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Which of the following is NOT a characteristic of viruses?
Which of the following is NOT a characteristic of viruses?
What is the primary challenge in developing effective antiviral drugs?
What is the primary challenge in developing effective antiviral drugs?
Which of the following is a characteristic shared by all antiviral drugs?
Which of the following is a characteristic shared by all antiviral drugs?
Which of the following viruses is responsible for causing chickenpox and shingles?
Which of the following viruses is responsible for causing chickenpox and shingles?
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Which of the following viruses is NOT classified as an RNA virus?
Which of the following viruses is NOT classified as an RNA virus?
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Which of the following viruses is linked to the development of AIDS?
Which of the following viruses is linked to the development of AIDS?
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What is the primary reason why clinical symptoms of viral infections often appear late in the disease course?
What is the primary reason why clinical symptoms of viral infections often appear late in the disease course?
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Which of the following is NOT a factor considered when developing new antiviral drugs?
Which of the following is NOT a factor considered when developing new antiviral drugs?
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Which of the following DAA drugs inhibits the NS3/NS4A protease?
Which of the following DAA drugs inhibits the NS3/NS4A protease?
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What is the primary mechanism of action for DAA drugs that target the NS3/NS4A protease?
What is the primary mechanism of action for DAA drugs that target the NS3/NS4A protease?
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Which of the following is NOT a common adverse effect of NS3/NS4A protease inhibitors?
Which of the following is NOT a common adverse effect of NS3/NS4A protease inhibitors?
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What is the advantage of using DAA combination therapy for HCV treatment?
What is the advantage of using DAA combination therapy for HCV treatment?
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Which of the following is a nucleoside/nucleotide analog NS5B polymerase inhibitor?
Which of the following is a nucleoside/nucleotide analog NS5B polymerase inhibitor?
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What is the primary role of the NS5B polymerase in the HCV life cycle?
What is the primary role of the NS5B polymerase in the HCV life cycle?
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Why might HCV protease inhibitors have a lower barrier to resistance compared to other DAA classes?
Why might HCV protease inhibitors have a lower barrier to resistance compared to other DAA classes?
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Which of the following best describes the role of NS5A in HCV replication?
Which of the following best describes the role of NS5A in HCV replication?
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Which of the following are NS5A inhibitors, co-formulated with other direct-acting antivirals (DAAs)?
Which of the following are NS5A inhibitors, co-formulated with other direct-acting antivirals (DAAs)?
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Which of the following statements is TRUE about daclatasvir?
Which of the following statements is TRUE about daclatasvir?
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What is the mechanism of action of ribavirin in treating HCV?
What is the mechanism of action of ribavirin in treating HCV?
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What is the most likely reason for the reduced absorption of ledipasvir when gastric pH is increased?
What is the most likely reason for the reduced absorption of ledipasvir when gastric pH is increased?
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Which of the following is NOT a member of the Herpesvirus family?
Which of the following is NOT a member of the Herpesvirus family?
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Which of the following statements is true about Herpes Simplex Virus (HSV) types 1 and 2?
Which of the following statements is true about Herpes Simplex Virus (HSV) types 1 and 2?
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Which of the following viruses is known to cause infectious mononucleosis?
Which of the following viruses is known to cause infectious mononucleosis?
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What is the main difference between chickenpox and shingles?
What is the main difference between chickenpox and shingles?
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What is the primary mechanism by which acyclovir exerts its antiviral effect?
What is the primary mechanism by which acyclovir exerts its antiviral effect?
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Which of the following conditions is acyclovir NOT typically used to treat?
Which of the following conditions is acyclovir NOT typically used to treat?
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Which of the following statements about the pharmacokinetics of acyclovir is TRUE?
Which of the following statements about the pharmacokinetics of acyclovir is TRUE?
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Which enzyme is responsible for the initial phosphorylation step of acyclovir activation?
Which enzyme is responsible for the initial phosphorylation step of acyclovir activation?
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Which of the following is a potential concern in patients with renal impairment receiving acyclovir treatment?
Which of the following is a potential concern in patients with renal impairment receiving acyclovir treatment?
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Valacyclovir is preferred over acyclovir for oral administration because of its:
Valacyclovir is preferred over acyclovir for oral administration because of its:
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Acyclovir is considered the treatment of choice for which condition?
Acyclovir is considered the treatment of choice for which condition?
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What is the primary reason for administering acyclovir prophylactically to seropositive patients before bone marrow or heart transplant?
What is the primary reason for administering acyclovir prophylactically to seropositive patients before bone marrow or heart transplant?
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Which antiviral drug, specifically designed for topical application, inhibits HSV DNA polymerase by forming a nucleoside triphosphate?
Which antiviral drug, specifically designed for topical application, inhibits HSV DNA polymerase by forming a nucleoside triphosphate?
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Which antiviral drug is a prodrug that is metabolized to the active penciclovir, making it effective for oral administration?
Which antiviral drug is a prodrug that is metabolized to the active penciclovir, making it effective for oral administration?
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Which antiviral drug is structurally similar to thymidine and inhibits the incorporation of thymidine triphosphate into viral DNA?
Which antiviral drug is structurally similar to thymidine and inhibits the incorporation of thymidine triphosphate into viral DNA?
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Which antiviral drug is restricted to topical ophthalmic use due to its potential toxicity for systemic administration?
Which antiviral drug is restricted to topical ophthalmic use due to its potential toxicity for systemic administration?
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Which antiviral drug, originally developed as an anticancer drug, is FDA-approved for the treatment of HSV infections of the eyelid, conjunctiva, and cornea?
Which antiviral drug, originally developed as an anticancer drug, is FDA-approved for the treatment of HSV infections of the eyelid, conjunctiva, and cornea?
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Which antiviral drug is administered topically and has an intracellular half-life much longer than acyclovir triphosphate?
Which antiviral drug is administered topically and has an intracellular half-life much longer than acyclovir triphosphate?
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Which antiviral drug is effective for treating acute herpes zoster, genital HSV infection, and recurrent herpes labialis?
Which antiviral drug is effective for treating acute herpes zoster, genital HSV infection, and recurrent herpes labialis?
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Which antiviral drug's frequent application is necessary due to its short half-life?
Which antiviral drug's frequent application is necessary due to its short half-life?
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Which of the following is NOT a characteristic of Pegylated interferon-α-2a?
Which of the following is NOT a characteristic of Pegylated interferon-α-2a?
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What is the main reason Pegylated interferon-α is no longer the primary treatment for chronic hepatitis C?
What is the main reason Pegylated interferon-α is no longer the primary treatment for chronic hepatitis C?
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Which of the following drugs is NOT used in the oral treatment of chronic hepatitis B?
Which of the following drugs is NOT used in the oral treatment of chronic hepatitis B?
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What is the primary role of Ribavirin in the treatment of chronic hepatitis C?
What is the primary role of Ribavirin in the treatment of chronic hepatitis C?
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Which of the following is a mechanism by which pegylation of interferon-α improves its therapeutic efficacy?
Which of the following is a mechanism by which pegylation of interferon-α improves its therapeutic efficacy?
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What is the role of the sodium taurocholate co-transporting polypeptide (NTCP) receptor in the HBV infection process?
What is the role of the sodium taurocholate co-transporting polypeptide (NTCP) receptor in the HBV infection process?
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Which of the following steps in the HBV replication cycle is targeted by nucleoside and nucleotide analogues?
Which of the following steps in the HBV replication cycle is targeted by nucleoside and nucleotide analogues?
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Which of the following antiviral strategies may involve the use of gene editing technology?
Which of the following antiviral strategies may involve the use of gene editing technology?
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Study Notes
Antiviral Drugs
- Antiviral drugs are used to treat viral infections.
- Treatment is difficult compared to bacterial infections.
- Difficulty arises because viruses use host metabolic machinery for replication.
- Symptoms appear later in the course of the disease, when most virus particles have replicated.
- Research focuses identifying agents with greater selectivity, higher potency, in vivo stability, and reduced toxicity.
- Antiviral drugs are virustatic, meaning they are only active against replicating viruses and do not affect latent viruses.
Viruses- Introduction
- Viruses are obligate intracellular parasites.
- They lack a cell wall and membrane.
- They do not carry out metabolic processes.
- They consist of nucleic acid (DNA or RNA) enclosed in a protein coat (capsid).
- Some have a lipoprotein envelope containing antigenic glycoproteins.
- Treatment is challenging due to reliance on host metabolic machinery for viral replication.
- Virus particles replicate before clinical symptoms appear.
Examples of DNA & RNA Viruses
-
DNA viruses:
- Adenoviruses (colds, conjunctivitis)
- Hepadnaviruses (hepatitis B)
- Herpesviruses (cytomegalovirus, chickenpox, shingles)
- Papillomaviruses (genital warts)
- Poxviruses (smallpox)
-
RNA viruses:
- Arborviruses (tick-borne encephalitis, yellow fever)
- Arenaviruses (Lassa fever, meningitis)
- Orthomyxoviruses (influenza)
- Paramyxoviruses (measles, mumps)
- Picornaviruses (polio, meningitis, colds)
- Rhabdoviruses (rabies), rubella virus (German measles)
- Retroviruses (AIDS)
Treatment Approaches to Viral Infections
- The three basic approaches for treating viral diseases are vaccination, antiviral chemotherapy, and stimulating host resistance.
- Antiviral chemotherapy involves interfering with different steps of viral replication.
- The main challenge in antiviral chemotherapy is finding drugs selectively toxic to viruses without harming host cells.
- Current chemotherapy targets herpes viruses, cytomegalovirus (CMV), influenza viruses, respiratory syncytial virus (RSV), hepatitis viruses, and human immunodeficiency virus (HIV).
Viral Replication Cycle & Major Sites of Antiviral Drug Action
- Antiviral drugs act at various stages of the viral replication cycle.
- Drugs can block viral attachment and entry, penetration, uncoating, nucleic acid synthesis, packaging/assembly, viral protein synthesis, integration and transcription.
- Interferon alphas are hypothesized to act in multiple sites.
Treatment of Respiratory Viral Infections
- Treatment for infections such as influenza A and B relies on vaccination.
- Antiviral agents are used for patients allergic to the vaccine or during outbreaks.
- RSV infections cause respiratory tract and lung infections.
- RSV is common in young children.
Neuroaminidase Inhibitors
- Neuraminidases hydrolyze terminal sialic acid residues from virions and host cells.
- Oseltamivir and zanamivir are sialic acid analogs.
- These drugs are effective against type A and type B influenza viruses, and can prevent infection if given before exposure.
- They reduce symptom intensity and duration when administered within 48 hours of symptom onset.
Neuroaminidase Inhibitors - Oseltamivir & Zanmivir
- Oseltamivir is a prodrug, activated by hepatic esterases.
- It's eliminated in urine.
- Common side effects include gastrointestinal discomfort (nausea, abdominal pain).
- These symptoms are often reduced by consuming the drug with food.
- Zanmivir is administered intranasally and is eliminated in urine.
- Common side effects include respiratory tract irritation, transient discomfort, cough, bronchospasm and reversible pulmonary dysfunction.
- These inhibitors should be avoided in patients with severe asthma or COPD.
Resistance to Neuroaminidase Inhibitors
- Mutations in the neuraminidase enzyme have been observed in patients treated with neuroaminidase inhibitors.
- Mutants are often less infectious and virulent than the wild-type virus.
Inhibitors of Viral Uncoating - Adamantanes
- Amantadine and rimantadine block the M2 protein, a viral membrane matrix protein that acts as a hydrogen ion channel in influenza A virus infections.
- These agents were effective at preventing infection, if started before or at the time of virus exposure.
- Widespread resistance has caused the United States to not recommend this treatment or prophylaxis.
Inhibitors of Viral Uncoating - Mechanism of Action of Adamantanes
- Amantadine's antiviral activity was first described in 1964.
- The target is the M2 influenza A viral protein.
- Resistance results from a single amino acid change in the M2 protein.
- The M2 protein plays a crucial role in releasing viral ribonucleoprotein complexes into the cytoplasm.
- The process involves the fusion of viral and endosomal membranes.
Inhibitors of Viral Uncoating - Mechanism of Action of Adamantanes
- The M2 protein functions as an ion channel, whose activity is pH dependent.
- Increased pH-dependent channel activity is enhanced upon endosomal acidification.
- Proton movement acidifies the internal of the virus particle, promoting the dissociation between M1 and viral ribonucleoproteins, releasing the viral ribonucleoprotein complexes into the cytoplasm.
Inhibitors of Viral Uncoating - Adverse Drug Events of Adamantanes
- Common gastrointestinal issues and central nervous system toxicity include nausea, anorexia, nervousness, and difficulty concentrating.
- These effects may occur in 5%-33% of patients treated with amantadine and less frequently with rimantadine.
Ribavirin
- Ribavirin is a synthetic guanosine analog.
- It's effective against a broad range of RNA and DNA viruses.
- It's used to treat immunosuppressed children with severe RSV infections, chronic hepatitis C infection (in combination with other direct-acting antivirals), and others.
- Ribavirin is effective by inhalation and oral ingestion.
- Absorption is increased with a fatty meal.
Ribavirin mechanism of action
- Ribavirin is modified by cellular kinases to RMP and RTP.
- RTP enhances HCV mutagenesis and may inhibit HCV replication by blocking RNA-dependent RNA polymerase.
- RMP inhibits IMPDH, depleting intracellular GTP and impeding viral replication.
- Ribavirin may enhance antiviral T cell function.
Treatment of Hepatic Viral Infections
- Currently identified hepatitis viruses are A, B, C, D and E.
- Pathogenesis involves replication and destruction of hepatocytes.
- Hepatitis A, is commonly encountered but not chronic.
- Hepatitis B and C are the most common causes of chronic hepatitis, cirrhosis and HCC
- Chronic Hepatitis B is treated with peginterferon-alpha, Lamivudine, Entecavir, Adefovir and Tenofovir.
- Chronic Hepatitis C treatment includes a combination of direct-acting antiviral agents.
Treatment of Hepatitis Viral Infections
- Ribavirin may be added to some regimens to enhance virologic response.
- Pegylated interferon is no longer recommended for HCV treatment due to low efficacy and poor tolerability.
Treatment of Hepatitis B Viral (HBV) Infections- Interferons
- Interferons are naturally occurring, inducible cytokines (glycoproteins).
- They interfere with viral infection of cells.
- Interferons are produced through recombinant DNA technology.
- There are at least three types: α, β, and γ.
- Pegylated interferon formulations improve drug size and duration of action, and decrease drug clearance.
Interferons- Mechanism of Action
- Interferon action is not fully understood but appears to involve induction of host cellular enzymes that inhibit viral RNA translation and degradation of viral mRNA and tRNA.
- Interferon also works by inducing intracellular signals, stopping viral penetration, and other processes.
- Interferons increase the expression of major histocompatibility complex antigens.
- Interferons increase the activity of macrophages.
- Interferons enhance the production and survival of cytotoxic T cells.
Interferons- Therapeutic Uses
- Pegylated interferon α-2a is approved for chronic HBV treatment.
- Interferons are indicated for chronic HCV treatment in combination with other antiviral agents, but their use is becoming less frequent due to the availability of effective DAAs.
Interferons- Adverse Effects
- Common flu-like symptoms like fever, chills, myalgia, arthralgia, and gastrointestinal problems.
- Symptoms appear within six hours during the first week of therapy.
- Symptoms usually resolve with continued medication.
- Transient hepatic enzyme elevations are common, especially in responders, within eight to twelve weeks of therapy.
- Fatigue, mental depression and bone marrow suppression.
Lamivudine
- Lamivudine (3TC) is a nucleoside analog of cytidine.
- It must be phosphorylated to its active triphosphate form.
- The active form competes with dCTP for incorporation into the developing viral DNA strand and results in chain termination.
- This inhibits HBV DNA polymerase activity.
- Lamivudine is well tolerated with rare cases of headaches and dizziness.
- High rates of HBV resistance with long-term therapy make it no longer recommended.
Entecavir
- Entecavir is a deoxyguanosine analog.
- It requires intracellular phosphorylation to triphosphate form.
- It competes with deoxyguanosine triphosphate (dGTP) for viral reverse transcriptase.
- It inhibits reverse transcription, DNA replication, and transcription, impacting HBV replication process effectively against lamivudine resistant HBV strains.
- It is eliminated through glomerular filtration and tubular secretion, so renal function should be assessed regularly.
Adefovir
- Adefovir is a nucleotide analog.
- It's phosphorylated by cellular kinases to adefovir diphosphate.
- Incorporation into viral DNA terminates chain elongation, preventing viral replication.
- It's administered once daily and eliminated primarily through glomerular filtration and tubular secretion.
- Nephrotoxicity is a concern, especially with chronic use, requiring cautious administration in patients with pre-existing renal dysfunction.
Telbivudine
- Telbivudine is a synthetic thymidine β-L-nucleoside analog.
- It's a L-isomer of thymidine, differing in the spatial location of the sugar and base moieties compared to natural deoxynucleosides.
- Intracellular phosphorylation to the triphosphate form inhibits HBV DNA replication by causing chain termination.
- Administered orally once daily, typically with or without food, and eliminated by glomerular filtration as the unchanged drug.
NS3/NS4A Protease Inhibitors
- HCV NS3/NS4A protease, crucial for processing the single polyprotein, is the target of these inhibitors.
- Disruption of this protease leads to RNA replication disruption and HCV life cycle disruption.
- Ritonavir boosting is sometimes required with some protease inhibitors to increase their serum concentrations, like Paritaprevir.
- Example inhibitors include Grazoprevir, Glecaprevir, Voxilaprevir.
NS5B Polymerase Inhibitors
- NS5B is the RNA polymerase responsible for HCV replication and is the target of several inhibitors.
- Sofosbuvir is a nucleoside analog that competes with enzyme's active site.
- Dasabuvir is a non-nucleoside analog, targeting allosteric sites.
- These inhibitors are well-tolerated.
NS5A Replication Complex Inhibitors
- NS5A is important for HCV RNA replication and assembly and forming a membranous web.
- Examples of NS5A inhibitors include Ledipasvir, Elbasvir, Velpatasvir, Pibrentasvir, and Daclatasvir.
Ribavirin
- Ribavirin is still used in combination with other DAAs for HCV treatment, helping with viral clearance and reducing relapse rates, despite the precise mechanism being unclear.
- Factors for its use include cirrhosis status, HCV genotype/subtype, and treatment history.
Herpes Viruses
- Herpes viruses are double-stranded DNA viruses causing various human diseases, including herpes simplex, varicella zoster, Epstein-Barr, human cytomegalovirus, and Kaposi's sarcoma-associated herpesvirus.
Acyclovir
- Used in treating Herpes Simplex Virus (HSV) types 1 and 2, Varicella-zoster virus (VZV) and some Epstein-Barr virus-mediated infections.
- It's the treatment of choice for HSV encephalitis.
- Commonly used for genital herpes infections.
Acyclovir - Pharmacokinetics
- Is given topically, orally or intravenously.
- Distributes throughout the body, including the cerebrospinal fluid (CSF).
- Partially metabolized to an inactive product and is eliminated through urine via glomerular filtration and tubular secretion.
- Accumulates in patients with renal failure.
- A valyl ester (valacyclovir) has higher oral bioavailability.
Acyclovir - Adverse Drug Events
- Generally well-tolerated.
- Potential oral and topical side effects may include nausea, vomiting, and headaches.
Ganciclovir
- An acyclovir analog effective against cytomegalovirus (CMV).
- Used to treat CMV retinitis in immunocompromised patients and for CMV prophylaxis in transplant patients.
Cidofovir
- A nucleotide analog of cytosine.
- Used to treat CMV retinitis in AIDS patients.
- Given intravenously.
Foscarnet
- A pyrophosphate derivative.
- Interferes with viral DNA and RNA polymerases.
- Used for CMV retinitis in immunocompromised patients, and acyclovir-resistant HSV infections.
- Administered intravenously as it's poorly absorbed orally.
Penciclovir & Famciclovir
- Penciclovir is an acyclic guanosine nucleoside, active against HSV-1, 2 and VZV.
- Famciclovir is a prodrug metabolized to its active form penciclovir.
- Used for acute herpes zoster, genital HSV infection and recurrence of herpes labialis
- Both are well tolerated.
Trifluridine
- A fluorinated pyrimidine analog.
- Inhibits incorporation of thymidine triphosphate into viral DNA.
- Primarily used topically for HSV keratoconjunctivitis and keratitis.
Idoxuridine
- It's a fluorinated pyrimidine analog of Uridine.
- Used for viral infections of the eyelids, conjunctiva and cornea.
- It was the first antiviral drug.
- Marketed strictly for topical ophthalmic use.
Docosanol
- 1-Docosanol (behenyl alcohol) is an emollient, emulsifier and thickener.
- Clinically effective against HSV.
- Used for herpes labialis treatment.
Fomivirsen
- FDA-approved antisense antiviral drug for treating CMV retinitis in patients with AIDS who do not respond to other treatments or are contraindicated.
- Administered via intraocular injection.
- Can affect the eyes (iritis and vitritis).
Vidarabine
- A nucleoside analog that inhibits viral DNA polymerase and DNA synthesis.
- Used to treat HSV keratoconjunctivitis and keratitis, and in patients unresponsive to topical idoxuridine.
- Most commonly observed side effects include lacrimation, burning, irritation, pain, photophobia.
Antiviral Drugs for HIV Infections
- HIV infection requires a multi-drug regimen.
- The antiviral components includes Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), entry inhibitors, and integrase inhibitors.
- Pharmacokinetic enhancers (boosters) help increase drug levels for less frequent dosing and less variation in drug levels.
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Description
Test your knowledge on antiviral drugs and the characteristics of viruses with this detailed quiz. Explore various aspects of virus classification, the development of antiviral treatments, and specific viral infections such as chickenpox and AIDS. Perfect for students and professionals in the medical and biological sciences.
