Fomivirsen Chemische Eigenschaften,Einsatz,Produktion Methoden
Indications
Fomivirsen (Vitravene), an anti-CMV agent, is the first
antisense oligonucleotide to be approved by the U. S.
Food and Drug Administration (FDA) as an antiviral
therapy. Fomivirsen is an oligonucleotide complementary
to the major immediate early region 2 (IE2) of
CMV mRNA. By binding to IE2 mRNA, fomivirsen
prevents its translation to protein and thereby blocks
viral replication. Because this mechanism of action is different from that of other antiviral agents, crossresistance
with other drugs used to treat CMV is unlikely.
Pharmazeutische Anwendungen
An antisense oligonucleotide, 21 bases in length, representing
the mirror image of a region of mRNA coding for a
regulatory protein of CMV. It is administered as the sodium
salt by intraocular injection. Experiments in monkeys suggest
that it has a very long elimination half-life (c. 3 days). Because
of its unique mode of action fomivirsen retains activity against
strains of CMV resistant to other antiviral agents.
Side effects commonly include ocular inflammation, which is
responsive to topical steroids, and raised intraocular pressure.
Mechanism of action
Fomivirsen inhibits CMV by at least two mechanisms. The first is a sequence-specific
antisense binding to inhibit expression of immediate-early genes, thus preventing viral
replication. The second is sequence-independent and involves inhibition of adsorption of
CMV to host cells, probably by direct binding to viral coat proteins. The
reduction of immediate-early protein synthesis occurs in a dose-dependent manner.
Although it does inhibit viral replication, fomivirsen does not eradicate the virus whose
DNA, as for all herpesviruses, is integrated into the human genome. Therefore,
treatment will have to continue for the life of the patient.
Pharmakokinetik
The series of clinical trials that led to approval by the U.S. Food and Drug
Administration involved 430 eyes in 330 patients. Fomivirsen significantly delayed
progression of CMV retinitis in patients with AIDS, including those who had failed
treatment with ganciclovir or foscarnet, the first-line therapies. Fomivirsen is
administered by intravitreal injection at doses of 165 μg once weekly for three weeks of
induction and then once every two weeks. It also can be administered in a dose of 330
μg on days 1 and 15 and then once a month thereafter. Mean maximum retinal
concentrations of fomivirsen occur at 2 days, and the elimination half-life after a single,
115-μg dose in monkey retina was 78 hours. There are no systemic side effects. Ocular
side effects include increased intraocular pressure and mild to moderate intraocular
inflammation that can be reversed with topical steroid treatment. It is important that side
effects be minor, because treatment will be lifelong.
Clinical Use
Fomivirsen is used to treat CMV retinitis in patients
with AIDS who have not responded to other treatments
or in whom other treatments are contraindicated. It appears
to be at least as effective as other treatments and
produces fewer side effects. Because CMV retinitis is
often associated with CMV infection elsewhere in the
body, patients undergoing treatment with fomivirsen
should be monitored for extraocular CMV disease.
Nebenwirkungen
Iritis, which affects up to 25% of patients undergoing
fomivirsen therapy, can be managed with topical corticosteroids.
Vitreitis and increased intraocular pressure
may also result from fomivirsen administration.
Fomivirsen is contraindicated in patients who have
been treated with cidofovir within the previous 2 to 4
weeks because cidofovir increases the risk of ocular inflammation.
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