144245-52-3 Usage
Description
Fomivirsen, also known as Fomivirsen sodium or Vitravene, is a 21-base phosphorothioate DNA antisense oligonucleotide specifically designed to be complementary to a cytomegalovirus (CMV) messenger RNA (mRNA) that encodes for the major immediate early region (IE2) proteins of the virus. It belongs to the first class of highly specific and novel therapeutics called antisense oligonucleotides. Fomivirsen sodium is a white to off-white, hygroscopic, amorphous powder, available as a sterile, aqueous, preservative-free, and bicarbonate-buffered solution.
Uses
Used in Ophthalmology:
Fomivirsen is used as an antiviral agent for the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS). It works by binding to the CMV mRNA, preventing the production of the IE2 proteins, which are essential for the virus's replication and pathogenesis. This action helps in controlling the progression of CMV retinitis and preserving the patient's vision.
Used in Pharmaceutical Industry:
Fomivirsen is used as a research tool for studying the mechanisms of gene expression and regulation, as well as the development of novel antisense oligonucleotide-based therapies. Its unique properties as an antisense oligonucleotide make it a valuable asset in the field of molecular biology and drug development, contributing to the advancement of personalized medicine and targeted treatments for various diseases.
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.
Pharmaceutical Applications
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.
Biological Activity
Ocular disposition and clearance of fomivirsen following an intravitreal injection has been studied in rabbits and cynomolgus monkeys. When fomivirsen was administered by a single intravitreal injection in rabbits it was cleared rapidly from the vitreous as a result of metabolism of the parent drug. Clearance of 14C-labeled fomivirsen from the vitreous followed first order kinetics with a t1/2 of 62 hours; within 10 days after dosing only about 20% of unchanged fomivirsen remained in the vitreous. In the retina the estimated t1/2 was 79 hours. Similarly, in monkeys, fomivirsen clearance was complete within 14 days. The doses administered were roughly equivalent to the 165- and 330-mg doses studied in humans, with an estimated elimination half-life between 45 and 78 hours with the products of fomivirsen metabolism (multiple chain-shortened oligonucleotides) in both the vitreous and retina.
Mechanism of action
Fomivirsen is a member of the first generation of antisense oligonucleotides known as phosphorothioates. In this class of compounds, one of the oxygen atoms in the phosphate backbone is replaced by a sulfur atom. This modification results in a negatively charged molecule that is chiral at each phosphorothioate and serves to stabilize the molecule against DNase and RNase degradation, a significant improvement over the parent phosphodiester. Improvements in antisense chemistry over the past two decades have conveyed increased stability to the molecules, increasing in vivo half-lives and allowing for less frequent dosing. Modifying the paired C-G motifs by cytosine methylation reduces the proinflammatory effects that are typically seen with phosphorothioates.
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.
Pharmacokinetics
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
CMV retinitis in AIDS patients intolerant of, or unresponsive to, other
treatments
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.
Side effects
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.
Toxicity evaluation
The two most common adverse events reported were intraocular inflammation and an increase in intraocular pressure. Both the inflammatory reactions and the elevated intraocular pressure were transient and successfully treated with medication. Fomivirsen is contraindicated in patients with a known hypersensitivity to the drug. Fomivirsen is not recommended if the patient has been treated within the last 2–4 weeks with cidofovir (Vistides) as there may be an increased risk of inflammation in the eye. Animal reproductive studies have not been conducted with fomivirsen. No studies were conducted in pregnant women. Therefore, there are no data on whether fomivirsen would cause harm to the fetus when administered to a pregnant woman, nor is there any information on the potential effect on reproductive capacity or potential fetal toxicity.
Check Digit Verification of cas no
The CAS Registry Mumber 144245-52-3 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,4,4,2,4 and 5 respectively; the second part has 2 digits, 5 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 144245-52:
(8*1)+(7*4)+(6*4)+(5*2)+(4*4)+(3*5)+(2*5)+(1*2)=113
113 % 10 = 3
So 144245-52-3 is a valid CAS Registry Number.
