthritis);

• Inflammation or pain medicine, except narcotics;

•  Lithium;

•  Methotrexate;

• Other anti-infectives (e.g., noted above);

• Penicillamine;

• Plicamycin;

• Streptozocin; or

• Tiopronin.

Use  of these medications may  increase chances for renal dysfunction.

Pentamidine

Use  of pentamidine  injection with foscarnet may  lower  the level  of calcium and  magnesium in  the  blood. This  increases the  chance for kidney problems.

Pregnant women. Not indicated for use in pregnant wom- en. Foscarnet causes birth defects in studies in animals.

Breast-feeding. It is not  known to what degree foscar- net  appears in breast milk  and  what effect there might be on the  breast-feeding infant.

Children. No studies of risk or efficacy  in children.

Hydration. Unless otherwise indicated, patients should drink several glasses of water each  day  to  help  pre- vent some  unwanted effects   foscarnet may  have on the  kidneys.

Docosonal

Introduction

1-Docosanol (n-docosanol) is an  alcohol  that exerts an  inhibi- tory effect on the replication of viruses, such  as herpes simplex and  respiratory syncytial virus. Combination of docosanol and antiviral nucleoside analogs (e.g., acyclovir) can have a syner- gistic  effect with few toxic side  effects  (Fig. 3.43).

Fig. 3.43 Associated names, structure, and  applicability of n-docosanol.

Mechanism of Action

n-Docosanol is a 22-carbon, straight-chain, saturated  alcohol formulated for  topical applications as  a  cream. The  mecha- nism of action is  unclear. Pope  et  al.  have reported that n- docosanol inhibits viral entry (407). Spruance reports that n- docosonal is a suspension as  it is insoluble in water, does  not inactivate the  virus directly, and  is not  cytotoxic (408). For  n- docosonal to  be  most  effective, it should be  applied before infection occurs  (409,410). Spruance further  reports that  n- docosonal may  be an  anti-inflammatory agent in the  murine model  and  a clinical trial supports the  idea  (411).

Treatment

Topical  docosanol is used to treat symptoms of herpes simplex viral infections on  the  lips  and  around the  mouth. Topical docosanol does  not  cure  herpes simplex but  relieves the  pain and  may  help  lesions heal faster.

IMPLICATIONS FOR NEW ANTIVIRAL AGENTS

As new  viral diseases emerge and  medicines that task the immune system become  more  common practice, challenges for developing new and  better antivirals as alternative treatment strategies gain  more  importance. DNA-based viruses are  a frequent cause of infection as  they are  able  to develop long- term latency after the  initial infection and  are  opportunistic when the  patient’s immune system is challenged (196).

Detection of viral diseases at an  early stage via  various diagnostic tests enables clinicians to  make immediate deci- sions  on treatment options. It is inappropriate to treat a dis- ease  with antivirals if the  disease is not  virus-based. Toxicity of many antivirals is a concern as it may  place  several compo- nents of a patient population at risk to the  point that the  risks outweigh the  benefits.

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