(Amantadine, Rimantadine, Zanamivir, and Oseltamivir)
Although amantadine and rimantadine have been in use for some time, their effectiveness is limited to the treatment of inﬂuenza A. Both interfere with the ion channel function of the M2 protein and act indirectly on hemagglutinin. Inﬂuenza B does not have an M2 protein. Both amantadine and riman- tadine can cause gastrointestinal (GI) and central nervous system (CNS) symptoms that are especially troubling in the elderly. Viral resistance occurs in up to 30% of the population
and mutant viruses have been isolated from patients who have never been treated (320–322).
The inﬂuenza virus has two glycoprotein areas that facil- itate virus attachment and help distribute newly formed virons. These glycoprotein areas are called hemagglutinin (HA) and neuraminidase (NA). HA initiates viral adsorption and penetration. The NA allows for the release of the virions from the infected cell and from each other. NA may also play a role in the movement of the virus into the respiratory tract mucin layer. Zanamivir, a neuraminidase inhibitor, was designed based on the interaction of the inﬂuenza virus NA and cell-surface receptors. The active site is conserved in all known inﬂuenza A and B strains, making zanamivir a broad- spectrum treatment for inﬂuenza. By delivering high concen- trations of zanamivir via oral inhalation, viral replication in the respiratory tract is hindered.
Oseltamivir was later developed as an orally active inhib- itor based on the antiviral properties of zanamivir. By replac- ing the sugar ring with one of cyclohexene, placing an amino group in the 4’ position on the ring, and replacing the glycerol side chain with a hydrophobic pentyl ether group, oseltamivir phosphate can be administered as a solid capsule or oral sus- pension medication.
An additional inhibitor, known as biocryst, is being devel- oped and tested. In vitro and in vivo studies with mice indicate that efﬁcacy is comparable to zanamivir and oseltamivir (323). Biocryst is a hybrid, in that it has a guanidine group, as in zanamivir, and the hydrophobic group, as in oseltamivir. This structure may cause biocryst to facilitate reduced develop- ment of drug resistance by the inﬂuenza virus as mutations are less likely to occur (324). Both zanamivir and oseltamivir have very few side effects.
Amantadine was ﬁrst introduced as an antiviral in the 1960s. It was incidentally found to be a drug for the treatment of Parkinson’s disease because it has the ability to release
dopamine. Amantadine has been extensively tested as a possible treatment for drug dependence with limited success (325–330). However, more recently amantadine has been restudied as an antiviral agent, particularly in patients with chronic hepatitis C infection, with greater efﬁcacy and less cost than interferon- alpha. Amantadine has activity against inﬂuenza and some of the Flaviviridae (Fig. 3.33). It is identiﬁed as a potential block- ade to new cell infections (331). With the success of combining interferon treatment with ribavarin, testing is being expanded to include amantadine and interferon combination treatment to address the expanding concern over drug resistance of hep- atitis C (332). The advent of pegylated interferons may result in better treatment options for combination therapy with amantadine—a better pharmaco-dynamic proﬁle and antivi- ral efﬁcacy (333).
Mechanisms of Action
How amantadine causes antiviral activity is not understood. Amantadine may be a major blocker of new cell infections rather than a cure, per se, for viral infections, such as inﬂu- enza. Figure 3.34 is a comparison of the viral load with treat- ments of interferon, interferon and ribivarin, and interferon and amantadine. The delayed reaction of the interferon and
amantadine indicates the combination may have no direct effect on viral replication (334). It may also indicate that aman- tadine alone can reduce the viral load, but not completely elim- inate it (335). Amantadine may prevent the release of infectous viral nucleic acid by interfering with transmembrane function. Amantadine does not interfere with the immunogenicity of inactivated inﬂuenza A virus vaccine.
Clinical Studies that Support Treatment with Amantadine
The clinical safety and efﬁcacy proﬁle of amantadine is sketchy with positive and negative effects of most treat- ment therapies (331,332,336–349) (Table 3.30). A number of studies involving large complexes of military personnel or schools indicate that amantadine may be effective in reducing the effects of inﬂuenza, but may increase the num- ber of adverse effects on the subject population. As the dos- age of amantadine increases, there is an increased number of adverse effects. Patients treated with amantadine gener- ally experience one day less fever than those who are untreated (Fig. 3.35). This translates to a signiﬁcant eco- nomic advantage for workers who can return to work one day earlier.
Dosage for treatment is shown in Table 3.31.
Neurological presentations. Includes, but is not limited to, jitteriness, inability to concentrate, insomnia, tremors, confusion, depression, hallucinations, congestive heart failure, orthostatic hypotension, and urinary retention.
Rash or nausea. Symptoms usually disappear within a week.
Livedo reticularis. Purplish swelling of the ankles.
Neuroleptic malignant syndrome (NMS). Character- ized by high fever, disturbance of consciousness, and increased muscular rigidity (350,351).
Fig. 3.35 Duration of fever after treatment of inﬂuenza with amantadine. Patients treated with amantadine for inﬂuenza ex- perience approximately one day less fever than those with placebo.
Patients with HIV. In vitro, high doses of amantadine increase HIV infectivity. However, normal levels of amantadine in the plasma of patients being treated (300 ng/ml) are not nearly as high as those that stimu- late HIV activity (352).
Drug resistance. Drug-resistant H3N2-subtype inﬂu- enza A viruses have been isolated during treatment with amantadine and rimantadine, especially in insti- tutions (353).
Coadministration with anticholinergic and anti- parkinsonian agents, thiazide-type diuretics, and triamterene. Amantadine will react with these medi- cations with increased dry mouth, ataxia, blurred vi- sion, slurred speech, and toxic psychosis as clinical manifestations.
Abrupt discontinuation. May cause a parkinsonian crisis.
Renal insufﬁciency. Congestive heart failure. Peripheral edema. Orthostatic hypotension.
Rimantadine is a systemic antiviral agent that is used to pre- vent and treat inﬂuenza A viral infections. Rimantadine is taken as either a tablet or liquid by mouth. For maximum efﬁ- cacy, it is usually coadministered with inﬂuenza vaccine. Rimantadine is not effective for the treatment of colds, other types of inﬂuenza, or other virus infections (Fig. 3.36).
Mechanisms of Action
The mechanisms of action for rimantadine remain a mystery. It possibly affects the uncoating of the virus as inhibition occurs early during viral replication.
Clinical Studies that Support Treatment with Rimantadine
Numerous studies indicate that treatment with rimantadine is effective (354–356) (Table 3.32).
Rimantadine is taken with food or milk as it may cause an upset stomach. Nervousness, tiredness, difﬁculty in sleeping or concentrating, and light-headedness are fairly common side effects (Table 3.33). Antiviral agents should be considered for the prophylaxis and treatment of inﬂuenza for the following
Table 3.33 Treatment of Inﬂuenza with Rimantadine
Inﬂuenza A (prevention and treatment
Adults and children 10 years of age or older:
100 mg 2 times daily.
Elderly adults: 100 mg once a day. Children <10 years of age: 5 mg/kg of body
weight once a day, not to exceed 150 mg/
day as a prophylaxis.
individuals: 1) unvaccinated, high-risk persons; 2) high-risk persons when the vaccine/epidemic virus match is poor; 3) those who need protection during the 14-day period when the immune response is not fully developed after vaccination; 4) those with immunodeﬁciencies; 5) unvaccinated persons in close contact with a high-risk person; and 6) for outbreak control in long- term care facilities. Prophylaxis should be considered when there are others in the household who might be exposed to inﬂuenza and to increase the protection of vaccinated high- risk persons. Treatment is recommended for all high-risk per- sons with inﬂuenza or persons with severe inﬂuenza. Others with inﬂuenza also should be considered for treatment with an antiviral agent (357).
Yellowing of the skin or eyes. Indication that there may be an effect on the liver.
Mood changes. Mental confusion. Vision changes.
History of epilepsy or other seizures. Patients with a history of seizures or epilepsy may experience an in- crease in the frequency of convulsive events.
Kidney disease. Rimantadine is excreted through the kidneys. Patients with impaired kidney function must receive a lower dose of rimantadine.
Liver disease. Patients with liver disease may need to receive lower doses of rimantadine.
Zanamivir was the ﬁrst neuraminidase inhibitor approved by the FDA. It is used to treat naturally occurring inﬂuenza A and B and is administered by oral inhalation only (Fig. 3.37).
Mechanisms of Action
Zanamivir is a sialic acid analog. Antiviral activity occurs with inhibition of the inﬂuenza virus neuraminidase with some possibility that there is alteration of the virus particle aggre- gation and subsequent release of virions. By using herpes sim- plex virus translocating protein (VP22) to induce inﬂuenza into cells for the study of apoptosis, Morris, Smith, and Sweet were able to conﬁrm that neuraminidase induces apoptosis and to indicate that other proteins may be involved as no sin- gle inﬂuenza virus protein is responsible for apoptosis (358).
Studies that Support Treatment with Zanamivir
A review of studies to address effectiveness of zanamivir in healthy and at-risk adults, adverse effects, and cost effective- ness was reported by Burls et al. (359). The review concluded that zanamivir could be especially useful in the at-risk popu- lation where fewer hospitalizations and complications and a lower death rate occur for those treated with zanamivir (360–362) (Table 3.34).
Zanamivir reduces ﬂu symptoms, such as weakness, head- ache, fever, cough, and sore throat, by 1.0 to 1.5 days. It does not,
Efﬁcacy and safety of zanamivir in treating inﬂuenza in adults
In adults with inﬂuenza A or B virus infections, zanamivir, administered within 30 hours of onset of infection by inhalation therapy alone or in combination with intranasal therapy is safe and reduced symptoms if begun early.
Inﬂuenza in children undergoing therapy for acute lymphoblastic leukemia
Efﬁcacy of biocryst, zanamivir and oseltamivir on inﬂuenza A and B susceptibility
Zanamivir used as inﬂuenza treatment in the immunocompromised is effective.
Biocryst (RWJ-270201) is most effective; oseltamivir was more effective than zanamivir.
however, prevent inﬂuenza infection. Therapy should begin within 2 days of the onset of ﬂu symptoms. Zanamivir is administered as a dry-powder inhaler (10 mg twice daily for 5 days). Patients must be taught proper use of the inhaler for best efﬁcacy of treatment. Treatment with zanamivir does not keep a patient from infecting others with the ﬂu virus. Dos- ages are shown in Table 3.35.
Adverse effects are difﬁcult to assess in administration of zan- amivir. Adverse events tend to be bronchial or gastrointestinal in nature. It is difﬁcult to separate out what is a symptom of the inﬂuenza infection versus what is an adverse effect from the zanamivir or the method of administration (inhaled or intranasal). Nasal irritation, upper respiratory problems, and gastrointestinal distress occur with placebo (363).
Bronchial irritation in patients with asthma or air- ways disease. Zanamivir should be discontinued im- mediately and medical treatment started for asthma or airways disease. Some patients without prior pulmo- nary disease may have respiratory abnormalities from acute respiratory infection that could resemble adverse drug reactions or increase vulnerability to drug reac- tions. Brochospasm and decline in lung function have been reported in some patients receiving zanamivir. Zanamivir is not generally recommended for treatment of patients with underlying airways disease, such as asthma or chronic obstructive pulmonary disease.
Cough. Cough occurs in 2% of treatment cases.
Allergic reactions. Oropharyngeal edema and serious rashes (facial edema or other cutaneous reactions) have been reported. Zanamivir should be stopped and ap- propriate treatment for allergy instituted.
Cardiac. Arrhythmias, syncope.
Neurologic. Seizures may occur.
Drug interactions. No drug interactions have been published to date.
No laboratory-documented inﬂuenza-virus infec- tion. Zanamivir is of no beneﬁt in non-inﬂuenza cases. Before prescribing zanamivir, use rapid viral diagnosis when the likelihood of infection is not high.
Allergic reactions. Zanamivir is contraindicated in pa- tients with a known hypersensitivity to any component of the formulation.
Renal impairment. Patients with renal impairment do not require any dosage adjustment as there is low sys- temic availability of zanamivir.
Oseltamivir is a neuraminidase inhibitor that has been intro- duced recently for inﬂuenza management and treatment (364). It has been marketed in the European Union for the prevention and treatment of suspected inﬂuenza during epi- demics although one article questions the choices of oselta- mivir, zanamivir, or amantadine as useful for the prevention and treatment of inﬂuenza (365). Oseltamivir may have anti- viral implications for both inﬂuenza A and B. While other known inﬂuenza A antivirals appear to work with some efﬁ- cacy, there have been few drugs (other than zanamivir) known to be effective for inﬂuenza B. Oseltamivir seems to provide prophylaxis, particularly in households where one or more high-risk, but vaccinated, patients live, or where vaccination is unsuitable for other members of a household (366,367). Sec- ondary complications from inﬂuenza, such as otitis media, bronchitis, pneumonia, and sinusitis, are reduced with oselta- mivir (368). Oseltamivir seems to have no severe adverse effects and clinical resistance in humans to oseltamivir by inﬂuenza virus has not been extensively reported (368). Inﬂu- enza symptoms tend to improve within 24 hours if treatment begins within 24 hours of onset (369) (Fig. 3.38).
Mechanisms of Action
The antiviral oseltamivir is an ethyl ester prodrug of oselta- mivir carboxylate, a selective inhibitor of inﬂuenza A and B (Fig. 3.39). It is metabolized in the liver where it then distrib- utes throughout the body, including the upper and lower res- piratory tracts, a major site of infection (370,371). The oseltamivir carboxylate is 3% bound to human plasma pro- teins and excreted through the kidneys.
Clinical Studies that Support Treatment with Oseltamivir
Oseltamivir appears to be effective for prevention of inﬂuenza with few side effects. A summary of clinical trials that support effective treatment with oseltamivir is shown in Table 3.36 (368,369,371–378).
Oseltamivir has been shown to be over 85% effective in pre- venting inﬂuenza outbreaks among contacts within a house- hold, even after exposure (372). It is considered to be a safe and effective prophylaxis of inﬂuenza for the frail and elderly as there are signiﬁcantly fewer cases of laboratory-conﬁrmed clinical inﬂuenza and fewer inﬂuenza complications in patients receiving oseltamivir than in the placebo group (347). In outbreaks of inﬂuenza A, after amantadine failed to control the outbreak, oseltamivir was used successfully for outbreak control (367). In children, oseltamivir treatment reduced cough, coryza, duration of fever, and new cases of otitis media (379). Dosages for children are higher than those for adults in that they metabolize and excrete oseltamivir more rapidly than adults (Table 3.37).
Gastrointestinal disorder. Tend to be mild and tran- sient. Taking oseltamivir with food reduces the dura- tion of the symptoms (371).
Nausea and vomiting. Most commonly reported side ef- fects. Taking oseltamivir with food reduces the dura- tion of the symptoms (371).
Neurological symptoms (373).
Phlegm-producing cough or wheezing. The patient should stop using this medicine and seek emergency help immediately.
Co-administration with probenecid. May result in high blood levels of the active metabolite oseltamivir which may cause an increase in blood pressure.
Viral illnesses other than inﬂuenza A or B. Kidney, heart, lung, and liver diseases may affect the efﬁcacy of oseltamivir.
Children. Children may experience unexplained nose- bleeds or excessive watering or tearing of the eyes.
Pyrimidines inhibit enzymes in the DNA pathway and become incorporated into both cellular and viral DNA. This causes faulty transcription of messenger RNA and results in non- functioning viral proteins.
Triﬂuridine (1% Ophthalmic Solution)
Triﬂuridine is effective against herpes simplex types 1 and 2, CM V, vaccinia virus, and some strains of adenovirus (380–382). Treatment of keratoconjunctivitis and recurrent
Fig. 3.40 Associated names, structure, and applicability of triﬂuridine ophthalmic solution, 1%.
epithelial keratitis from HSV-1 and HSV-2 with triﬂuridine is FDA approved (Fig. 3.40). Topical triﬂuridine has been sug- gested as an alternative medicine following treatment failure with acyclovir-related agents, particularly in HIV-positive women (382). Triﬂuridine ophthalmic solution (1%) is an antiviral drug for the treatment of epithelial keratitis caused by herpes simplex virus. Triﬂuridine can also be used to treat vaccinia of the cornea and may be useful in ocular complica- tions from other poxviruses (383–386). A potential emerging problem is mass smallpox vaccination of 100 million persons where it is estimated that 1000–2000 cases of ocular vaccinia may occur.
Mechanism of Action
This compound is known to interfere with viral DNA synthe- sis in cultured mammalian cells. Triﬂuridine is a ﬂuorinated pyrimidine nucleoside. Although the mechanism of action is not known, triﬂuridine administration results in non-functional viral proteins.
Clinical Studies that Support Treatment with Triﬂuridine
Triﬂuridine is effective in treating herpes simplex and ocular complications from vaccinia (303,383–387) (Table 3.38).
Ocular burning or stinging. Approximately 4.6 % of patients experience this adverse effect.
Palpebral edema. Palpebral edema occurs in 2.8% of treatments.
Superﬁcial punctate keratopathy.
The eyes of those persons who continue to touch a smallpox immunization site are at risk, particularly those who use con- tact lenses. Hand-washing and covering the vaccination site are important. Triﬂuridine can be used to treat these outbreaks.
Mutagenicity. Chromatid exchange occurs with triﬂuri- dine in human lymphocytes and ﬁbroblasts. Teratoge- nicity occurs in injected eggs and chick embryos (388).