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Antiviral Drugs

Antiviral drugs

Definition

Antiviral drugs act against diseases caused by viruses.

Description

Viruses represent a large group of infective agents that are composed of a core of nucleic acids, either RNA or DNA, surrounded by a layer of protein. They are not really living organisms according to general understanding, since they lack the cell membrane that is associated with living cells. Viruses can reproduce only inside a living cell, and they cause many diseases. Viruses are not normally affected by antibiotics but a small number of viruses can either be destroyed or have their growth stopped by drugs.

The drugs as of 2004 available for treatment of viral diseases in children are:

  • Acyclovir (Zovirax), used for treatment of diseases caused by the erpes simplex virus and herpes zoster virus. Although it is approved only for children over the age of six months, the drug has been used for newborn infants with encephalitis . This drug is most reliable when given intravenously.
  • Amantidine (Symmetrel), used to prevent or treat infections of the influenza virus type A. It is recommended for patients who cannot or should not receive influenza virus vaccine. As of 2004 it has not been studied in children below the age of one year.
  • Foscarnet (Foscavir), is not recommended for young children but may be given to adolescents. It is used to treat cytomegalovirus infections of the eye, and for herpes simplex infections that are resistant to other drugs.
  • Ganciclovir (Cytovene), used to treat cytomegalovirus infections of the eye. Although the manufacturer does not recommend use of ganciclovir in patients below the age of 12 years, the drug is recommended by standard pediatric references for children as young as three months.
  • Oseltamivir (Tamiflu), used for treatment of influenza virus infections of children over the age of 13 years. In adults, oseltamivir has also been used for prevention if influenza, but this use has not been studied in children.
  • Ribavirin (Rebetol, Virazol), used for treatment of hospitalized infants and young children with severe lower respiratory tract infections caused by respiratory syncytial virus (RSV), but its value is controversial.
  • Rimantidine (Flumadine), used to protect against the influenza virus type A.
  • Valacyclovir (Valtrex), used for treatment of diseases caused by the herpes simplex virus and herpes zoster virus. This drug is converted to acyclovir inside the body and is more reliable for oral use. Although the manufacturer says that safety and efficacy in children have not been established, valacyclovir is recommended for use in standard pediatric resources.
  • Vidarabine (Vira-A), used to treat severe herpes infections in the newborn, but its primary value is in the form of an eye ointment to treat herpes infections of the eye.
  • Zanamivir (relenza), used to treat influenza infections caused by viruses types A and B in adults and children over the age of seven.

In addition to the above drugs, there are drugs which treat retrovirus infections. Retroviruses are composed of RNA molecules instead of DNA, and the only treatable one is the one that causes acquired immune deficiency syndrome (AIDS ). The drugs in this group that are appropriate for treatment of children are as follows:

  • abacavir (Ziagen)
  • amprenavir (Agenerase), for children above the age of four
  • didanosine (Videx)
  • efavirenz (Sustiva), for children over the age of three
  • indinavir (Crixavan), according to the manufacturer safety and efficacy of which in children has not been established, but the drug has been recommended in standard pediatric references
  • lamivudine (Epivir), for treatment of hepatitis B as well as for AIDS
  • lopinavir/Ritonavir fixed combination (Kaletra), used in children as young as six months
  • stavudine (Zerit)
  • nelfinavir (Viracept), the manufacturer of which does not recommend use of this drug for children younger than two, but it has been studied with some success in children as young as newborns
  • ritonavir (Norvir)
  • saquinavir (Fortovase, Invirase)
  • zalcitabine (Hivid)
  • zidovudine (Retrovir)

Other drugs for treatment of HIV disease are marketed, but there have been neither sufficient studies not clinical experience to recommend their use in children.

General use

The antiviral drugs are used to prevent or treat the diseases listed above. These drugs are specific for individual viruses and offer no benefit for conditions caused by other viruses.

Precautions

Each of the drugs listed has specific warnings. See specific drugs references or ask a pediatrician.

Side effects

Each of the drugs listed has its own side effects. See specific drugs references or ask a pediatrician.

Indinavir (Crixivan) has the unique adverse effects of causing changes in patterns of fat distribution. This has been called Crix belly and may be more distressing to the patient than more serious side effects caused by other drugs since these effects are clearly visible. As of 2004 it is not clear whether this effect can be reversed when the drug is discontinued. Antiretroviral drugs should not be discontinued unless there is an alternative antiretroviral regimen to adopt.

Interactions

See specific drugs references or ask a pediatrician about interactions for an antiviral drug that has been prescribed.

Patients should use these drugs exactly as directed. With regard to the AIDS drugs in particular, the drugs should not be discontinued without consultation with the prescriber. AIDS drugs are normally prescribed in combinations of two and three drugs used together, and discontinuing any single drug may lead to the virus developing resistance to the other agents.

Parental concerns

Liquid dosage forms must always be measured with a calibrated teaspoon or dropper, never with a household teaspoon. Household teaspoons vary in the volume they deliver and may result in inadvertent overdose or under dose.

Anti-influenza drugs should be used only for patients who cannot receive vaccinations. Annual vaccination remains the preferred method of preventing influenza.

Antiretroviral drugs are routinely given in combinations of three to four drugs at a time. In some cases, fixed combinations of medications are the most practical way to administer these drugs, since they require the lowest number of doses each day.

Some antiviral drugs, particularly the antiretroviral agents, have potentially severe adverse effects. They should be prescribed only by qualified professionals experienced in their use. These drugs must be routinely monitored. Regular laboratory testing is essential for safe and effective use. Adverse effects and side effects must be reported to the prescriber as soon as they are observed.

Antiherpetic drugs may have only a limited value in reducing the severity or duration of herpes attacks. They are more important for their effect in reducing the period of viral shedding, the period of time in which a person infected with herpes virus can infect other people. For this reason, continued use of the drugs is important to family members and those in close proximity to the patient. The drugs should not be discontinued, even if there is no observed benefit.

KEY TERMS

Herpes virus A family of viruses including herpes simplex types 1 and 2, and herpes zoster (also called varicella zoster). Herpes viruses cause several infections, all characterized by blisters and ulcers, including chickenpox, shingles, genital herpes, and cold sores or fever blisters.

Influenza virus type The nature of the proteins in the outer coat of an influenza virus. Depending on the proteins, influenza viruses may be classified as A, B, or C.

Retrovirus A family of RNA viruses containing a reverse transcriptase enzyme that allows the viruses' genetic information to become part of the genetic information of the host cell upon replication. Human immunodeficiency virus (HIV) is a retrovirus.

Virus A small infectious agent consisting of a core of genetic material (DNA or RNA) surrounded by a shell of protein. A virus needs a living cell to reproduce.

See also Herpes simplex; HIV infection and AIDS; Influenza.

Resources

BOOKS

Beers, Mark H., and Robert Berkow, eds. The Merck Manual, 2nd home ed. West Point, PA: Merck & Co., 2004.

Mcevoy, Gerald, et al. AHFS Drug Information 2004. Bethesda, MD: American Society of Healthsystems Pharmacists, 2004.

PERIODICALS

Bell, G. S. "Highly active antiretroviral therapy in neonates and young infants." Neonatal Netword: The Journal of Neonatal Nursing 23, no. 2 (March-April 2004: 5564.

Eksborg, S. "The pharmacokinetics of antiviral therapy in pediatric patients." Herpes 10, no. 3 (December 2003): 6671.

Fraaij, Pieter L., et al. "Therapeutic drug monitoring in children with HIV/AIDS." Therapeutic Drug Monitoring 26, no. 2 (April 2004): 1226.

Feder, Henry M., Jr., and Diane M. Hoss. "Herpes zoster in otherwise healthy children." Pediatric Infectious Diseases Journal 23, no. 5 (May 2004): 4517.

Jaspan, H. B., and R. F. Garry. "Preventing neonatal HIV: a review." Current HIV Research 1, no. 3 (July 2003): 3217.

Kamin, D., and C. Hadigan C. "Hyperlipidemia in children with HIV infection: an emerging problem." Expert Reviews in Cardiovascular Therapy 1, no. 1 (May 2003): 14350.

Maggon, Krishan, and Sailen Barik. "New drugs and treatment for respiratory syncytial virus." Reviews in Medical Virology 14, no. 3 (May-June 2004): 14968.

Rakhmanina, Natella Y., et al. "Therapeutic drug monitoring of antiretroviral therapy." AIDS Patient Care and STDS 18, no. 1 (January 2004): 714.

Whitley, Richard. "Neonatal herpes simplex virus infection." Current Opinion in Infectious Diseases 17, no. 3 (June 2004): 2436.

ORGANIZATIONS

Elisabeth Glaser Pediatric AIDS Foundation. 1140 Connecticut Avenue NW, Suite 200, Washington, DC 20036. Web site: <www.charitywire.com/charity60/>.

WEB SITES

National Institute of Allergy and Infectious Diseases. Available online at <www.niaid.nih.gov/default.htm> (accessed October 17, 2004).

National Institute of Child Health & Human Development. Available online at <www.nichd.nih.gov/> (accessed October 17, 2004).

National Pediatric AIDS Network. Available online at <www.npan.org/> (accessed October 17, 2004).

The Pediatric AIDS Clinical Trials Group. Available online at <http://pactg.s-3.com/> (accessed October 17, 2004)

"Pediatric Antiretroviral Drug Information." Available online at <http://aidsinfo.nih.gov/guidelines/pediatric%5CSUP_PED_012004.html> (accessed October 17, 2004).

Samuel Uretsky, PharmD

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Antiviral Drugs

Antiviral Drugs

Definition

Antiviral drugs are medicines that cure or control virus infections.

Purpose

Antivirals are used to treat infections caused by viruses. Unlike antibacterial drugs, which may cover a wide range of pathogens, antiviral agents tend to be narrow in spectrum, and have limited efficacy.

Description

Exclusive of the antiretroviral agents used in HIV (AIDS) therapy, there are currently only 11 antiviral drugs available, covering four types of virus. Acyclovir (Zovirax), famciclovir (Famvir), and valacyclovir (Valtrex) are effective against herpesvirus, including herpes zoster and herpes genitalis. They may also be of value in either conditions caused by herpes, such as chickenpox and shingles. These drugs are not curative, but may reduce the pain of a herpes outbreak and shorten the period of viral shedding.

Amantadine (Symmetrel), oseltamivir (Tamiflu), rimantidine (Flumadine), and zanamivir (Relenza) are useful in treatment of influenza virus. Amantadine, rimantadine, and oseltamivir may be administered throughout the flu season as preventatives for patients who cannot take influenza virus vaccine.

KEY TERMS

Asthenia Muscle weakness.

Cytomegalovirus (CMV) A type of virus that attacks and enlarges certain cells in the body. The virus also causes a disease in infants.

Herpes simplex A virus that causes sores on the lips (cold sores) or on the genitals (genital herpes).

HIV Acronym for human immunodeficiency virus, the virus that causes AIDS.

Parkinsonism A group of conditions that all have these typical symptoms in common: tremor, rigidity, slow movement, and poor balance and coordination.

Pregnancy category A system of classifying drugs according to their established risks for use during pregnancy. Category A: Controlled human studies have demonstrated no fetal risk. Category B: Animal studies indicate no fetal risk, but no human studies, or adverse effects in animals, but not in well-controlled human studies. Category C: No adequate human or animal studies, or adverse fetal effects in animal studies, but no available human data. Category D: Evidence of fetal risk, but benefits outweigh risks. Category X: Evidence of fetal risk. Risks outweigh any benefits.

Prophylactic Guarding from or preventing the spread or occurrence of disease or infection.

Retrovirus A group of viruses that contain RNA and the enzyme reverse transcriptase. Many viruses in this family cause tumors. The virus that causes AIDS is a retrovirus.

Shingles An disease caused by an infection with the Herpes zoster virus, the same virus that causes chickenpox. Symptoms of shingles include pain and blisters along one nerve, usually on the face, chest, stomach, or back.

Virus A tiny, disease-causing structure that can reproduce only in living cells and causes a variety of infectious diseases.

Cidofovir (Vistide), foscarnet (Foscavir), and ganciclovir (Cytovene) have been beneficial in treatment of cytomegalovirus in immunosupressed patients, primarily HIV-positive patients and transplant recipients. Ribavirin (Virazole) is used to treat respiratory syncytial virus. In combination with interferons, ribavirin has shown some efficacy against hepatitis C, and there have been anecdotal reports of utility against other types of viral infections.

As a class, the antivirals are not curative, and must be used either prophylactically or early in the development of an infection. Their mechanism of action is typically to inactivate the enzymes needed for viral replication. This will reduce the rate of viral growth, but will not inactive the virus already present. Antiviral therapy must normally be initiated within 48 hours of the onset of an infection to provide any benefit. Drugs used for influenza may be used throughout the influenza season in high risk patients, or within 48 hours of exposure to a known carrier. Antiherpetic agents should be used at the first signs of an outbreak. Anti-cytomegaloviral drugs must routinely be used as part of a program of secondary prophylaxis (maintenance therapy following an initial response) in order to prevent reinfection in immunocompromised patients.

Recommended dosage

Dosage varies with the drug, patient age and condition, route of administration, and other factors. See specific references.

Precautions

Ganciclovir is available in intravenous injection, oral capsules, and intraoccular inserts. The capsules should be reserved for prophylactic use in organ transplant patients, or for HIV infected patients who cannot be treated with the intravenous drug. The toxicity profile of this drug when administered systemically includes granulocytopenia, anemia and thrombocytopenia. The drug is in pregnancy category C, but has caused significant fetal abnormalities in animal studies including cleft palate and organ defects. Breast feeding is not recommended.

Cidofovir causes renal toxicity in 53% of patients. Patients should be well hydrated, and renal function should be checked regularly. Other common adverse effects are nausea and vomiting in 65% or patients, asthenia in 46% and headache and diarrhea, both reported in 27% of cases. The drug is category C in pregnancy, due to fetal abnormalities in animal studies. Breast feeding is not recommended.

Foscarnet is used in treatment of immunocompromised patients with cytomegalovirus infections and in acyclovir-resistant herpes simples virus. The primary hazard is renal toxicity. Alterations in electrolyte levels may cause seizures. Foscarnet is category C during pregnancy. The drug has caused skeletal abnormailities in developing fetuses. It is not known whether foscarnet is excreted in breast milk, however the drug does appear in breast milk in animal studies.

Valaciclovir is metabolized to acyclovir, so that the hazards of the two drugs are very similar. They are generally well tolerated, but nausea and headache are common adverse effects. They are both pregnancy category B. Although there have been no reports of fetal abnormalities attributable to either drug, the small number of reported cases makes it impossible to draw conclusions regarding safety in pregnancy. Acyclovir is found in breast milk, but no adverse effects have been reported in the newborn. Famciclovir is similar in actions and adverse effects.

Ribavirin is used by aerosol for treatment of hospitalized infants and young children with severe lower respiratory tract infections due to respiratory syncytial virus (RSV). When administered orally, the drug has been used in adultys to treat other viral diseases including acute and chronic hepatitis, herpes genitalis, measles, and Lassa fever, however there is relatively little information about these uses. In rare cases, initiation of ribavirin therapy has led to deterioration of respiratory function in infants. Careful monitoring is essential for safe use.

The anti-influenza drugs are generally well tolerated. Amantadine, which is also used for treatment of Parkinsonism, may show more frequent CNS effects, including sedation and dizziness. Rapid discontinuation of amantidine may cause an increase in Parkinsonian symptoms in patients using the drug for that purpose. All are schedule C for pregnancy. In animal studies, they have caused fetal malformations in doses several times higher than the normal human dose. Use caution in breast feeding.

Interactions

Consult specific references for information on drug interactions.

Use particular caution in HIV-positive patients, since these patients are commonly on multi-drug regimens with a high frequency of interactions. Ganciclovir should not be used with other drugs which cause hematologic toxicity, and cidofovir should not be used with other drugs that may cause kidney damage.

Resources

PERIODICALS

Gray, Mary Ann. "Antiviral Medications." Orthopaedic Nursing 15 (November-December 1996): 82.

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Antiviral Drugs

Antiviral drugs

Definition

Antiviral drugs are medicines that cure or control virus infections.

Purpose

Antivirals are used to treat infections caused by viruses. Unlike antibacterial drugs, which may cover a wide range of pathogens, antiviral agents tend to be narrow in spectrum, and have limited efficacy.

Description

Exclusive of the antiretroviral agents used in HIV (AIDS ) therapy, there are currently only 11 antiviral drugs available, covering four types of virus. Acyclovir (Zovirax), famciclovir (Famvir), and valacyclovir (Valtrex) are effective against the herpes virus, including herpes zoster and herpes genitalis. They may also be of value in either conditions caused by herpes, such as chicken pox and shingles . These drugs are not curative, but may reduce the pain of a herpes outbreak and shorten the period of viral shedding.

Amantadine (Symmetrel), oseltamivir (Tamiflu), rimantidine (Flumadine), and zanamivir (Relenza) are useful in treatment of the influenza virus. Amantadine, rimantadine, and oseltamivir may be administered throughout the flu season as preventatives for patients who cannot take influenza virus vaccine.

Cidofovir (Vistide), foscarnet (Foscavir), and ganciclovir (Cytovene) have been beneficial in treatment of cytomegalovirus in immunosupressed patients, primarily HIV-positive patients and transplant recipients. Ribavirin (Virazole) is used to treat respiratory syncytial virus. In combination with interferons , ribavirin has shown some efficacy against hepatitis C, and there have been anecdotal reports of utility against other types of viral infections.

As a class, the antivirals are not curative, and must be used either prophylactically or early in the development of an infection. Their mechanism of action is typically to inactivate the enzymes needed for viral replication. This will reduce the rate of viral growth, but will not inactive the virus already present. Antiviral therapy must normally be initiated within 48 hours of the onset of an infection to provide any benefit. Drugs used for influenza may be used throughout the influenza season in high risk patients, or within 48 hours of exposure to a known carrier. Antiherpetic agents should be used at the first signs of an outbreak. Anti-cytomegaloviral drugs must routinely be used as part of a program of secondary prophylaxis (maintenance therapy following an initial response) in order to prevent reinfection in immunocompromised patients.

Recommended dosage

Dosage varies with the drug, patient age and condition, route of administration, and other factors. See specific references.

Precautions

Ganciclovir is available in intravenous injection, oral capsules, and intraoccular inserts. The capsules should be reserved for prophylactic use in organ transplant patients, or for HIV infected patients who cannot be treated with the intravenous drug. The toxicity profile of this drug when administered systemically includes granulocytopenia, anemia, and thrombocytopenia. The drug is in pregnancy category C, but has caused significant fetal abnormalities in animal studies including cleft palate and organ defects. Breast-feeding is not recommended.

Cidofovir causes renal toxicity in 53% of patients. Patients should be well hydrated, and renal function should be checked regularly. Other common adverse effects are nausea and vomiting in 65% or patients, asthenia in 46% and headache and diarrhea, both reported in 27% of cases. The drug is category C in pregnancy, due to fetal abnormalities in animal studies. Breast-feeding is not recommended.

Foscarnet is used in treatment of immunocompromised patients with cytomegalovirus infections and in acyclovir-resistant herpes simples virus. The primary hazard is renal toxicity. Alterations in electrolyte levels may cause seizures . Foscarnet is category C during pregnancy. The drug has caused skeletal abnormalities in developing fetuses. It is not known whether foscarnet is excreted in breast milk, however the drug does appear in breast milk in animal studies.

Valaciclovir is metabolized to acyclovir, so that the hazards of the two drugs are very similar. They are generally well tolerated, but nausea and headache are common adverse effects. They are both pregnancy category B. Although there have been no reports of fetal abnormalities attributable to either drug, the small number of reported cases makes it impossible to draw conclusions regarding safety in pregnancy. Acyclovir is found in breast milk, but no adverse effects have been reported in the newborn. Famciclovir is similar in actions and adverse effects.

Ribavirin is used by aerosol for treatment of hospitalized infants and young children with severe lower respiratory tract infections due to respiratory syncytial virus (RSV). When administered orally, the drug has been used in adults to treat other viral diseases including acute and chronic hepatitis, herpes genitalis, measles, and Lassa fever, however there is relatively little information about these uses. In rare cases, initiation of ribavirin therapy has led to deterioration of respiratory function in infants. Careful monitoring is essential for safe use.

The anti-influenza drugs are generally well tolerated. Amantadine, which is also used for treatment of Parkinsonism, may show more frequent CNS effects, including sedation and dizziness . Rapid discontinuation of amanti-dine may cause an increase in Parkinsonian symptoms in patients using the drug for that purpose. All are schedule C for pregnancy. In animal studies, they have caused fetal malformations in doses several times higher than the normal human dose. Use caution in breast-feeding.

Interactions

Consult specific references for information on drug interactions.

Use particular caution in HIV-positive patients, since these patients are commonly on multi-drug regimens with a high frequency of interactions. Ganciclovir should not be used with other drugs which cause hematologic toxicity, and cidofovir should not be used with other drugs that may cause kidney damage.

Resources

PERIODICALS

Gray, Mary Ann. "Antiviral Medications." Orthopaedic Nursing 15 (November-December 1996): 82.

Samuel D. Uretsky, PharmD

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Antiviral Drugs

Antiviral drugs

Antiviral drugs are compounds that are used to prevent or treat viral infections, via the disruption of an infectious mechanism used by the virus, or to treat the symptoms of an infection.

Different types of antiviral drugs have different modes of operation. For example, acyclovir is a drug that is used to treat the symptoms of the infections arising from the herpes virus family. Such infection includes lesions on the genitals, oral region, or in the brain. Acyclovir is also an antiviral agent in the treatment of chickenpox in children and adults, and shingles in adults caused by the reactivation of the chickenpox virus after a period of latency. Shingles symptoms can also be treated by the administration of valacyclovir and famciclovir.

Eye infections caused by cytomegalovirus can be treated with the antiviral agent known as ganciclovir. The drug acts to lessen the further development and discomfort of the eye irritation. But, the drug may be used as a preventative agent in those people whose immune system will be compromised by the use of an immunosupressant.

Another category of antiviral drugs is known as the antiretroviral drugs. These drugs target those viruses of clinical significance called retroviruses that use the mechanism of reverse transcription to manufacture the genetic material needed for their replication. The prime example of a retrovirus is the Human immunodeficiency virus (HIV ), which is the viral agent of acquired immunodeficiency syndrome (AIDS ). The development of antiviral drugs has been stimulated by the efforts to combat HIV. Some anti-HIV drugs have shown promise against hepatitis B virus, herpes simplex virus, and varicella-zoster virus.

The various antiviral agents are designed to thwart the replication of whatever virus they are directed against. One means to achieve this is by blocking the virus from commandeering the host cell's nuclear replication machinery in order to have its genetic material replicated along with the host's genetic material. The virus is not killed directly. But the prevention of replication will prevent the numbers of viruses from increasing, giving the host's immune system time to deal with the stranded viruses.

The incorporation of the nucleotide building blocks into deoxyribonucleic acid (DNA ) can be blocked using the drug idoxuridine or trifluridine. Both drugs replace the nucleoside thymidine, and its incorporation produces a nonfunctional DNA. However, the same thing happens to the host DNA. So, this antiviral drug is also an anti-host drug. Vidarabine is another drug that acts in a similar fashion. The drug is incorporated into DNA in place of adenine. Other drugs that mimic other DNA building blocks.

Blockage of the viral replicative pathway by mimicking nucleosides can be successful. But, because the virus utilizes the host's genetic machinery, stopping the viral replication usually affects the host cell.

Another tact for antiviral drugs is to block a viral enzyme whose activity is crucial for replication of the viral genetic material. This approach has been successfully exploited by the drug acyclovir. The drug is converted in the host cell to a compound that can out compete another compound for the binding of the viral enzyme, DNA polymerase, which is responsible for building DNA. The incorporation of the acyclovir derivative exclusively into the viral DNA stops the formation of the DNA. Acyclovir has success against herpes simplex viruses, and Epstein-Barr virus . Another drug that acts in a similar fashion is famiciclovir.

Other antiviral drugs are directed at the translation process, whereby the information from the viral genome that has been made into a template is read to produce the protein product. For example, the drug ribavirin inhibits the formation of messenger ribonucleic acid .

Still other antiviral drugs are directed at earlier steps in the viral replication pathway. Amantadine and rimantadine block the influenza A virus from penetrating into the host cell and releasing the nuclear material.

Antiviral therapy also includes molecular approaches. The best example is the use of oligonucleotides. These are sequences of nucleotides that are specifically synthesized to be complimentary with a target sequence of viral ribonucleic acid. By binding to the viral RNA , the oligonucleotide blocks the RNA from being used as a template to manufacture protein.

The use of antiviral drugs is not without risk. Host cell damage and other adverse host reactions can occur. Thus, the use of antiviral drugs is routinely accompanied by close clinical observation.

See also Immunodeficiency diseases; Viruses and responses to viral infection

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antiviral drug

antiviral drug, any of several drugs used to treat viral infections. The drugs act by interfering with a virus's ability to enter a host cell and replicate itself with the host cell's DNA. Some drugs block the virus's attachment or entry into the cell; others inhibit replication or prevent the virus from shedding the protein coat that surrounds the viral DNA. Antiviral drug development has been concurrent with advances in molecular biology and genetic engineering that allow study and definition of the genetic codes of viral DNA. Study at this level was not possible until electron microscopes became available and it is only since the 1980s that antiviral drugs have been on the market.

Antivirals are now available for a wide variety of viral diseases. Ribavirin, available since the mid-1980s, is used to treat respiratory syncytial virus (RSV), a cause of severe childhood respiratory infections. It is thought to inhibit messenger RNA. Ribavirin has few side effects, but is prohibitively expensive for all but the most serious cases. Amantadine and rimantadine, which are effective against strains of influenza A, act by interfering with viral uncoating.

Herpes simplex virus can now be treated by a highly selective drug, acyclovir (Zovirax), that interferes with an enzyme critical to the growth of the DNA chain. Although not a cure, the drug lessens the frequency and severity of outbreaks. Acyclovir is also used to lessen the pain and speed the healing of herpes zoster (shingles).

The search for cures and palliatives for AIDS has yielded drugs such as zidovudine (AZT), which inhibits the transcription of RNA to DNA in human immunodeficiency virus (HIV). Ganciclovir and cidofovir are used in the treatment of cytomegalovirus (CMV), a virus that affects the eyes of immunosuppressed patients. Fomivirsen, which is an antisense drug, is also used to treat CMV.

See also nucleic acid, virus, retrovirus.

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antiviral

antiviral Describing a drug or other agent that kills or inhibits viruses and is used to combat viral infections. Several types of antiviral drug are now in use, such as acyclovir, effective against herpesviruses, and zidovudine (AZT), a reverse transcriptase inhibitor that is used to treat HIV infection. The body's own natural antiviral agents, interferons, can now be produced by genetic engineering and are sometimes used therapeutically. However, many antiviral agents are extremely toxic, and viruses evolve rapidly so that a drug's effectiveness can soon be lost.

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antiviral drug

antiviral drug (anti-vy-răl) n. a drug effective against viruses that cause disease. Antiviral drugs include aciclovir, ganciclovir, foscarnet, oseltamivir, and ribavirin, used for treating herpes, cytomegalovirus, influenza, and respiratory syncytial virus infections; and antiretroviral drugs, used for treating HIV infections and AIDS.

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antiviral

an·ti·vi·ral / ˌantēˈvīrəl; ˌantī-/ • adj. Med. (chiefly of a drug or treatment) effective against viruses.

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Antiviral Drugs

Antiviral Drugs

Definition

Antiviral drugs are medicines that cure or control virus infections.

Purpose

Antivirals are used to treat infections caused by viruses. Unlike antibacterial drugs, which may cover a wide range of pathogens, antiviral agents tend to be narrow in spectrum, and have limited efficacy.

Description

Exclusive of the antiretroviral agents used in HIV (AIDS ) therapy, there are currently only 11 antiviral drugs available, covering four types of virus. Acyclovir (Zovirax), famciclovir (Famvir), and valacyclovir (Valtrex) are effective against herpesvirus, including herpes zoster and herpes genitalis. They may also be of value in either conditions caused by herpes, such as chickenpox and shingles. Thesedrugs arenot curative,but mayreducethe pain of a herpes outbreak and shorten the period of viral shedding.

Amantadine (Symmetrel), oseltamivir (Tamiflu), rimantidine (Flumadine), and zanamivir (Relenza) are useful in treatment of influenza virus. Amantadine, rimantadine, and oseltamivir may be administered throughout the flu season as preventatives for patients who cannot take influenza virus vaccine.

Cidofovir (Vistide), foscarnet (Foscavir), and ganciclovir (Cytovene) have been beneficial in treatment of cytomegalovirus in immunosupressed patients, primarily HIV-positive patients and transplant recipients. Ribavirin (Virazole) is used to treat respiratory syncytial virus. In combination with interferons, ribavirin has shown some efficacy against hepatitis C, and there have been anecdotal reports of utility against other types of viral infections.

As a class, the antivirals are not curative, and must be used either prophylactically or early in the development of an infection. Their mechanism of action is typically to inactivate the enzymes needed for viral replication. This will reduce the rate of viral growth, but will not inactive the virus already present. Antiviral therapy must normally be initiated within 48 hours of the onset of an infection to provide any benefit. Drugs used for influenza may be used throughout the influenza season in high risk patients, or within 48 hours of exposure to a known carrier. Antiherpetic agents should be used at the first signs of an outbreak. Anti-cytomegaloviral drugs must routinely be used as part of a program of secondary prophylaxis (maintenance therapy following an initial response) in order to prevent reinfection in immuno-compromised patients.

Recommended dosage

Dosage varies with the drug, patient age and condition, route of administration, and other factors. See specific references.

Precautions

Ganciclovir is available in intravenous injection, oral capsules, and intraoccular inserts. The capsules should be reserved for prophylactic use in organ transplant patients, or for HIV infected patients who cannot be treated with the intravenous drug. The toxicity profile of this drug when administered systemically includes granulocytopenia, anemia, and thrombocytopenia. The drug is in pregnancy category C, but has caused significant fetal abnormalities in animal studies, including cleft palate and organ defects. Breastfeeding is not recommended.

Cidofovir causes renal toxicity in 53% of patients. Patients should be well hydrated, and renal function should be checked regularly. Other common adverse effects are nausea and vomiting in 65% or patients, asthenia in 46% and headache and diarrhea, both reported in 27% of cases. The drug is category C in pregnancy, due to fetal abnormalities in animal studies. Breastfeeding is not recommended.

Foscarnet is used in treatment of immunocom-promised patients with cytomegalovirus infections and in acyclovir-resistant herpes simples virus. The primary hazard is renal toxicity. Alterations in electrolyte levels may cause seizures. Foscarnet is category C during pregnancy. The drug has caused skeletal abnormailities in developing fetuses. It is not known whether foscarnet is excreted in breast milk, however the drug does appear in breast milk in animal studies.

Valaciclovir is metabolized to acyclovir, so that the hazards of the two drugs are very similar. They are generally well tolerated, but nausea and headache are common adverse effects. They are both pregnancy category B. Although there have been no reports of fetal abnormalities attributable to either drug, the small number of reported cases makes it impossible to draw conclusions regarding safety in pregnancy. Acyclovir is found in breast milk, but no adverse effects have been reported in the newborn. Famciclovir is similar in actions and adverse effects.

KEY TERMS

Asthenia— Muscle weakness.

Cytomegalovirus (CMV)— A type of virus that attacks and enlarges certain cells in the body. The virus also causes a disease in infants.

Herpes simplex— A virus that causes sores on the lips (cold sores) or on the genitals (genital herpes).

HIV— Acronym for human immunodeficiency virus, the virus that causes AIDS.

Parkinsonism— A group of conditions that all have these typical symptoms in common: tremor, rigidity, slow movement, and poor balance and coordination.

Pregnancy category— A system of classifying drugs according to their established risks for use during pregnancy. Category A: Controlled human studies have demonstrated no fetal risk. Category B: Animal studies indicate no fetal risk, but no human studies, or adverse effects in animals, but not in well-controlled human studies. Category C: No adequate human or animal studies, or adverse fetal effects in animal studies, but no available human data. Category D: Evidence of fetal risk, but benefits outweigh risks. Category X: Evidence of fetal risk. Risks outweigh any benefits.

Prophylactic— Guarding from or preventing the spread or occurrence of disease or infection.

Retrovirus— A group of viruses that contain RNA and the enzyme reverse transcriptase. Many viruses in this family cause tumors. The virus that causes AIDS is a retrovirus.

Shingles— An disease caused by an infection with the Herpes zoster virus, the same virus that causes chickenpox. Symptoms of shingles include pain and blisters along one nerve, usually on the face, chest, stomach, or back.

Virus— A tiny, disease-causing structure that can reproduce only in living cells and causes a variety of infectious diseases.

Ribavirin is used by aerosol for treatment of hospitalized infants and young children with severe lower respiratory tract infections due to respiratory syncytial virus (RSV). When administered orally, the drug has been used in adults to treat other viral diseases including acute and chronic hepatitis, herpes genitalis, measles, and Lassa fever, however there is relatively little information about these uses. In rare cases, initiation of ribavirin therapy has led to deterioration of respiratory function in infants. Careful monitoring is essential for safe use.

The anti-influenza drugs are generally well tolerated. Amantadine, which is also used for treatment of parkinsonism, may show more frequent CNS effects, including sedation and dizziness. Rapid discontinuation of amantidine may cause an increase in parkinsonian symptoms in patients using the drug for that purpose. All are schedule C for pregnancy. In animal studies, they have caused fetal malformations in doses several times higher than the normal human dose. Use caution in breastfeeding.

Interactions

Consult specific references for information on drug interactions.

Use particular caution in HIV-positive patients, since these patients are commonly on multi-drug regimens with a high frequency of interactions. Ganciclovir should not be used with other drugs which cause hematologic toxicity, and cidofovir should not be used with other drugs that may cause kidney damage.

Resources

PERIODICALS

Gray, Mary Ann. "Antiviral Medications." Orthopaedic Nursing 15 (November-December 1996): 82.

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Antiviral Drugs

Antiviral Drugs

Introduction

History and Scientific Foundations

Applications and Research

Impacts and Issues

BIBLIOGRAPHY

Introduction

Antiviral drugs are used to prevent or treat viral infections. They are antimicrobial compounds, as are anti-biotics. However, antiviral compounds do not have the same mode of action as antibiotics. This is because most antibiotics rely on the ability of the bacteria to grow and divide. Bacteria grow and divide independently. In contrast, viruses must infect a host cell before they can exploit the host cell's genetic machinery to manufacture the components of new virus particles. Antibiotics are useless against viruses, both because viruses are localized inside of another cell or tissue, and because viruses are not alive in the absence of the host cell.

Antibiotics and antiviral drugs are similar in that specific drugs are designed for specific targets. For example, anti-retroviral drugs specifically inhibit infections caused by retroviruses, such as the human immunodeficiency virus (HIV). Other antiviral drugs specifically target other viruses, including herpes viruses and the various hepatitis viruses.

History and Scientific Foundations

The history of antiviral compounds dates back only to the 1960s. Prior to that time, a viral illness had to run its course. In the 1960s, antiviral drugs were developed to deal with herpes infections (which include cold sores, genital infection, chickenpox, mononucleosis, and Kaposi's sarcoma). At that time, the development of the drugs was more a trial-and-error process than a directed process. The process typically involved growing cultures of a particular type of cell and then infecting the cells with a particular virus. Successful infection is often apparent by a change in the appearance of the host cell. By adding compounds during the infection, researchers could monitor whether the visible signs of infection occurred or not. The absence of changes in the host cells was an indication that the particular compound was a potential antiviral agent.

This process was tedious and time-consuming. Beginning in the 1970s, advances in molecular biology made antiviral drug design more focused. The genetic sequences of disease-causing viruses began to be determined. In addition, it was learned that many viruses initiated infection by recognizing and binding to sites on the surface of host cells. As the three-dimensional shapes of these host sites and the molecular details of the binding of the virus were clarified, it became possible to design compounds to block the binding.

The binding process can be blocked in two ways. In one approach, the target site on the host surface is occupied by an added molecule. Because the site is occupied, the virus is unable to bind to it. In the second approach, the viral recognition site is blocked by the addition of a molecule. The blocking molecule may be an antibody—a protein that is produced by the immune system—that has been produced in the laboratory. Then virus particles cannot gain access to the host cell; they are stranded outside the host cells and can be destroyed when they are recognized by the hosts’ immune system, which causes antiviral immune molecules to be made and deployed.

This strategy of blocking viral infection very early in the infectious process is the basis of some viral vaccines. It can be very successful if the host or viral target sites do not change. However, in viral infections such as influenza, the viral site can change from year to year. A vaccine designed for the viral strain that dominates one year may be ineffective the next year, which is why new influenza vaccines need to be produced and administered prior to each flu season.

Some antiviral drugs operate slightly differently, by blocking the uptake of virus into the host cell. Other antiviral drugs prevent the infecting virus from using the host cell's genetic replication (duplication) mechanisms. The numbers of infecting viruses are not reduced, but, because the infection process is blocked, new viruses are not made. Once again, the host's immune system can more easily deal with the stranded viruses.

Two antiviral drugs, idoxuridine and trifluridine, halt viral infection at the genetic level. These drugs act by replacing one of the units (a compound called thymidine) that forms the genetic material. The drugs are able to do this because their structure is similar to the structure of thymidine. The incorporation of either drug produces DNA that does not function. Other drugs mimic other compounds, and their incorporation produces the same result. However, the drugs can also be incorporated into the DNA of the host cells, which disrupts their function. This action can cause side effects, but if the infection is stopped it can be worthwhile in the longer term.

Other antiviral drugs, such as acyclovir, target an enzyme produced by the virus, usually early in the infection, that is vital for the replication of the genetic material. The drug binds to the enzyme, which prevents the enzyme from binding to its normal target. As a result, DNA formation stops. Acyclovir is used to treat infections due to herpes simplex viruses and Epstein-Barr virus.

Zidovudine (AZT) acts against HIV by blocking the activity of the reverse transcriptase enzyme. This enzyme makes it possible for the infecting virus to convert its RNA to DNA, and this DNA is subsequently used by the host cell's replication machinery to produce new viral constituents. The compound can become incorporated into the host cell DNA, which also blocks the replication of viral genetic material. AZT is beneficial in reducing the transmission of HIV from a pregnant woman to her developing fetus and to her newborn during labor or breastfeeding.

WORDS TO KNOW

ANTIBODY: Antibodies, or Y-shaped immunoglobulins, are proteins found in the blood that help to fight against foreign substances called antigens. Antigens, which are usually proteins or polysaccharides, stimulate the immune system to produce antibodies. The antibodies inactivate the antigen and help to remove it from the body. While antigens can be the source of infections from pathogenic bacteria and viruses, organic molecules detrimental to the body from internal or environmental sources also act as antigens. Genetic engineering and the use of various mutational mechanisms allow the construction of a vast array of antibodies (each with a unique genetic sequence).

ENZYME: Enzymes are molecules that act as critical catalysts in biological systems. Catalysts are substances that increase the rate of chemical reactions without being consumed in the reaction. Without enzymes, many reactions would require higher levels of energy and higher temperatures than exist in biological systems. Enzymes are proteins that possess specific binding sites for other molecules (substrates). A series of weak binding interactions allow enzymes to accelerate reaction rates. Enzyme kinetics is the study of enzymatic reactions and mechanisms. Enzyme inhibitor studies have allowed researchers to develop therapies for the treatment of diseases, including AIDS.

MESSENGER RIBONUCLEIC ACID (MRNA): A molecule of RNA that carries the genetic information for producing one or more proteins; mRNA is produced by copying one strand of DNA, but in eukaryotes is able to move from the nucleus to the cytoplasm (where protein synthesis takes place).

REPLICATION: A process of reproducing, duplicating, copying, or repeating something, such as the duplication of DNA or the recreation of characteristics of an infectious disease in a laboratory setting.

RESISTANCE: Immunity developed within a species (especially bacteria) via evolution to an antibiotic or other drug. For example, in bacteria, the acquisition of genetic mutations that render the bacteria invulnerable to the action of antibiotics.

STRAIN: A subclass or a specific genetic variation of an organism.

Still other antiviral drugs focus on translation—the process whereby the messenger ribonucleic acid (mRNA) (which is formed from instructions encoded in DNA) is used to manufacture compounds, such as protein. Some antiviral drugs block mRNA formation and disrupt the translation process. Antiviral therapy also involves molecular tools. The best example is oligonucleotides, which are sequences of the building blocks of genetic material that are deliberately made to be complimentary to a target sequence of viral genetic material. The term complimentary means that the two sequences are able to chemically associate with one another. When the oligonucleotide binds to a stretch of viral genetic material, it prevents that stretch from being used in viral replication. One oligonucleotide-based drug is available for the treatment of eye infections in patients with acquired immunodeficiency syndrome (AIDS, also cited as acquired immune deficiency syndrome).

Applications and Research

The different mechanisms of action of different antiviral drugs have been useful in treating a variety of viral infections. For example, acyclovir, which was the first successful antiviral drug developed, is used to treat infections caused by herpes viruses, which include lesions on the genitals, in the mouth, and even in the brain, as well as treating chickenpox and shingles. The antiviral drug ganciclovir has been useful in the treatment of cytomegalovirus-mediated eye infections.

A well-known type of antiviral drug acts against retroviruses, in particular human HIV, the virus that causes AIDS. Most of the anti-retroviral drugs that have been developed have focused on combating HIV. The antiviral drug combination known as highly active anti-retroviral therapy (HAART) is targeted at blocking the use of the HIV RNA to manufacture DNA (which is then used to make the viral components); blocking the integration of viral genetic material into the host genome; and blocking adhesion of the virus to host cells. This multi-pronged approach can delay the progression of AIDS.

Research is progressing on antiviral drugs to block enzymes that cut DNA or RNA or proteins. These enzymes are important in the viral manufacturing process, and so their disruption can stop viral replication. Researchers are also exploring ways to block the release of an assembled virus from the host cell. If release can be blocked, new host cells cannot be infected and the infection stops.

Impacts and Issues

Antiviral drugs are invaluable in the treatment of viral diseases. Millions of people infected with HIV or suffering from the symptoms of AIDS utilize them. The U.S. National Institutes of Health recommends HAART even if symptoms are absent. HAART is expensive, however. This has limited its use to those who can afford it, either because of personal finances or government assistance. In the regions that are most affected by AIDS, such as sub-Saharan Africa, HAART is far less available. Economics deprive those most in need of help. Organizations, including the International Center for Research on Health, are working to introduce HAART more widely in Africa, and to encourage its use.

Anti-retroviral drugs, such as those used in HAART, are urgently needed in sub-Saharan Africa, where more than 25 million people are infected with HIV. It has been argued that widespread availability and use of anti-retroviral drugs could make AIDS in Africa a treatable (although still chronic) disease, similar to the situation in Europe, Australia, and North America. However, such a large-scale humanitarian effort may be unrealistic, given that private industry would likely bear most of the economic burden.

Despite this gloomy picture, some hope can be drawn from a 2003 pilot project by Médecins Sans Frontières, which demonstrated that anti-retroviral programs could be implemented in regions as poor as rural Africa. Furthermore, a United Nations summit held in 2005 produced a pledge from the leaders of the economically advantaged Group of Eight countries to make access to anti-retroviral drugs universal by 2010. However, many challenges remain to realize this ambitious goal.

Another issue involving antiviral drugs is the risks posed by their use. One example is the reverse transcriptase inhibitor, AZT. While the use of AZT has reduced maternal transmission of HIV, research published in 2007, which utilized animal models of the infection and also the genetic examination of humans, indicates that this benefit may be accompanied by a risk of cancer later in the infant's life. Fetuses exposed to AZT were found to display markedly more mutations in their genetic material than those not exposed to the drug. Since many cancers are associated with mutations, the research has highlighted a previously unrecognized risk of AZT therapy.

A second example concerns the antiviral drug oseltamivir phosphate (sold as Tamiflu®). The drug, which is used to combat viral influenza and which is approved for Americans one year of age and older, has recognized side effects. The most common (nausea and vomiting) are relatively inconsequential, but Tamiflu has been anecdotally linked to instances of abnormal mental behavior in teenagers in Japan and 84 adverse events in Canada, including the deaths of 10 elderly people. Health Canada is monitoring its use and is prepared to take more stringent action if warranted, in light of the possibility that a flu epidemic could result in the use of Tamiflu® by millions of people worldwide.

In 2006, Tamiflu® resistance was reported in several people infected with the H5N1 strain of the influenza virus. H5N1 is the cause of a serious and sometimes lethal form of flu called avian influenza (bird flu). Resistance to drugs is always a concern, since over time and with the increased use of the particular drug, the resistant strain becomes predominant in a population, making the disease much harder, and usually more expensive, to treat. Since Tamiflu® is available at pharmacies, the possibility that the drug might be used improperly or inappropriately increases the likelihood that such resistance will develop. Monitoring by the U.S. Centers for Disease Control and Prevention (CDC) did not detect the resistant strain in the U.S. during 2006. However, surveillance is ongoing, since the global range of H5N1 is growing, and because the evolving ability of the virus to be more easily transmitted from person to person makes the possibility of a global epidemic increasingly likely.

See AlsoDeveloping Nations and Drug Delivery; Pandemic Preparedness.

BIBLIOGRAPHY

Books

Driscoll, John S. Antiviral Drugs. New York: Wiley, 2005.

Torrence, Paul F. Antiviral Drug Discovery for Emerging Diseases and Bioterrorism Threats. New York: Wiley-Interscience, 2005.

Periodicals

Monto, Arnold S. “Vaccines and Antiviral Drugs in Pandemic Preparedness.” Emerging Infectious Diseases 12 (January 2006): 55–61.

Witt, Kristine L., et al. “Elevated Frequencies of Micronucleated Erythrocytes in Infants Exposed to Zidovudine in Utero and Postpartum to Prevent Mother-to-Child Transmission of HIV.” Environmental and Molecular Mutagenesis 48 (April-May 2007): 322–329.

Brian Hoyle

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Antiviral Drugs

Antiviral drugs

Definition

Antiviral drugs are medicines that kill or weaken viruses , infectious agents that can only live and reproduce inside living host cells.

Antiviral drugs
Brand name Generic name
(Illustration by GGS Information Services. Cengage Learning, Gale)
Copegus, Rebetolribavirin
Cytoveneganciclovir
Famvirfamciclovir
Flumadinerimantadine hydrochloride
Foscavirfoscarnet sodium
Relenzazanamivir
Symmetrelamantadine hydrochloride
Synagispalivizumab
Tamifluoseltamivir phosphate
Valcytevalganciclovir
Valtrexvalacyclovir hydrochloride
Vistidecidofovir
Zoviraxacyclovir

Purpose

For seniors, antivirals are usually used to treat two conditions: influenza (flu) and Shingles (Herpes Zoster).

Influenza (flu)

Flu can produce a variety of symptoms ranging from mild, with low-grade fever, aching muscles, cough and sore throat, to severe, with high fever, shaking chills, pneumonia and even death .

People who are chronically ill or undergoing chemotherapy are more susceptible to flu complications.

Older seniors are more prone to complications from the flu.

Annual vaccination is the best way of preventing and controlling flu.

Flu viruses change and can become resistant to medications as they spread around the world, so vaccination and antiviral drug therapy may be only partially effective in reducing the severity of the flu.

Antiviral medications are used in three important situations: to treat the flu and reduce its severity, to prevent flu in high-risk groups living closely together, like in nursing homes , and to protect people exposed to someone with the flu.

Shingles (herpes zoster)

Shingles is a usually painful outbreak of rash, sometimes with blisters, on the skin that is caused by the same virus that causes chicken pox.

Shingles occurs in people who have had chicken pox as children. The virus appears to lie dormant in the body for many years.

The first signs of Shingles may vary from numbness and itching to tingling and burning

Shingles rash is usually only on one side and can appear as a band or line anywhere on the head, chest or back.

The pain of Shingles can be mild or intense and is often worsened by light touch or even a slight breeze on the involved area.

Antiviral drugs, including acyclovir, valcyclovir, or famcyclovir, when given early, can reduce the severity and duration and perhaps lessen the possibility of painful after-effects of Shingles.

Shingles rash and pain usually lasts around four weeks.

Seniors who have shingles can pass the virus, causing chicken pox, to children who haven't had the disease.

Postherpetic neuralgia can be a painful aftereffect of Shingles that continues after the blisters and rash have disappeared.

Other drugs like corticosteroids, antidepressants, anticonvulsants, and topical anesthetics are also used to treat postherpetic neuritis.

VZV vaccine (Zostavax) is available for seniors to reduce the risk, severity, and complications of Shingles.

Resources

PERIODICALS

Gray, Mary Ann. “Antiviral Medications.” Orthopaedic Nursing 15 (November-December 1996): 82.

Sam Uretsky PharmD

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