18Authorized in 8/8/2015
The drug is available in 100-, 500-, 1,000-, and 2,000-mg multi doses
vials for IV use. Cytarabine is used in the treatment of acute
myelogenous leukemia and CML. This drug is a deoxycytidine analog
originally isolated from the sponge Cryptothethya crypta. It is active
following intracellular activation to the nucleotide ####bolite ara-CTP.
The resulting ara-CTP is incorporated into DNA resulting in chain
termination and inhibition of DNA synthesis and function. Resistance
can occur because of decreased activation or transport and
increased catabolic breakdown. ####bolic breakdown within the GI
tract leads to poor bioavailability. The drug distributes rapidly into
tissues and total body water with cerebrospinal fluid (CSF) levels
reaching 20% to 40% of those in plasma. Cytidine deaminase is the
primary catabolic enzyme involved in the inactivation of cytarabine.
Drug interactions include antagonism of the effects of gentamicin,
decreasing the oral bioavailability of digoxin, as well as enhancing the
cytotoxicity of various alkylating agents, cisplatin, and ionizing
radiation. Pretreatment with methotrexate enhances the formation of
ara-CTP ####bolites resulting in enhanced cytotoxicity. Toxicities
include myelosuppression, leukopenia and thrombocytopenia,
nausea and vomiting anorexia, diarrhea, and mucositis. Neurotoxicity
is usually expressed as ataxia, lethargy, and confusion. An allergic
reaction often described in pediatric patients includes fever, myalgia,
malaise, bone pain, skin rash, conjunctivitis, and chest pain.
FLOXURIDINE (FLUORODEOXYURIDINE, FUDR)
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Authorized in 8/8/2015
The drug is available as a 500-mg vial of lyophilized powder.
The drug is used to treat ####static GI adenocarcinoma. The
mechanism of action of this fluoropyrimidine deoxynucleoside analog
involves ####bolic conversion to 5-fluorouracil (5-FU) ####bolites
resulting in inhibition of TS thus disrupting DNA synthesis, function,
and repair. Resistance can occur because of increased expression of
TS, decreased levels of reduced folate 5,10-
methylenetetrahydrofolate, increased activity of DNA repair enzymes,
and increased expression of dihydropyrimidine dehydrogenase (the
major catabolic enzyme). The drug is poorly absorbed from the GI
tract and is extensive ####bolized to 5-FU and 5-FU ####bolites.
Dihydropyrimidine dehydrogenase is the main enzyme responsible
for 5-FU catabolism, and it is present in liver, GI mucosa, white blood
cells, and kidney. The drug interaction and toxicity profiles are
#####alent to those of 5-FU.
GEMCITABINE (DFDC, GEMZAR)
The drug is available as the hydrochloride salt in 200- and
1,000-mg lyophilized single-dose vials for IV use. Gemcitabine is
used to treat bladder cancer, breast cancer, pancreatic cancer, and
NSCLC. Gemcitabine is a potent radio sensitizer, and it increases the
cytotoxicity of cisplatin. The mechanism of action of this fluorinesubstituted
deoxycytidine analog involves inhibition of DNA synthesis
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Authorized in 8/8/2015
and function via DNA chain termination. The triphosphate ####bolite
is incorporated into DNA inhibiting several DNA polymerases and
incorporated into RNA inhibiting proper function of mRNA. Resistance
can occur because of decreased expression of the activation enzyme
deoxycytidine kinase or decreased drug transport as well as
increased expression of catabolic enzymes. Drug oral bioavailability
is low because of deamination within the GI tract, and the drug does
not cross the blood-brain barrier. ####bolism by deamination to 2_,
2_ difluorouridine (dFdU) is extensive. Drug toxicity includes
myelosuppression, fever, malaise, chills, headache, myalgia, nausea,
and vomiting.
Uracil uses as Antiviral Drugs
Inhibitors of DNA polymerase
Idoxuridine
Idoxuridine, 5-iodo-2_deoxyuridine (Stoxil, Herplex)
This drug was introduced in 1963 for the treatment of herpes simplex
keratitis. The drug is an iodinated analog of thymidine that inhibits
replication of several DNA viruses in vitro. The susceptible viruses
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Authorized in 8/8/2015
include the herpes viruses and poxviruses (vaccinia). The mechanism
of action of Idoxuridine has not been completely defined, but several
steps are involved in the activation of the drug. Idoxuridine enters the
cell and is phosphorylated at O-5 by a viral thymidylate kinase to yield
a monophosphate, which undergoes further biotransformation to a
triphosphate. The triphosphate is believed to be both a substrate and
an inhibitor of viral DNA polymerase, causing inhibition of viral DNA
synthesis and facilitating the synthesis of DNA that contains the
iodinated pyrimidine. The altered DNA is more susceptible to strand
breakage and leads to faulty transcription. When the iodinated
DNA is transcribed, the results are miscoding errors in RNA and
faulty protein synthesis. The ability of idoxuridylic acid to substitute for
deoxythymidylic acid in the synthesis of DNA may be a result of the
similar van der Waals radii of iodine (2.15 Å) and the thymidine
methyl group (2.00 Å). In the United States, Idoxuridine is approved
only for the topical treatment of herpes simplex virus (HSV) keratitis;
although outside the United States, a solution of Idoxuridine in
dimethyl sulfoxide is available for the treatment of herpes labialis,
genitalis, and zoster. The use of Idoxuridine is limited because the
drug lacks selectivity; low, sub therapeutic concentrations inhibit the
growth of uninfected host cells. The effective concentration of
Idoxuridine is at least 10 times greater than that of acyclovir.
Idoxuridine occurs as a pale yellow, crystalline solid that is soluble in
water and alcohol but poorly soluble in most organic solvents. The
compound is a weak acid, with a pKa of 8.25. Aqueous solutions are
slightly acidic, yielding a pH of about 6.0. Idoxuridine is light and heat
sensitive. It is supplied as a 0.1% ophthalmic solution and a 0.5%
ophthalmic ointment.
Cytarabine
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Authorized in 8/8/2015
This drug is mentioned above.
Trifluridine
Trifluridine, 5-trifluoromethyl-29-deoxyuridine (Viroptic),
Is a fluorinated pyrimidine nucleoside that demonstrates in vitro
inhibitory activity against HSV-1 and HSV-2, CMV, vaccinia, and
some adenoviruses. Trifluridine possesses a trifluoromethyl group
instead of an iodine atom at the 5-position of the pyrimidine ring. The
van der Waals radius of the trifluoromethyl group is 2.44 Å, somewhat
larger than that of the iodine atom. Like Idoxuridine, the antiviral
mechanism of Trifluridine involves inhibition of viral DNA synthesis.
Trifluridine monophosphate is an irreversible inhibitor of thymidylate
synthetase, and the biologically generated triphosphate competitively
inhibits thymidine triphosphate incorporation into DNA by DNA
polymerase. In addition, Trifluridine in its triphosphate form is
incorporated into viral and cellular DNA, creating fragile, poorly
functioning DNA. Trifluridine is approved in the United States for the
treatment of primary keratoconjunctivitis and recurrent epithelial
keratitis caused by HSV types 1 and 2. Topical Trifluridine shows
some efficacy in patients with acyclovir-resistant HSV cutaneous
infections. Trifluridine solutions are heat sensitive and require
refrigeration.
Cidofovir
Cidofovir, (S)-3-hydroxy-2-phosphonomethoxypropyl cytosine
(HPMPC, Vistide)
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Authorized in 8/8/2015
Is an acyclonucleotide analog that possesses broad-spectrum
activity against several DNA viruses. Unlike other nucleotide analogs
that are activated to nucleoside phosphates, Cidofovir is a
phosphonic acid derivative. The phosphonic acid is not hydrolyzed by
phosphatases in vivo but is phosphorylated by cellular kinases to
yield a diphosphate. The diphosphate acts as an anti####bolite to
deoxycytosine triphosphate (dCTP). Cidofovir diphosphate is a
competitive inhibitor of viral DNA polymerase and can be
incorporated into the growing viral DNA strand, causing DNA chain
termination. Cidofovir possesses a high therapeutic index against
CMV and has been approved for treating CMV retinitis in patients
with AIDS. Cidofovir is administered by slow, constant intravenous
infusion in a dose of 5 mg/kg over a 1-hour period once a week for 2
weeks. This treatment is followed by a maintenance dose every 2
weeks. About 80% of a dose of Cidofovir is excreted unchanged in
the urine, with a t1/2elim of 2 to 3 hours. The diphosphate
anti####bolite, in contrast, has an extremely long half-life (17–30
hours). The main dose-limiting toxicity of Cidofovir involves renal
impairment. Renal function must be monitored closely. Pretreatment
with probenecid and prehydration with intravenous normal saline can
be used to reduce the nephrotoxicity of the drug. Patients must be
advised that Cidofovir is not a cure for CMV retinitis. The disease
may progress during or following treatment.
Zidovudine
Zidovudine, 3_-azido-3_-deoxythymidine or AZT .
Is an analog of thymidine that possesses antiviral activity against
HIV-1, HIV-2, HTLV-1, and several other retroviruses. This
nucleoside was synthesized in 1978 by Lin and Prusoff47 as an
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Authorized in 8/8/2015
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