ION CHANNEL FUNCTION INHIBITORS OF M2 PROTEINS AND NEURAMINIDASE INHIBITORS

5 Jun

(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

Introduction

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.

Treatment

Dosage for treatment is shown in Table 3.31.

Adverse Effects

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.

Special Considerations

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

Introduction

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).

Treatment

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

Symptom                                                Treatment

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).

Adverse Effects

Skin rash.

Yellowing of  the skin or  eyes. Indication that there may  be an effect on the  liver.

Mood changes. Mental confusion. Vision changes.

Special Considerations

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

Introduction

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).

Treatment

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

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.

Special Considerations

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

Introduction

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).

Treatment

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).

Adverse Effects

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.

Special Considerations

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

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)

Introduction

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).

Adverse Effects

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.

Special Considerations

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).

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