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Ganciclovir and Cidofovir.
Ganciclovr y Cidofovir.
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****** DATA-MÉDICOS *********
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GANCICLOVIR Y CIDOFOVIR
GANCICLOVIR AND CIDOFOVIR
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***** DERMAGIC-EXPRESS No 70 *******
** 15 SEPTIEMBRE 1.999 / 15 SEPTEMBER 1999**
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EDITORIAL ESPAÑOL:
=====================
Hola Amigos de la red, DERMAGIC continua el tema de los
antivirales, en esta ocasion: EL GANCICLOVIR Y CIDOFOVIR.
El GANCICLOVIR
también es una pro-droga estructuralmente similar al ACICLOVIR, la cual se
convierte intracelularmente en su forma GANCICLOVIR trifosfato, que inhibe
la DNA POLIMERASA VIRAL y ha demostrado ser efectivo contra la enfermedad
por Citomegalovirus y Herpes Simple Virus. También el GANCICLOVIR se esta
usando en pacientes con HIV pues potencia la acción del antiviral didanosine
en pacientes con SIDA.
El CIDOFOVIR ((S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine,)
es miembro de una nueva clase de antivirales, conocido también como HPMMC. Es el primer antiviral
análogo de nucleótidos, con una vida media
intracelular de 17 a 30 horas, con actividad anti-tumoral y anti-viral,
tiene un espectro de acción mas amplio: Herpes Virus, Adenovirus, VPH,
Poxvirus, Poliomavirus, Leuco-encefalopatía progresiva multifocal (SIDA),
Sarcoma de Kaposi (SIDA Y Herpes Virus 8), y también:
TÓPICAMENTE:
Molusco
Contagioso, Verruga Vulgar, Condiloma Acuminado Ano genital, Herpes
Genital Recurrente, Queratoconjuntivitis Viral (Citomegalovirus y Herpes
Virus), y Sarcoma de Kaposi.
Ya ha sido descrita resistencia VIRAL a
estos 2 nuevos agentes antivirales. Al final, la monografía de ambos
productos. En estas 54 REFERENCIAS BIBLIOGRÁFICAS, los hechos.
Saludos a todos !!!
Dr. José Lapenta R.,,,
EDITORIAL ENGLISH:
=====================
Hello Friends of the net, DERMAGIC continuos the topic of the
antiviral, in this occasion: THE GANCICLOVIR AND CIDOFOVIR.
The
GANCICLOVIR is also a prodrug structurally similar to the ACICLOVIR, which
becomes intracellular in their form GANCICLOVIR triphosphate. He inhibits
the viral DNA polymerase and it has demonstrated to be effective against the
disease for Cytomegalovirus and Herpes Simplex Virus. Also the ganciclovir
it is using in patient with VIH since It INCREASES the action of the
antiviral didanosine in patient with AIDS.
The CIDOFOVIR ((S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine,)
is member of a new antiviral class, also known as HPMMC, it is the first
antiviral nucleotide analog with a intracellular life half of 17 at 30
hours, with anti-viral and/or tumoral activity, he has also a broad spectrum:
Herpes Virus, Adenovirus, HVP, Poxvirus, Polyomavirus, Progressive Multifocal
Leukoencephalopathy (AIDS), Kaposi's Sarcoma (AIDS AND Herpes Virus 8),
also:
TOPICALLY: Contagious Molluscum, Vulgar Wart, Anogenital Condyloma
Acuminata,
Recurrent Genital Herpes, Viral Keratoconjunctivitis (Cytomegalovirus and
Herpes Virus), and Cutaneous Kaposi's Sarcoma.
VIRAL resistance has
already been described to these 2 new antiviral agents. At the end a
monograph of the products. In these 54 bibliographical references, the facts.
Greetings to ALL, !!
Dr. José Lapenta R.,,,
====================================================================
DERMAGIC/EXPRESS(70)
====================================================================
REFERENCIAS BIBLIOGRÁFICAS /
BIBLIOGRAPHICAL REFERENCES
====================================================================
====================================================================
GANCICLOVIR
====================================================================
1.)
Oral ganciclovir for the prevention of cytomegalovirus disease inpersons
with AIDS. Roche Cooperative Oral Ganciclovir Study Group.
2.) Oral
ganciclovir as maintenance treatment for cytomegalovirus retinitisin
patients with AIDS. Syntex Cooperative Oral Ganciclovir
3.) Absence of
teratogenicity of oral ganciclovir used during earlypregnancy in a liver
transplant recipient.
4.) Clinical course of cytomegalovirus (CMV)
viremia with and withoutganciclovir treatment in CMV-seropositive kidney
transplant recipients.Longitudinal follow-up of CMV pp65 antigenemia assay.
5.) A study of the pharmacokinetics, antiviral activity, and tolerability
oforal ganciclovir for CMV prophylaxis in marrow transplantation.
6.)
Forscarnet vs ganciclovir for cytomegalovirus (CMV) antigenemia after
allogeneic hemopoietic stem cell transplantation (HSCT): a randomised study.
7.) Ganciclovir. An update of its use in the prevention of cytomegalovirus
infection and disease in transplant recipients.
8.) Superior
cytotoxicity with ganciclovir compared with acyclovir and 1-beta-D-
arabinofuranosylthymine in herpes simplex virus-thymidine kinase-expressing
cells: a novel paradigm for cell killing.
9.) High-dose (2000-microgram)
intravitreous ganciclovir in the treatment of cytomegalovirus retinitis.
10.) Cytomegalovirus polymerase chain reaction viraemia in patients
receiving ganciclovir maintenance therapy for retinitis.
11.) The use of
oral ganciclovir in the treatment of cytomegalovirus retinitis in patients
with AIDS.
12.) Metabolism of ganciclovir and cidofovir in cells
infected with drug-resistant and wild-type strains of murine cytomegalovirus.
13.) The effect of ganciclovir on herpes simplex virus-mediated oncolysis.
14.) Treatment of cytomegalovirus retinitis with a sustained-release
ganciclovir implant. The Ganciclovir Implant Study Group.
15.)
Pharmacokinetics of oral ganciclovir capsules in HIV-infected persons.
16.) Cytomegalovirus (CMV) resistance in patients with CMV retinitis and
AIDS treated with oral or intravenous ganciclovir.
17.) The
pharmacokinetics and safety profile of oral ganciclovir combined with
zalcitabine or stavudine in asymptomatic HIV- and CMV-seropositive patients.
18.) GANCICLOVIR (Systemic) The product
====================================================================
CIDOFOVIR
====================================================================
19.) Trifluridine, cidofovir, and penciclovir in the treatment of
experimental herpetic keratitis.
20.) Bioavailability and metabolism of
cidofovir following topical administration to rabbits.
21.) Cidofovir: a
new therapy for cytomegalovirus retinitis.
22.) Parenteral cidofovir for
cytomegalovirus retinitis in patients with AIDS: the HPMPC peripheral
cytomegalovirus retinitis trial. A randomized, controlled trial. Studies of
Ocular complications of AIDS Research Group in Collaboration with the AIDS
Clinical Trials Group.
23.) Cidofovir and experimental herpetic stromal
disease.
24.) Clinical pharmacokinetics of the antiviral nucleotide
analogues cidofovir and adefovir.
25.) Cidofovir in the treatment of
cytomegaloviral disease.
26.) Antitumor potential of acyclic nucleoside
phosphonates.
27.) Clinical uses of cidofovir.
28.) Characterization
of the DNA polymerase and thymidine kinase genesof herpes
simplex virus
isolates from AIDS patients in whom acyclovirand foscarnet therapy
sequentially failed.
29.) A case study: the use of cidofovir for the
management of progressive multifocal leukoencephalopathy.
30.)
Antiinfectives update: focus on treatment and prevention of viral and
associated infections.
31.) Identification and rapid quantification of
early- and late-lytic human herpesvirus 8 infection in single cells by flow
cytometric analysis: characterization of antiherpesvirus agents.
32.)Inhibiting
effects of cidofovir (HPMPC) on the growth of the human cervical carcinoma (SiHa)
xenografts in athymic nude mice.
33.) Antiproliferative effects of
acyclic nucleoside phosphonates on human papillomavirus (HPV)-harboring cell
lines compared with HPV-negative cell lines.
34.) Resolution of
recalcitrant molluscum contagiosum virus lesions in human immunodeficiency
virus-infected patients treated with cidofovir.
35.) Therapeutic
potential of Cidofovir (HPMPC, Vistide) for the treatment of DNA virus (i.e.
herpes-, papova-, pox- and adenovirus) infections.
36.) Topical and
intralesional cidofovir: a review of pharmacology and therapeutic effects.
37.) Treatment of classical Kaposi's sarcoma with intralesional injections
of cidofovir: report of a case.
38.) Selective inhibition of human
papillomavirus-induced cell proliferation by (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine.
39.) Resistance of human cytomegalovirus to antiviral drugs.
40.)
Comparative antiviral efficacies of cidofovir, trifluridine, and acyclovir
in the HSV-1 rabbit keratitis model.
41.) [Human herpesvirus 8 (HHV8).
II. Pathogenic role and sensitivity toantiviral drugs].
42.) Inhibitory
effects of novel nucleoside and nucleotide analogues on Epstein-Barr virus
replication.
43.) Comparison of antiviral compounds against human
herpesvirus 6 and 7.
44.) [Advances in the diagnosis and treatment of
infections caused by herpesvirus and JC virus].
45.) A multicenter phase
I/II dose escalation study of single-dose cidofovir gel for treatment of
recurrent genital herpes.
46.) Cidofovir use in acyclovir-resistant
herpes infection.
47.) A randomized, double-blind, placebo-controlled
trial of cidofovir gel for the treatment of acyclovir-unresponsive
mucocutaneous herpes simplex virus infection in patients with AIDS.
48.)
Isolation of human adenovirus type 5 variants resistant to the antiviral
cidofovir.
49.) Herpesvirus resistance to antiviral drugs: a review of
the mechanisms, clinical importance and therapeutic options.
50.)
Topical cidofovir for severe molluscum contagiosum.
51.) Abatement of
cutaneous Kaposi's sarcoma associated with cidofovir treatment.
52.)
Treatment of verruca vulgaris with topical cidofovir.
53.) Topical
cidofovir for severe molluscum contagiosum.
54.) CIDOFOVIR, The product
====================================================================
====================================================================
GANCICLOVIR
====================================================================
1.)
Oral ganciclovir for the prevention of cytomegalovirus disease in
persons with AIDS. Roche Cooperative Oral Ganciclovir Study Group.
====================================================================
Journal: N Engl J Med 334:1491-7, 1996
Publication Date: 1996 June
6
Author(s): Spector SA, McKinley GF, Lalezari JP, Samo T, Andruczk
R, Follansbee S, Sparti PD, Havlir DV, Simpson G, Buhles W, Wong R,
Stempien M
Abstract:
BACKGROUND. In the advanced stages of
the acquired immunodeficiency syndrome (AIDS), cytomegalovirus (CMV)
disease, particularly vision-damaging retinitis due to CMV is common. We
evaluated prophylactic treatment with orally administered ganciclovir as
a way to prevent CMV disease.
METHODS. We conducted a
prospective, randomized, double-blind, placebo-controlled study of CMV
infected persons with AIDS with either CD4+ lymphocyte counts of < or =
50 per cubic millimeter or counts of < or = 100 per cubic millimeter in
those with a history of an AIDS defining opportunistic infection.
Patients were randomly assigned, in a 2:1 ratio, to receive either oral
ganciclovir (1000 mg three times daily) or placebo.
RESULTS. The
study was stopped after a median 367 days of follow-up. In an intention-to-treat analysis, the twelve month cumulative rates of confirmed CMV disease were 26 percent in the placebo group (n = 239) and 14 percent in the ganciclovir group (n = 486), representing an overall reduction in risk of 49 percent in the ganciclovir group (P < 0.001). The incidence of CMV retinitis after 12 months was 24 percent in the placebo group and 12 percent in the ganciclovir group (P < 0.0001). The prevalence of CMV-positive urine cultures at base line was 42 percent; after two months it was 43 percent in the placebo group and 10 percent in the ganciclovir group (P < 0.0001). The one year mortality rate was 26 percent in the placebo group and 21 percent in the ganciclovir group (P = 0.14). Therapy with granulocyte colony stimulating factor was more frequent in the ganciclovir group (24 percent) than in the placebo group (9 percent).
CONCLUSIONS. In persons with advanced AIDS, phophylactic oral
ganciclovir significantly reduces the risk of CMV disease.
====================================================================
2.)
Oral ganciclovir as maintenance treatment for cytomegalovirus retinitis
in patients with AIDS. Syntex Cooperative Oral Ganciclovir
====================================================================
Study Group (see comments)
Journal: N Engl J Med 333:615-20, 1995
Publication Date: 1995 September 7
Author(s): Drew WL, Ives D,
Lalezari JP, Crumpacker C, Follansbee SE,
Spector SA, Benson CA,
Friedberg DN, Hubbard L, Stempien MJ, et al
Abstract:
BACKGROUND. Cytomegalovirus retinitis, a sight-threatening infection
associated with the acquired immunodeficiency syndrome (AIDS), currently
requires lifelong intravenous treatment. An effective oral treatment would
be an important advance.
METHODS. We compared oral with intravenous
ganciclovir in an open-label, randomized study in patients with AIDS and
newly diagnosed, stable cytomegalovirus retinitis (the disease was
stabilized by three weeks of treatment with intravenous ganciclovir).
Sixty subjects were randomly assigned to maintenance therapy with
intravenous ganciclovir at a dose of 5 mg per kilogram of body weight
daily, and 63 to maintenance therapy with oral ganciclovir at a dose of
3000 mg daily. The subjects were followed for up to 20 weeks, with
photography of the fundi conducted every other week. The photographs
were evaluated at the completion of the study by an experienced grader
who was unaware of the subjects' treatment assignments.
RESULTS.
Efficacy could be evaluated in 117 subjects; photographs were ungradable
for 2 of the 117. On the basis of the masked assessment of photographs
from 115 subjects, the mean time to the progression of retinitis was 62
days in those given intravenous ganciclovir and 57 days in those given
oral ganciclovir (P = 0.63; relative risk (oral vs. intravenous), 1.08;
95 percent confidence interval for the difference in means, -22 to +12
days). On the basis of funduscopy by ophthalmologists who were aware of
the subjects' treatment assignments, the mean time to progression was 96
days in subjects given intravenous ganciclovir and 68 days in subjects
given oral ganciclovir (P = 0.03; relative risk (oral vs. intravenous),
1.68; 95 percent confidence interval for the difference in means, -45 to
-11 days). Survival, changes in visual acuity, the incidence of viral
shedding, and the incidence of adverse gastrointestinal events were
similar in the two groups. Neutropenia, anemia,
intravenous-catheter-related adverse events, and sepsis were more common in
the group given intravenous ganciclovir.
CONCLUSIONS. Oral
ganciclovir is safe and effective as maintenance therapy for
cytomegalovirus retinitis and is more convenient for patients to take
than intravenous ganciclovir.
====================================================================
3.) Absence of teratogenicity of oral ganciclovir used during early
pregnancy in a liver transplant recipient.
====================================================================
Transplantation 1999 Mar 15;67(5):758-9
Pescovitz MD
Department
of Surgery, Indiana University, Indianapolis 46202-5253, USA.
BACKGROUND: Ganciclovir (GCV) is effective for prevention of
cytomegalovirus (CMV) disease. In animals it may cause some teratogenicity.
There is little information on the effect of GCV on a human fetus.
METHODS:
The chart of a liver transplant recipient who received oral GCV during the
first trimester was reviewed as was the published literature.
RESULTS:
There was no evidence of teratogenicity in the baby or in a case reported
elsewhere.
CONCLUSIONS: GCV has been used in a few female transplant
recipients without untoward effects. The still uncertain risk of short term
and long term teratogenicity, however, must be weighed against the risk of
CMV disease in the recipient and the development of congenital CMV in the
baby.
====================================================================
4.) Clinical course of cytomegalovirus (CMV) viremia with and without
ganciclovir treatment in CMV-seropositive kidney transplant recipients.
Longitudinal follow-up of CMV pp65 antigenemia assay.
====================================================================
Author
Yang CW; Kim YO; Kim YS; Kim SY; Moon IS; Ahn HJ; Koh YB; Bang
BK
Address
Division of Nephrology, Department of Internal Medicine,
Kangnam St. Mary's Hospital, Catholic University Medical College, Seoul,
South Korea.
Source
Am J Nephrol, 18(5):373-8 1998
Abstract
This study was designed to evaluate the longitudinal history of
cytomegalovirus (CMV) infection and to test the capacity of ganciclovir as
effective therapy in CMV-seropositive renal transplant recipients. The CMV
viremia was detected with CMV pp65 antigenemia assay in 153 renal
transplants. The recipients were classified as having low-grade and
high-grade CMV infections according to the severity of CMV infection. The
recipients with low-grade CMV infections were observed without ganciclovir
treatment, and the recipients with high-grade CMV infection were randomly
assigned to ganciclovir-treated and untreated groups.
The clinical course
between low-grade and high-grade CMV infections was evaluated. All
recipients with low-grade CMV infection (n = 62) showed spontaneous
remission regardless of immunosuppresants. In high-grade CMV infection (n =
31), the ciclosporin A treated group (n = 11) showed no evidence of CMV
disease, and the methylprednisolone-treated group (n = 8) showed CMV
disease in 1 (25%) of 4 ganciclovir-untreated recipients. In the OKT3 group
(n = 12), symptomatic CMV infection was observed in 6 (100%)
ganciclovir-untreated recipients contrary to no CMV disease in the
ganciclovir-treated group (p < 0.05). In conclusion, the CMV antigenemia
assay is effective in monitoring CMV viremia, and ganciclovir treatment
should be done during early CMV viremia in OKT3-treated recipients.
====================================================================
5.)
A study of the pharmacokinetics, antiviral activity, and tolerability of
oral ganciclovir for CMV prophylaxis in marrow transplantation.
====================================================================
Author
Boeckh M; Zaia JA; Jung D; Skettino S; Chauncey TR; Bowden RA
Address
Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024,
USA.
Source
Biol Blood Marrow Transplant, 4(1):13-9 1998
Abstract
Oral ganciclovir is effective in preventing cytomegalovirus
(CMV) disease in HIV-infected patients despite a bioavailability of only
6-9%. To determine safety, pharmacokinetics, and the influence of acute
gastrointestinal graft-vs.-host disease (GI-GVHD) on the bioavailability
and antiviral effect of oral ganciclovir after marrow transplantation, CMV
seropositive patients received oral ganciclovir (1000 mg 3 times per day)
from day 35 (+/- 7 days) until day 100 after transplantation. Single-dose
(intravenous and oral) and steady-state oral pharmacokinetic profiles and
weekly trough levels were performed.
Twenty-one patients received oral
ganciclovir (seven with GI-GVHD, 14 without); 17 had steady-state
pharmacokinetic profiles and seven had single-dose profiles. The absolute
bioavailability was similar in patients with or without acute GI-GVHD (7.2
vs. 6.9%). At steady state, the extent and rate of absorption of oral
ganciclovir were comparable in these same patient subgroups (area under the
curve [AUC] = 13.5 and 10.2 mg x hours/L, respectively; time to peak serum
ganciclovir concentrations = 5.5 and 3.8 hours, respectively). Breakthrough
CMV antigenemia, viremia, or plasma polymerase chain reaction positivity
occurred in eight of 21 (38%) patients (four of seven with GVHD and four of
14 without). Drug discontinuation because of GI adverse effects was
required in six of 21 (29%) patients.
Neutropenia occurred in two of 15
(13%) patients who had received oral ganciclovir for more than 10 days. In
conclusion, the bioavailability of oral ganciclovir seems similar to that
reported in other settings. The presence of acute GVHD of the GI tract did
not appear to adversely affect absorption of oral ganciclovir. The use of
oral ganciclovir was limited by the presence of GI intolerance in the early
posttransplant period. The efficacy of oral ganciclovir in preventing CMV
infection in marrow transplant recipients is being assessed in a separate
randomized controlled trial.
====================================================================
6.)
Forscarnet vs ganciclovir for cytomegalovirus (CMV) antigenemia after
allogeneic hemopoietic stem cell transplantation (HSCT): a randomised
study.
====================================================================
Author
Moretti S; Zikos P; Van Lint MT; Tedone E; Occhini D; Gualandi
F;
Lamparelli T; Mordini N; Berisso G; Bregante S; Bruno B; Bacigalupo
A
Address
Divisione Ematologia II, Ospedale San Martino, Genova,
Italy.
Source
Bone Marrow Transplant, 22(2):175-80 1998 Jul
Abstract
This trial was designed to compare foscarnet with ganciclovir
as pre-emptive therapy for CMV infection in patients undergoing
allogeneic hemopoietic stem cell transplant (HSCT).
Thirty-nine patients
were randomized to receive foscarnet 90 mg/kg every 12 h (n = 20) or
ganciclovir 5 mg/kg every 12 h (n = 19) for 15 days at the time of
development of CMVAg-emia. Primary-end points of the study were
(1)
outcome of CMVAg-emia;
(2) progression to CMV disease; and (3)
side-effects of treatment. The secondary end-point was
transplant-related mortality (TRM). The two groups were comparable for
diagnosis, status of disease, donor type, acute graft-versus-host
(aGVHD) prophylaxis, interval between HSCT and CMVAg-emia and number of
CMVAg positive cells; the donor and recipient age were borderline older
in the foscarnet group.
Increments of serum creatinine in the foscarnet
group, and cytopenia in the ganciclovir group were controlled by
reducing the administered dose: in the first 15 days of therapy 9/20
foscarnet and 10/19 ganciclovir patients had a dose reduction greater than
20% (P = 0.43). Clearance of CMVAg-emia was faster in the foscarnet group
although with borderline statistical significance. Failures of treatment
occurred in 3/20 patients in foscarnet group vs 8/19 patients in
ganciclovir group (P= 0.06): causes of failure were the need for
combination therapy to control antigenemia (1/20 vs 5/19), and reactivation
during treatment for 2 vs 3 patients, respectively. CMV disease was
diagnosed in 1 vs 2 patients (P = 0.5) who subsequently died. The actuarial
1-year TRM was 25 vs 12%, respectively (P = 0.3).
This study suggests that
foscarnet and ganciclovir are both effective for pre-emptive therapy of
CMVAg-emia, although the number of failures would seem to be slightly
higher in the ganciclovir patients. Side-effects are seen in both groups
and can be managed with appropriate dose reduction.
====================================================================
7.)
Ganciclovir. An update of its use in the prevention of cytomegalovirus
infection and disease in transplant recipients.
====================================================================
Author
Noble S; Faulds D
Address
Adis International Limited,
Auckland, New Zealand.
Source
Drugs, 56(1):115-46 1998 Jul
Abstract
Ganciclovir is a nucleoside analogue which is used to treat and
prevent cytomegalovirus (CMV) infection. Most recent clinical studies
of ganciclovir in transplant recipients have focused on preventive
approaches. When ganciclovir was last reviewed in Drugs in 1994,
substantial data on post-transplantation CMV prophylaxis with this drug
were available only for patients undergoing allogeneic bone marrow
transplantation (BMT). Two strategies had emerged: prophylaxis for all
patients or early treatment started after detection of asymptomatic CMV
infection. Subsequently, a large double-blind study has shown that
ganciclovir prophylaxis is more effective than early treatment in
preventing early CMV disease after allogeneic BMT and is not associated
with an increased incidence of neutropenia. However, mortality for the 2
strategies was similar.
The efficacy of prophylactic intravenous
ganciclovir in liver transplant recipients [including high risk donor
seropositive/recipient seronegative (D+/R-) or antilymphocyte-treated
patients] is now well established. Prophylaxis with oral ganciclovir was
effective both overall and in D+/R-patients in a large placebo
controlled study, and prolonged intravenous ganciclovir was
significantly more effective than high dose aciclovir (acyclovir) in
seropositive liver recipients.
Early treatment with ganciclovir has
proved useful in this setting. More limited data indicate that CMV
prophylaxis with intravenous ganciclovir may be useful after heart or
lung transplantation but its value in D+/-patients remains unclear.
Combined chemoimmunotherapy may be valuable in these high risk patients
but controlled data are lacking. Targeted prophylaxis with intravenous
ganciclovir is effective in renal transplant recipients receiving
antilymphocyte therapy; the role of oral ganciclovir in this setting is
less clear. The value of ganciclovir in D+/- renal transplant recipients
and its efficacy compared with high dose aciclovir have not been
determined.
Conclusions: Ganciclovir is the only antiviral chemotherapy
which reduces the risk of CMV infection or disease after most types of
major transplantation. Unresolved issues include the best (and most
cost-effective) use of ganciclovir and aciclovir after allogeneic BMT, the
efficacy of oral ganciclovir compared with other anti-CMV regiments, the
potential clinical effect of viral resistance during prolonged ganciclovir
exposure and the value of ganciclovir in certain high risk transplant
populations. In the meantime, ganciclovir has an important role in the
prevention of CMV infection and disease after bone marrow and liver
transplantation and is likely to gain wider clinical use in heart, lung and
kidney transplant recipients.
====================================================================
8.)
Superior cytotoxicity with ganciclovir compared with acyclovir and
1-beta-D-arabinofuranosylthymine in herpes simplex virus-thymidine
kinase-expressing cells: a novel paradigm for cell killing.
====================================================================
Author
Rubsam LZ; Davidson BL; Shewach DS
Address
Department of
Pharmacology, University of Michigan Medical Center, Ann
Arbor
48109-0504, USA.
Source
Cancer Res, 58(17):3873-82 1998 Sep 1
Abstract
Enzyme-prodrug therapy using ganciclovir and herpes simplex
virus-thymidine kinase (HSV-TK) has demonstrated excellent antitumor
activity in many different types of malignant cells.
Previously, we
noted that ganciclovir was substantially more cytotoxic than other
HSV-TK substrates. Therefore, we embarked on a study to determine the
basis for the superior cytotoxicity of ganciclovir. In U251tk human
glioblastoma cells that stably express HSV-TK, ganciclovir elicited a >4
log cell kill instead of the < or =1.5 log cell kill mediated by two
other HSV-TK substrates, 1-beta-D-arabinofuranosylthymine (araT) and
acyclovir.
Study of the metabolism of these drugs demonstrated that
acyclovir was poorly phosphorylated to its active triphosphate with DNA
incorporation below the limit of detection, which may explain the < 1
log cell kill in these cells. Lower levels of ganciclovir triphosphate
accumulated compared with araT triphosphate (araTTP) under conditions
that induced < or =1 log cell kill (67 versus 1235 pmol/10(7) cells,
respectively), and the half-life for the triphosphate of ganciclovir was
shorter than that of araT (terminal half-lives of 15 and 41 h,
respectively).
Incorporation of ganciclovir monophosphate into DNA was
less than that of araT monophosphate, and both analogues were retained
in DNA for > or =48 h. Thus, the superior cytotoxicity of ganciclovir
was not due to enhanced metabolism to active forms. Highly cytotoxic
concentrations of ganciclovir produced only weak inhibition of DNA
synthesis.
This allowed cells to proceed through S and G2-M phases
during and after drug exposure, resulting in a doubling of cell number
by 48 h after drug washout. As they attempted to progress through the
cell cycle a second time, ganciclovir-treated cells accumulated in early
S-phase and remained there until cell death, suggesting that ganciclovir
incorporation in the DNA template was important for cytotoxicity. In
contrast, strong inhibition of DNA synthesis by araTTP prevented cells
from traversing the cell cycle for at least 12 h after drug washout,
when the active metabolite was largely degraded araT-treated cells were
unable to divide for at least 72 h after drug exposure, at which point
the surviving cells displayed a normal cell cycle distribution pattern.
Based on the results presented here, we propose a novel paradigm in which
the ability of ganciclovir to incorporate into DNA without inhibiting
progression through S-phase, combined with high cytotoxicity for
incorporated ganciclovir monophosphate, produces multilog cytotoxicity.
====================================================================
9.) High-dose (2000-microgram) intravitreous ganciclovir in the treatment
of cytomegalovirus retinitis.
====================================================================
Author
Young S; Morlet N; Besen G; Wiley CA; Jones P; Gold J; Li Y;
Freeman WR;
Coroneo MT
Address
Department of Ophthalmology,
University of New South Wales, Sydney,
Australia.
Source
Ophthalmology, 105(8):1404-10 1998 Aug
Abstract
OBJECTIVE: The
authors prospectively studied visual outcome, relapse, complications,
and survival of patients with acquired immune deficiency syndrome
(AIDS)-related cytomegalovirus (CMV) treated with high-dose
intravitreous ganciclovir (2 mg/0.1 ml) injections. The outcomes were
compared with those of patients treated with standard doses of intravenous
ganciclovir in the same institution. The histopathologic and
electrophysiologic effects of high-dose intravitreous ganciclovir
injections in rabbits also were studied.
DESIGN: A nonrandomized case
series.
PARTICIPANTS: A total of 42 patients (74 eyes) were treated with
intravitreous injections and 18 patients (27 eyes) were treated with
intravenous ganciclovir. Five eyes of three New Zealand white rabbits were
injected with ganciclovir, and the sixth eye was a control specimen.
INTERVENTION: Patients treated with intravitreous injections received
twice-weekly doses of 2 mg/0.1 ml ganciclovir for 3 weeks, then weekly
injections. Patients treated with intravenous ganciclovir received standard
doses. Patients were monitored with regular examinations. Rabbit eyes were
given intravitreous injections of 1 mg/0.1 ml of ganciclovir weekly for 4
weeks.
MAIN OUTCOME MEASURES: Assessments of vision, retinal inflammation,
and survival were made. Electroretinograms were performed on the rabbit
eyes, and they were processed for light and electron microscopy. RESULTS:
In the intravitreous group, visual acuity (VA) was stable in 64 of 74 eyes,
5 improved, and 5 deteriorated. Sixty-three (85%) of 74 eyes had final VA
of 20/20 to 20/40. Relapse occurred in five eyes (7%; median time, 42
weeks). There were three cases of endophthalmitis. Median survival after
diagnosis of CMV retinitis was 36 weeks. In the intravenous group, VA was
stable in 18 eyes, 0 improved, and 9 deteriorated. Sixteen (59%) of 27 eyes
had final VA of 20/20 to 20/40. Relapse occurred in 15 eyes (56%) at a
median time of 21 weeks. Median survival was 21 weeks. The rabbit studies
showed no evidence of toxicity.
CONCLUSION: High-dose intravitreous
ganciclovir effectively suppressed CMV retinitis, preserved vision, and
prevented relapse without deterioration in survival.
====================================================================
10.) Cytomegalovirus polymerase chain reaction viraemia in patients
receiving ganciclovir maintenance therapy for retinitis.
====================================================================
Author
Bowen EF; Emery VC; Wilson P; Johnson MA; Davey CC; Sabin CA;
Farmer D;
Griffiths PD
Address
Department of Virology, Royal
Free Hospital and School of Medicine, London, UK.
Source
AIDS,
12(6):605-11 1998 Apr 16
Abstract
OBJECTIVES: To determine whether
recurrence of polymerase chain reaction (PCR) viraemia during
maintenance ganciclovir for cytomegalovirus (CMV) retinitis correlates
with (i) CMV disease at a new anatomical site, (ii) progression of the
presenting retinitis, or (iii) acquisition of genetic changes in gene
UL97 associated with resistance to ganciclovir.
DESIGN: A previously
described cohort of 45 patients presenting with first episode retinitis
was followed clinically using ophthalmoscopy and serial tests for PCR
viraemia for a median of 7 months. CMV viral load and genetic markers of
ganciclovir resistance were measured in PCR-positive samples. METHODS:
PCR amplification of the glycoprotein B region of CMV and quantitative
competitive PCR assays were employed. Genetic changes in UL97 were
identified by sequencing/point mutation assay.
RESULTS: PCR viraemia
correlated significantly with new episodes of CMV disease (P=0.011) and a
trend was seen for the association with progression of retinitis (P=0.07).
Amongst the 14 patients PCR-positive during maintenance ganciclovir, 10
(71%) had genetic markers of resistance. None of these patients became
PCR-negative in blood after reinduction ganciclovir therapy compared with
three out of four without markers of resistance (P=0.022).
CONCLUSIONS: CMV
PCR viraemia correlated strongly with the development of new episodes of
CMV disease. Most patients with progression of retinitis remained
PCR-negative in blood, consistent with therapeutic failure due to poor
intraocular penetration of ganciclovir. However, the minority who were
PCR-positive in blood may have reinfected their eye, and frequently had
markers of ganciclovir resistance. The implications of these findings for
the management of patients with CMV disease are discussed.
====================================================================
11.) The use of oral ganciclovir in the treatment of cytomegalovirus
retinitis in patients with AIDS.
====================================================================
Author
Ward-Able C; Phillips P; Tsoukas CM
Address
BioMed
Business Unit of Hoffmann-La Roche (Canada), Mississauga, Ont.
Source
CMAJ, 154(3):363-8 1996 Feb 1
Abstract
OBJECTIVE: To recommend the
appropriate use of oral ganciclovir as an alternative to intravenous
(i.v.) maintenance therapy for cytomegalovirus (CMV) retinitis in
patients with AIDS.
OPTIONS: i.v. infusion of ganciclovir and foscarnet
have been the only approved choices for maintenance therapy until the
introduction of oral ganciclovir.
OUTCOMES: Ease of administering
maintenance therapy and improved quality of life for patients with AIDS.
VALUES: The medical advisory group comprised physicians treating
patients with AIDS therapy. Ease of administration of maintenance
therapy and quality of patients' lives were considered important. BENEFITS,
HARMS AND COSTS: Oral ganciclovir is a safe and convenient alternative to
i.v. maintenance therapy for patients with CMV retinitis. However, its low
bio-availability precludes its use for induction therapy and necessitates
careful monitoring for compliance. Compared with i.v. administration of
ganciclovir, oral maintenance therapy is cost effective.
EVIDENCE: Evidence
for the guidelines was gathered from data presented at a symposium on CMV
retinitis and oral ganciclovir, clinical trials of oral ganciclovir and
input from a visiting expert. It was presented at a meeting of the advisory
board whose members are involved in the care of patients with AIDS and the
management of CMV retinitis. The guidelines were approved by each member of
the advisory board.
RECOMMENDATIONS: Diagnosis, treatment and follow-up of
CMV retinitis should always be in consultation with an ophthalmologist who
is experienced in treating this disease. The patient should be fully
informed about the limitations of the oral form of ganciclovir; he or she
should be involved in decision making and carefully monitored. Oral
ganciclovir should not be used for induction therapy or for maintenance
therapy in high-risk patients.
VALIDATION: Similar guidelines have been
produced in England where the drug has been available since January 1995.
SPONSOR: The deliberations of the advisory board and the preparation of
this report were funded through an educational grant from Hoffmann-La Roche
(Canada).
====================================================================
12.) Metabolism of ganciclovir and cidofovir in cells infected with
drug-resistant and wild-type strains of murine cytomegalovirus.
====================================================================
Author
Okleberry KM; Warren RP; Smee DF
Address
Institute for
Antiviral Research, Utah State University, Logan, USA.
Source
Antiviral Res, 35(2):83-90 1997 Jul
Abstract
Murine cytomegalovirus
(MCMV) has been used extensively as an animal model for human
cytomegalovirus (HCMV).
Understanding drug resistance and its treatment
in MCMV may lead to more effective treatments of HCMV disease. Most
ganciclovir-resistant HCMV clinical isolates exhibit a decreased
capacity to induce ganciclovir phosphorylation (to its biologically active
form) in infected cells. Using an MCMV strain resistant to both ganciclovir
and cidofovir, the intracellular metabolism of these drugs was studied to
determine if MCMV resistance correlates with decreases in drug
phosphorylation.
The wild-type (WT) MCMV used for comparison was inhibited
in plaque reduction assays, by ganciclovir and cidofovir by 50% at 5.1 and
0.24 microM, respectively; the resistant strain was inhibited at 72 and 2.7
microM, respectively. In uninfected, WT, or resistant virus-infected cells,
the extent of metabolism of 10 microM ganciclovir or 1 microM cidofovir to
intracellular triphosphorylated species was similar. Phosphorylation and
catabolism (following drug removal) rates over time were also similar.
Intracellular levels of ganciclovir triphosphate and cidofovir diphosphate
increased less than two-fold with increasing multiplicity of virus
infection.
Because few differences in drug phosphorylation between WT and
resistant virus-infected cells were found, virus resistance to ganciclovir
and cidofovir apparently is not linked to altered drug phosphorylation.
Since the viral DNA polymerase is the antiviral target for these compounds,
the resistant MCMV is most likely a DNA polymerase mutant.
====================================================================
13.) The effect of ganciclovir on herpes simplex virus-mediated oncolysis.
====================================================================
Author
Carroll NM; Chase M; Chiocca EA; Tanabe KK
Address
Department of Surgery, Massachusetts General Hospital, Boston 02114, USA.
Source
J Surg Res, 69(2):413-7 1997 May
Abstract
Entry of herpes
simplex virus (HSV) into tumor cells results in viral gene expression
followed by cellular lysis.
Attenuated HSVs selectively destroy tumors
with sparing of surrounding normal tissue. HSV encodes a thymidine
kinase (TK) that converts ganciclovir to a toxic metabolite. This
metabolite may be transferred between cells and lead to the death of
neighboring uninfected cells, termed bystanders. We sought to determine if
HSV-mediated oncolysis is enhanced by ganciclovir treatment.
In addition,
we examined bystander killing in cocultures of TK transfectants and
parental cells. hrR3, an attenuated HSV, expresses TK. The 50% lethal dose
of hrR3 for a rat gliosarcoma (9L) and three human colorectal carcinomas
(HT29, KM12C6, and KM12L4) was determined. Cells were infected with a 50%
lethal dose of hrR3, followed by treatment with ganciclovir, and then cell
survival was quantitated.
In separate experiments 9L and HT29 cells were
transfected with TK. Parental cells and TK transfectants were cocultured in
various ratios, in the presence of ganciclovir, and cell survival was
quantitated. hrR3-mediated oncolysis was enhanced by ganciclovir in the
gliosarcoma but not in the three colorectal carcinomas. Cocultures of both
9L and HT29 parental cells with their corresponding TK transfectants
demonstrated bystander killing.
The mortality of 9L cocultures was 54%
greater than that predicted for exclusive killing of transfectants. HT29
mortality was 8% greater than predicted. The ability of ganciclovir to
augment hrR3-mediated oncolysis varies significantly between tumor cells
lines. The extent of ganciclovir-mediated killing of neighboring
nontransduced parental cells similarly varies. Consideration should be
given to these factors in the design of gene therapy strategies using HSV
vectors as oncolytic agents.
====================================================================
14.) Treatment of cytomegalovirus retinitis with a sustained-release
ganciclovir implant. The Ganciclovir Implant Study Group.
====================================================================
Author
Musch DC; Martin DF; Gordon JF; Davis MD; Kuppermann BD
Address
Department of Ophthalmology, University of Michigan, Ann Arbor,
USA.
Source
N Engl J Med, 337(2):83-90 1997 Jul 10
Abstract
BACKGROUND: Sustained-release, intraocular implants that deliver
ganciclovir are an alternative method for the treatment of cytomegalovirus
retinitis in patients with the acquired immunodeficiency syndrome (AIDS).
METHODS: We conducted a randomized study of 188 patients with AIDS and
newly diagnosed cytomegalovirus retinitis. The patients were randomly
assigned to treatment with an implant delivering 1 microg of ganciclovir
per hour, an implant delivering 2 microg of ganciclovir per hour, or
intravenous ganciclovir.
The primary outcome we studied was progression of
cytomegalovirus retinitis.
RESULTS: The median time to progression of
retinitis was 221 days with the 1-microg-per-hour implant (75 eyes), 191
days with the 2-microg-per-hour implant (71 eyes), and 71 days with
ganciclovir administered intravenously (76 eyes; P<0.001). The risk of
progression of retinitis was almost three times as great among patients
treated with intravenous ganciclovir as among those treated with a
ganciclovir implant (risk ratio, 2.8; P<0.001). However, the risk of
disease in the initially uninvolved eye was lower with intravenous
ganciclovir than with a ganciclovir implant (risk ratio, 0.5; P=0.19).
Patients treated with intravenous ganciclovir were also less likely to have
extraocular cytomegalovirus infections (0, vs. 10.3 percent in the two
implant groups; P=0.04).
CONCLUSIONS: For the treatment of cytomegalovirus
retinitis, the sustained-release ganciclovir implant is more effective than
intravenous ganciclovir, but patients treated with a ganciclovir implant
alone remain at greater risk for the development of cytomegalovirus disease
outside of the treated eye.
====================================================================
15.) Pharmacokinetics of oral ganciclovir capsules in HIV-infected persons.
====================================================================
Author
Griffy KG
Address
Roche Bioscience, Palo Alto,
California, USA.
Source
AIDS, 10 Suppl 4():S3-6 1996 Dec
Abstract
OBJECTIVES: To delineate the pharmacokinetic profile of the
oral capsule formulation of ganciclovir, and determine whether oral
ganciclovir has any pharmacokinetics interactions with zidovudine,
didanosine or probenecid.
MEASUREMENTS: Serum and urine concentrations
of ganciclovir, zidovudine and didanosine were measured. From these
concentrations, standard pharmacokinetic parameters such as peak
concentration, area under the curve (AUC), elimination half-life and
renal clearance were determined.
RESULTS: The bioavailability of oral
ganciclovir averages 6-9%. Inter- and intrasubject variability of AUC is
low (coefficient of variation 21.8 and 12.6%, respectively). The
steady-state AUCs achieved with oral ganciclovir (1000 mg three times
daily or 500 mg six times daily) are approximately 70% of the AUC
achieved with the daily maintenance dose of intravenous ganciclovir (5
mg/kg). Serum concentrations of ganciclovir are 20% higher when the oral
formulation is administered with a high fat meal than when taken
following an overnight fast. Serum concentrations of didanosine (200 mg
every 12 h) are approximately doubled when taken in combination with
oral ganciclovir (1000 mg every 8 h).
CONCLUSIONS: Although bioavailability
of the oral formulation of ganciclovir is low, the serum concentrations are
predictable, with low inter- and intrasubject variability in peak
concentrations and AUC.
The two oral regimens studied (500 mg six times
daily or 1000 mg three times daily) have comparable bioavailability. Food
has a beneficial effect of increasing serum concentrations. There is a
potentially important pharmacokinetic interaction between oral ganciclovir
and didanosine.
====================================================================
16.) Cytomegalovirus (CMV) resistance in patients with CMV retinitis and
AIDS treated with oral or intravenous ganciclovir.
====================================================================
Author
Drew WL; Stempien MJ; Andrews J; Shadman A; Tan SJ; Miner R;
Buhles W
Address
Clinical Microbiology and Infectious Diseases,
University of California at San Francisco-Mt. Zion Medical Center, San
Francisco, CA, USA. [email protected]
Source
J Infect Dis,
179(6):1352-5 1999 Jun
Abstract
Treatment of cytomegalovirus (CMV)
retinitis with oral ganciclovir results in relatively low plasma
concentrations of drug, which theoretically could cause more frequent
viral resistance compared with intravenous (iv) ganciclovir.
By use of a
plaque-reduction assay to quantify phenotypic sensitivity to
ganciclovir, virus isolates were studied from patients with CMV
retinitis participating in four clinical trials of oral ganciclovir.
Before treatment, 69% of patients were culture-positive but just 1.1% of
patients yielded a resistant CMV, defined as a median inhibitory
concentration (IC50) >6 microM.
On treatment, the first resistant isolate
was recovered at 50 days. Overall, 3.1% of patients receiving iv
ganciclovir and 6. 5% of those taking oral ganciclovir shed resistant CMV
(median ganciclovir exposures of 75 and 165 days, respectively). Since
IC50s for clinical isolates increased proportionately with treatment
duration, it is likely that viral resistance would be more frequent with
longer treatment.
====================================================================
17.) The pharmacokinetics and safety profile of oral ganciclovir combined
with zalcitabine or stavudine in asymptomatic HIV- and CMV-seropositive
patients.
====================================================================
Author
Jung D; AbdelHameed MH; Teitelbaum P; Dorr A; Griffy K
Address
Roche Global Development, Palo Alto, California, USA.
Source
J Clin Pharmacol, 39(5):505-12 1999 May
Abstract
Two
open-label, randomized, multiple-dose, three-way crossover studies were
performed to assess the pharmacokinetics and safety of oral ganciclovir
1000 mg q8h in asymptomatic patients seropositive for human
immunodeficiency virus and cytomegalovirus. Ganciclovir was administered
alone and in combination with zalcitabine 0.75 mg q8h (study 1) or
stavudine 40 mg q12h (study 2).
In the presence of zalcitabine, the only
statistically significant change in the pharmacokinetic parameters of
ganciclovir was a 22.2% mean increase in AUC0-8. However, there was no
significant change in the renal clearance of ganciclovir when
coadministered with zalcitabine, suggesting that the increase in serum
ganciclovir concentration cannot be attributed to competition for active
renal tubular secretion.
No change in zalcitabine pharmacokinetics was
observed in combination with ganciclovir. There were no significant changes
in the pharmacokinetics of ganciclovir or stavudine when coadministered.
Ganciclovir was well tolerated when given alone and in combination with
either zalcitabine or stavudine.
====================================================================
18.) GANCICLOVIR (Systemic) The product
====================================================================
Revised: 08/08/95
VA CLASSIFICATION
(Primary/Secondary);AM800
Commonly used brand name(s):
Cytovene;
Cytovene-IV.
Another commonly used name is DHPG
Note: For a listing of dosage forms and brand names by country
availability, see Dosage Forms section(s).
Category
Antiviral (systemic).
Indications
Note: Bracketed
information in the Indications section refers to uses that are not
included in U.S. product labeling.
Accepted
Cytomegalovirus
retinitis (treatment);Parenteral ganciclovir is indicated for
induction and maintenance in the treatment of cytomegalovirus (CMV)
retinitis in immunocompromised patients, including patients with acquired
immunodeficiency syndrome (AIDS). Oral ganciclovir is indicated only for
the maintenance of CMV retinitis in patients who have had a complete
resolution of active retinitis after an induction course of parenteral
ganciclovir1,61; however, oral ganciclovir has been associated with a
shorter time to CMV retinitis progression.1,2,15,60,62 [Intravitreal
administration of ganciclovir has also been used in patients who have been
unresponsive to intravenous ganciclovir, or in whom serious
myelosuppression has precluded the continuation of intravenous
therapy.]29,31,34
Cytomegalovirus disease
(prophylaxis)*;Parenteral ganciclovir is indicated for the
prophylaxis of CMV disease in transplant patients who are at risk for
the disease.1,49,50,51,52,53,54
[Cytomegalovirus disease
(treatment)]*;Parenteral ganciclovir is used in the treatment of
severe CMV disease, including CMV pneumonia, CMV gastrointestinal
disease, and disseminated CMV infections, in immunocompromised
patients.3,6,11,15,20
[Polyradiculopathy
(treatment)]*;Parenteral ganciclovir is used in the treatment of
polyradiculopathy caused by CMV in patients with AIDS.38,39,40
Resistance to ganciclovir has been reported. One paper described CMV
disease refractory to ganciclovir therapy due to infections with a
resistant virus, a susceptible virus that became resistant, and an
infection first by a susceptible strain, and later by a genetically
distinct, resistant one.26 The primary mechanism of resistance to
ganciclovir is the decreased ability to form the active triphosphate
moiety.1 Recurrence may be more frequent in patients treated with
ganciclovir for prolonged periods, (> 3 to 6 months).33,43
*Not
included in Canadian product labeling.
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
High pH (11).1
Molecular weight;;
Ganciclovir:
255.234
Ganciclovir sodium: 277.224
Mechanism of action/Effect:
Ganciclovir is a prodrug6 that is structurally similar to acyclovir.8
Its antiviral activity results from its intracellular conversion to the
triphosphate form. In cytomegalovirus (CMV)-infected cells, ganciclovir is
thought to be rapidly phosphorylated to the monophosphate form by a
CMV-encoded enzyme63, then subsequently converted to the diphosphate and
triphosphate forms by cellular kinases. Ganciclovir is phosphorylated much
more rapidly in infected cells7; however, uninfected cells can also produce
low levels of ganciclovir-triphosphate.3Ganciclovir-triphosphate
competitively inhibits DNA polymerase by acting as a substrate and becoming
incorporated into the DNA.5 This inhibits DNA synthesis by suppressing DNA
chain elongation.5The drug inhibits viral DNA polymerases more effectively
than it does cellular polymerase.24 Chain elongation resumes when
ganciclovir is removed.5
Absorption:
Ganciclovir is poorly
absorbed after oral administration;
bioavailability under fasting
conditions is approximately 5%, and when administered with food, 6 to
9%.1,15,59
Distribution:
Ganciclovir is widely distributed
to all tissues and crosses the placenta15,58; however, there is no
marked accumulation in any one type of tissue. Penetration into the
cerebral spinal fluid averaged 38% in one study9, and ranged from 7 to
67% in others.10,22 Ganciclovir also appears to have good intraocular
penetration.3 In one patient, the subretinal fluid ganciclovir
concentration was 7.2 micromoles per L with a corresponding plasma
concentration of 8.2 micromoles per L 5.5 hours after a dose of 5 mg per
kg of body weight (mg/kg), and 2.58 micromoles per L with a
corresponding plasma concentration of 1.3 micromoles per L 8 hours after a
subsequent dose of 5 mg/kg.28
VolD(steady state) ;Adults and
neonates: Approximately 0.74 L per kg.1,57
Protein binding:
Low (1 to 2%).1
Biotransformation:
Little to no
metabolism.3,6
Half-life:
Serum;
Intravenous
Adults;Normal renal function: 2.5 to 3.6 hours (average, 2.9
hours).1,3,6,7
Adults;Renal function impairment: 9 to 30
hours (creatinine clearance of 20 to 50 mL per minute [0.33 to 0.83 mL
per second]).15
Neonates;Approximately 2.4 hours.1,57
Oral:
Normal renal function;3.1 to 5.5 hours.59
Renal
function impairment;15.7 to 18.2 hours (creatinine clearance of 10
to 50 mL per minute [0.17 to 0.83 mL per second]).1
Vitreous
fluid; Approximately 13 hours.34
Time to peak
concentration:
Intravenous;
End of infusion
(approximately 1 hour).13
Oral;
Fasting: Approximately
1.8 hours.1
With food: Approximately 3 hours.1
Peak
concentrations
Intravenous;
Adults: 5 mg/kg over 1
hour;8.3 to 9 mcg/mL.1
Neonates: 4 and 6 mg/kg over 1
hour;Approximately 5.5 and 7 mcg/mL,
respectively.1,57
Oral;
3 grams per day: 1 to 1.2 mcg/mL.1
Intravitreal
injection; 1000 mcg administered in 5 divided doses over 15 days:
16.2 mcg/mL; ganciclovir was not detected in plasma.15
Elimination:
Renal; almost 100% excreted unchanged in the urine by
glomerular filtration and tubular secretion.1,9,11,15
In
dialysis;Plasma ganciclovir concentrations are reduced by
approximately 50% after a single, 4-hour hemodialysis.1,12
Precautions to Consider
Cross-sensitivity and/or related problems
Patients hypersensitive to acyclovir may also be hypersensitive to
ganciclovir because of the chemical similarity of the 2 medications.1,2
Carcinogenicity/Tumorigenicity
Ganciclovir is carcinogenic in
animals and should be considered a potential carcinogen in humans.
Ganciclovir was carcinogenic in the mouse at oral doses of 20 and 1000
mg/kg per day (approximately 0.1 and 1.4 times, respectively, the mean
drug exposure in humans following the recommended intravenous dose of 5
mg/kg, based on the area under the concentration-time curve [AUC])
comparisons. Mice given oral doses of 20 mg per kg of body weight
(mg/kg) per day showed a slightly increased incidence of tumors in the
preputial and harderian glands in males, forestomach in males and
females, and liver in females.
Studies in mice given oral doses of 1000
mg/kg per day showed an increased incidence of tumors of the forestomach in
males and females, preputial gland in males, and reproductive tissues and
liver in females. All ganciclovir-induced tumors were of epithelial or
vascular origin, except for histiocytic sarcoma of the liver. No
carcinogenic effect occurred at a dose of 1 mg/kg per day.1
Mutagenicity Ganciclovir was mutagenic in mouse lymphoma cells at
concentrations between 50 and 500 mcg/mL, and caused chromosomal damage
in vitro in human lymphocytes at concentrations between 250 and 2000
mcg/mL.
Parenteral ganciclovir was also clastogenic in the mouse
micronucleus assay at doses of 150 and 500 mg/kg (2.8 to 10 times the
human exposure based on area under the concentration-time curve [AUC] of
a single intravenous dose of 5 mg/kg), but not at a dose of 50 mg/kg
(exposure approximately comparable to the human dose based on AUC).
Ganciclovir was not mutagenic in the Ames Salmonella assay at
concentrations of 500 to 5000 mcg/mL.1
Pregnancy/Reproduction
Fertility;Although data in humans have not been obtained,
temporary or permanent suppression of fertility in women and
spermatogenesis in men may occur.1
In female mice, ganciclovir
caused decreased mating behavior, decreased fertility, and increased
death in utero at doses approximately 1.7 times the recommended human
dose (based on the AUC of a single intravenous dose of 5 mg/kg).
Ganciclovir was also found to cause decreased fertility in male mice,
and hypospermatogenesis in mice and dogs following daily oral or
intravenous administration of doses ranging from 0.2 to 10
mg/kg.1Inhibition of spermatogenesis and subsequent infertility was
reversible at lower doses and irreversible at higher doses in
animals.2Systemic drug exposure (as measured by AUC) at the lowest dose
showing toxicity in each species ranged from 0.03 to 0.1 times the AUC of
the recommended human intravenous dose.1
Pregnancy;Adequate
and well-controlled studies in humans have not been done. However,
ganciclovir has been found to cross the placenta.15,58 Due to the high
toxicity and mutagenic and teratogenic potential of ganciclovir, use
during pregnancy should be avoided whenever possible. Women of
childbearing age should use effective contraception. Men should use
barrier contraception during, and for at least 90 days following,
treatment with ganciclovir.1
Ganciclovir was found to be
carcinogenic in animals and teratogenic in rabbits, causing cleft
palate, anophthalmia/microphthalmia, aplastic organs (kidneys and
pancreas), hydrocephaly, bradygnathia, and fetal growth retardation. It
also was found to be embryotoxic in mice, and to cause death in utero
and maternal toxicity in both rabbits and mice. Fetal resorptions
occurred in at least 85% of rabbits and mice administered 60 mg/kg per
day and 108 mg/kg per day (2 times the human exposure based on AUC
comparisons), respectively. Daily intravenous doses of 90 mg/kg
administered to female mice prior to mating, during gestation, and during
lactation caused hypoplasia of the testes and seminal vesicles in the
month-old male offspring, as well as pathologic changes in the nonglandular
region of the stomach. The drug exposure in mice as estimated by the AUC
was approximately 1.7 times the human AUC.1
FDA Pregnancy Category
C.
Breast-feeding
It is not known whether ganciclovir is
distributed into breast milk1; however, it is likely that some drug will
accumulate because of its pharmacokinetic properties.35 Because of the
potential for serious adverse effects in nursing infants, breast-feeding
should be stopped during ganciclovir therapy.1 Ganciclovir has caused
irreversible toxicity in nursing animal pups.14
Pediatrics
There is little information currently available on the use of
ganciclovir in children, especially those up to the age of 12. At this
time, the side effects seen in children appear to be similar to those
seen in adults, especially granulocytopenia (17%) and thrombocytopenia
(10%). However, the probability of long-term carcinogenicity and
reproductive toxicity seen in animal studies should also be
considered.1 Geriatrics
No information is available on the
relationship of age to the effects of ganciclovir in geriatric patients.
However, elderly patients are more likely to have an age-related
decrease in renal function, which may require an adjustment of dosage or
dosing interval in patients receiving ganciclovir.1,2
Dental
The neutropenic and thrombocytopenic effects of ganciclovir may result
in
an increased incidence of microbial infection, delayed healing, and
gingival bleeding. Patients should be instructed in proper oral hygiene,
including caution in use of regular toothbrushes, dental floss, and
toothpicks.
Drug interactions and/or related problems
The
following drug interactions and/or related problems have been selected
on the basis of their potential clinical significance (possible mechanism
in parentheses where appropriate);not necessarily inclusive (>> =
major clinical significance):
Note: Combinations containing any
of the following medications, depending on the amount present, may also
interact with this medication.
Blood dyscrasia-causing medications
(See Appendix II) or >> Bone marrow depressants, other (See Appendix II)
or Radiation therapy1;(concurrent use with ganciclovir may
increase the bone marrow-depressant effects of these medications and
radiation therapy)
Didanosine;(concurrent and sequential [2
hours apart] administration of didanosine with ganciclovir results in a
significant increase in the steady-state area under the
concentration-time curve [AUC] of didanosine [range, 72 to 111%]1,19,21;
when didanosine was administered 2 hours before oral ganciclovir, the
steady-state AUC of ganciclovir was decreased by approximately 21%1;
there was no significant change in renal clearance of either
medication1) Imipenem and cilastatin
combination1,2;(generalized seizures have been reported in
patients receiving ganciclovir and imipenem and cilastatin combination
concurrently)
>> Nephrotoxic medications (See Appendix
II)1;(concurrent use with ganciclovir may increase serum
creatinine; concurrent use with nephrotoxic medications, such as
cyclosporine or amphotericin B, may increase the chance of renal
function impairment; this may also decrease elimination of ganciclovir
and increase the risk of toxicity)
Probenecid;(concurrent use
with probenecid increases the AUC of ganciclovir by approximately 53%21
and decreases its renal clearance by approximately 22%1; concurrent use
of ganciclovir with probenecid, or other medications that inhibit renal
tubular secretion, may reduce the renal clearance of ganciclovir and
lead to toxicity1,21)
>> Zidovudine1,2,16,18;(concurrent use
of ganciclovir with zidovudine has been associated with severe
hematologic toxicity in some patients, even when the zidovudine dose was
reduced to 300 mg per day37; concurrent use increases the AUC of
zidovudine by approximately 14 to 19%1,21; in vitrostudies found
concurrent use of these 2 drugs to be synergistically cytotoxic48;
concurrent administration should be used with caution)
Laboratory
value alterations
The following have been selected on the basis of
their potential clinical significance (possible effect in parentheses
where appropriate);not necessarily inclusive (>> = major clinical
significance): With physiology/laboratory test values Alanine
aminotransferase (ALT [SGPT]), serum and Alkaline phosphatase, serum
and Aspartate aminotransferase (AST [SGOT]), serum and Bilirubin,
serum;(values may be increased1,2,3,13,17) Blood urea
nitrogen (BUN) or Creatinine, serum;(values may be increased1,2)
Medical considerations/Contraindications
The medical
considerations/contraindications included have been selected on the
basis of their potential clinical significance (reasons given in
parentheses where appropriate);not necessarily inclusive (>> = major
clinical significance).
Risk-benefit should be considered when the
following medical problems exist
>> Absolute neutrophil count (ANC)
<500 cells/mm3 or platelet count <25,000 cells/mm31;
>>
Hypersensitivity to acyclovir or ganciclovir1;
>> Renal
function impairment1,3,6;(because ganciclovir is excreted through
the kidneys, the dose of ganciclovir should be reduced or the dosing
interval increased in patients with renal function impairment)
Patient monitoring
The following may be especially important in
patient monitoring (other tests may be warranted in some patients,
depending on condition; >> = major clinical significance):
>>
Complete blood counts (CBCs) and >> Platelet
counts1,2,3,11,13,45,46,47;(because ganciclovir may cause
granulocytopenia and thrombocytopenia, neutrophil and platelet counts
should be monitored prior to treatment, every 2 days during induction
therapy, then at least weekly thereafter. Neutrophil and platelet counts
should be performed daily in patients undergoing hemodialysis, patients
with neutrophil counts less than 1000 cells/mm3 at the beginning of
treatment, and those in whom use of ganciclovir or other nucleoside analogs
previously resulted in leukopenia. When severe neutropenia [absolute
neutrophil count < 500 cells/mm3] or severe thromboctyopenia [platelet
count < 25,000 cells/mm3] occurs, discontinuation of ganciclovir may be
necessary; however, a small number of patients have been successfully
treated with concurrent use of sargramostim [GM-CSF; granulocyte-macrophage
colony stimulating factor] or filgrastin [G-CSF; granulocyte colony
stimulating factor]61)
Liver function tests15,17;(liver
function tests, including serum ALT [SGPT] and AST [SGOT] values, and
serum bilirubin concentration, should be monitored periodically since
elevations, usually reversible, have occurred during ganciclovir
therapy)
>> Renal function determinations1;(blood urea
nitrogen and serum creatinine determinations should be monitored at
least every 2 weeks since patients with renal function impairment will
require an adjustment in dosage or dosage interval)
For
treatment of cytomegalovirus [CMV] retinitis, in addition to the above
>> Ophthalmologic examinations30,61,64;(ophthalmologic
examinations should be performed weekly during induction and every 4
weeks during maintenance since ganciclovir is not a cure for
cytomegalovirus [CMV] retinitis, and progression of retinitis may occur
during or following ganciclovir treatment; however, the frequency of
examinations may vary, depending on the extent of disease, activity, and
proximity to the macula and optic disc)
Side/Adverse Effects
The following side/adverse effects have been selected on the basis of
their potential clinical significance (possible signs and symptoms in
parentheses where appropriate);not necessarily inclusive:
Those indicating need for medical attention
Incidence more
frequent
For intravenous and oral administration
Granulocytopenia (sore throat and fever)1,3,6,24,59; thrombocytopenia
(unusual bleeding or bruising)1,3,6,7,24,32,59
Note:
Granulocytopenia is usually reversible, with an overall incidence of
approximately 40%1,2,3,6; the incidence of dose-limiting toxicity is
<20%.24
Thrombocytopenia is also usually reversible, with an overall
incidence of approximately 20%1,2,3,6,7; the incidence of dose-limiting
toxicity is 5 to 10%.24,32
Incidence less frequent
For
intravenous and oral administration Anemia (unusual tiredness and
weakness)1,2,59; central nervous system (CNS) effects (mood or other
mental changes; nervousness; tremor)1,3,6,13,41; hypersensitivity
(fever; skin rash)1,2,59phlebitis (pain at site of injection)1,3,6
For intravitreal administration35 Bacterial endophthalmitis;
conjunctival scarring, mild; foreign body sensation; retinal detachment;
scleral induration; or subconjunctival hemorrhage (decreased vision or
any change in vision)
Those indicating need for medical attention
only if they continue or are bothersome
Incidence less frequent
Gastrointestinal disturbances (abdominal pain; loss of appetite; nausea
and vomiting)1,2,6,7,59
Patient Consultation
As an aid to
patient consultation, refer to Advice for the Patient, Ganciclovir
(Systemic).
In providing consultation, consider emphasizing the
following selected information (>> = major clinical significance):
Before using this medication
>> Conditions affecting use,
especially:
Hypersensitivity to acyclovir or ganciclovir
Pregnancy; Use of ganciclovir during pregnancy should be avoided
whenever possible. Ganciclovir crosses the placenta and has been found
to be carcinogenic and teratogenic in animals. Use of effective
contraception by men and women who are undergoing treatment and in men
for 90 days following treatment is recommended
Breast-feeding; Because of ganciclovir's potential for severe
toxicity, breast-feeding should be stopped during therapy
Use in
children;There is little information currently available on the use
of ganciclovir in children, especially those up to the age of 12; long-term
carcinogenicity and reproductive toxicity due to ganciclovir use in
children is unknown
Dental;The neutropenic and
thrombocytopenic effects of ganciclovir may result in an increased
incidence of microbial infection, delayed healing, and gingival
bleeding
Other medications, especially other bone marrow
depressants, nephrotoxic medications, or zidovudine
Other
medical problems, especially renal function impairment, an absolute
neutrophil count (ANC) <500 cells/mm3, or platelet count <25,000 cells/mm3
Proper use of this medication
>> Taking ganciclovir capsules
with food
>> Importance of receiving medication for full course of
therapy and on a regular schedule
>> Proper dosing
Precautions while using this medication
To reduce the risk of
bleeding during periods of low blood counts: >> Checking with physician
immediately if getting an infection or fever or chills
>>
Checking with physician immediately if unusual bleeding or bruising;
black, tarry stools; blood in urine or stools; or pinpoint red spots on
skin occur
Using caution in use of regular toothbrushes, dental
floss, and toothpicks; physician, dentist, or nurse may suggest
alternative methods for cleaning teeth and gums; checking with physician
before having dental work done
Using caution to avoid accidental
cuts with use of sharp objects such as a safety razor or fingernail or
toenail cutters
>> Using contraception since ganciclovir has
mutagenic and teratogenic potential; women should use effective
contraception during treatment, and men should use barrier contraception
during and for at least 90 days following treatment1
>> Regular
visits to physician to check blood counts
>> For CMV
retinitis;Regular visits to ophthalmologist to examine eyes since
progression of retinitis and visual loss may occur during ganciclovir
therapy
Side/adverse effects
Signs of potential side
effects, especially granulocytopenia, thrombocytopenia, anemia, CNS
effects, hypersensitivity, and phlebitis when ganciclovir is
administered intravenously or orally; and bacterial endophthalmitis,
mild conjunctival scarring, foreign body sensation, retinal detachment,
scleral induration, and subconjunctival hemorrhage when it is
administered intravitreally
General Dosing Information
Ganciclovir is not a cure for cytomegalovirus infections. Maintenance
therapy is almost always necessary in AIDS patients to prevent relapse,
which is very common once the medication has been withdrawn.1
Monitoring of serum ganciclovir concentrations has not been shown to be
useful for ensuring efficacy or avoiding toxicity.24
Ganciclovir
sodium should be administered by intravenous infusion only.
Intramuscular or subcutaneous injection will result in severe tissue
irritation due to ganciclovir's high pH (11).1,2
Intravenous
infusions of ganciclovir should be administered at a constant rate over
at least a 1-hour period, and patients must be adequately hydrated, to
avoid increased toxicity. The recommended dosage, frequency, and
infusion rate should not be exceeded.1
Severe neutropenia or
thrombocytopenia (absolute neutrophil count [ANC] <500 cells/mm3 or
platelet count <25,000 cells/mm3) requires an interruption in therapy
until there is evidence of bone marrow recovery (ANC ³750
cells/mm3); however, a small number of patients have been successfully
treated with concurrent use of sargramostim (GM-CSF;
granulocyte-macrophage colony stimulating factor).45,46,47
Ganciclovir capsules should be taken with food for maximum absorption.1
The dose of ganciclovir must be decreased in patients with renal
function impairment.
Patients undergoing hemodialysis should not
receive a dose in excess of 1.25 mg per kg of body weight (mg/kg) every
24 hours. On dialysis days, the dose of ganciclovir should be
administered after hemodialysis has been performed since dialysis will
reduce plasma ganciclovir concentrations by approximately 50%.1,2
Ganciclovir capsules are indicated as an alternative to intravenous
ganciclovir for maintenance therapy of CMV retinitis in immunocompromised
patients, including those with AIDS. Oral ganciclovir should be used in
patients in whom retinitis is stable and quiescent following appropriate
induction therapy and for whom the risk of more rapid progression is
balanced by the benefit associated with avoiding long-term daily intravenous infusions, usually requiring indwelling intravenous catheters.1
Intravitreal administration of ganciclovir has been used in patients
who have been unresponsive to intravenous ganciclovir, or in whom
serious myelosuppression has precluded the continuation of intravenous
therapy. Intravitreal doses of 200 micrograms have resulted in
improvement or stabilization of retinitis, and have been well tolerated.
In one report describing a patient who received 28 intravitreal
injections, plasma concentrations after intravitreal injections showed
no significant systemic absorption. The elimination half-life of
ganciclovir from the vitreous fluid was estimated to be 13.3 hours, and
the intravitreal concentration remained above the ID 50 of
cytomegalovirus for approximately 62 hours after a single
injection.29,31,34
Safety considerations for handling this
medication
Caution should be exercised in the handling and
preparation of ganciclovir. Because ganciclovir shares some properties
of anti-tumor agents (i.e., carcinogenicity and mutagenicity), it should
be handled and disposed of according to guidelines issued for cytotoxic
drugs. Ganciclovir solution is alkaline (pH 11). Avoid inhalation,
ingestion, or direct contact of ganciclovir with the skin or mucous
membranes. If contact does occur, wash area thoroughly with soap and
water; rinse eyes thoroughly with plain water.42 Ganciclovir capsules
should not be opened or crushed.1
Oral Dosage Forms
GANCICLOVIR CAPSULES
Usual adult and adolescent dose
Cytomegalovirus retinitis;
Induction: Ganciclovir capsules should
not be used for induction therapy. See Sterile Ganciclovir Sodium1
Maintenance: Oral, 1000 mg three times a day with food, or 500 mg six
times a day every three hours with food, during waking hours.1
Note: For maintenance, patients with impaired renal function may require a
reduction in dose as follows:1,3,12
Creatinine Clearance
(mL/min)/(mL/sec) Dose
sup3;70/1.17 See Usual adult and
adolescent dose 50-69/0.83-1.15 1500 mg once a day, or 500 mg three
times a day 25-49/0.42-0.82 1000 mg once a day, or 500 mg twice
a day 10-24/0.17-0.40 500 mg once a day <10/0.17 500 mg three times
a week, following hemodialysis
Usual pediatric dose
Dosage has not been established.1
Strength(s) usually available
U.S.; 250 mg (Rx)[Cytovene].
Canada; Not
commercially available.
Packaging and storage:
Store below
40 °C (104 °F), preferably between 15 and 30 °C (59 and 86
°F), unless otherwise specified by manufacturer.
Auxiliary
labeling:
middot; Continue medicine for full time of treatment.
Note: Ganciclovir capsules should not be opened or crushed.
Parenteral Dosage Forms
GANCICLOVIR SODIUM STERILE
Usual
adult and adolescent dose
Cytomegalovirus retinitis
(treatment);
Induction; Intravenous infusion, 5 mg
per kg of body weight, administered over at least one hour, every twelve
hours for fourteen to twenty-one days.1,2,3,6,8,20 Note: Doses
of 7.5 to 15 mg per kg of body weight per day divided into two or three
doses have been used, and treatment has been continued for longer than
twenty-one days; if retinitis does not show significant improvement, the
possibility of viral resistance should be considered.32
Intravitreal
injection, 200 mcg two times a week for three weeks.35,44
Note: For
induction, patients with impaired renal function may require a reduction
in dose as follows1:
Creatinine Clearance (mL/min)/(mL/sec)
Dose
sup3;70/1.17 See Usual adult and adolescent dose
50-69/0.83-1.15 2.5 mg per kg every twelve hours 25-49/0.42-0.82 2.5
mg per kg every twenty-four hours 10-24/0.17-0.40 1.25 mg per kg
every twenty-four hours <10 1.25 mg per kg three times a week,
following hemodialysis
Maintenance;
Intravenous infusion, 5 mg per kg of body weight a day, administered over
at least one hour, once a day for seven days per week; or 6 mg per kg of
body weight, administered over at least one hour, once a day for five days
of the week.1,2,3,6
Note: If CMV retinitis progresses during
maintenance therapy, patients should be retreated with the twice-a-day
induction regimen.
Intravitreal injection, 200 mcg once a
week.35,36
Note: For maintenance, patients with impaired renal
function may require a reduction in dose as follows1:
Creatinine Clearance (mL/min)/(mL/sec) Dose ³70/1.17 See Usual
adult and adolescent dose
50-69/0.83-1.15 2.5 mg per kg every
twelve hours 25-49/0.42-0.82 1.25 mg per kg every twenty-four
hours 10-24/0.17-0.40 0.625 mg per kg every twenty-four hours
<10 0.625 mg per kg three times a week, following hemodialysis
Cytomegalovirus disease (prophylaxis); Intravenous
infusion, 5 mg per kg of body weight, administered over at least one
hour, every twelve hours for seven to fourteen days; then 5 mg per kg of
body weight, administered over at least one hour, once a day for seven
days of the week, or 6 mg per kg of body weight, administered over at
least one hour, once a day for five days of the week.49
Usual
pediatric dose
Dosage has not been established. However, induction
doses of 7.5 to 10 mg per kg of body weight divided into two or three
doses, and maintenance doses of 2.5 to 5 mg per kg of body weight a day
have been used in children.25,27,28,32
Strength(s) usually
available U.S.; 500 mg (Rx)[Cytovene-IV (sodium 46 mg)].
Canada; 500 mg (Rx)[Cytovene].
Packaging and
storage:
Store below 40 deg;C (104 deg;F), preferably between 15
and 30 deg;C (59 and 86 deg;F), unless otherwise specified by
manufacturer.
Preparation of dosage form:
To prepare initial
dilution for intravenous infusion, 10 mL of sterile water for injection
(without parabens) should be added to each 500-mg vial to provide 50 mg
per mL. To ensure complete dissolution, the vial should be shaken until
solution is clear. The resulting solution should be further diluted,
usually with 100 mL of 0.9% sodium chloride injection, 5% dextrose
injection, Ringer's injection, or lactated Ringer's injection. Final
concentrations of 10 mg per mL or less are recommended.2,23
Note:
Caution should be exercised in the handling and preparation of
ganciclovir. Because ganciclovir shares some properties of anti-tumor
agents (i.e., carcinogenicity and mutagenicity), it should be handled and
disposed of according to guidelines issued for cytotoxic drugs. Ganciclovir
solution is alkaline (pH 11). Avoid inhalation, ingestion, or direct
contact of ganciclovir with the skin or mucous membranes. If contact does
occur, wash area thoroughly with soap and water; rinse eyes thoroughly with
plain water.2,42
Stability:
The manufacturer states that
after reconstitution, solutions at concentrations of 50 mg per mL retain
their potency for 12 hours at room temperature. Refrigeration is not
recommended. After further dilution for intravenous infusion, it is
recommended that solutions be used within 24 hours since
nonbacteriostatic infusion solutions must be used; refrigerate the
diluted solution; do not freeze.2,23
However, studies have found
that ganciclovir, when diluted to concentrations of 1, 5, and 10 mg per
mL in 5% dextrose injection and 0.9% sodium chloride injection, was
stable when assayed at 28 and 35 days.55,56 These solutions were
refrigerated in polyvinyl chloride (PVC) bags and syringes. Ganciclovir
was also stable when 5 and 10 mg per mL solutions were frozen in PVC
bags for 28 days.56
Incompatibilities:
Parabens are
incompatible with ganciclovir sodium and may cause precipitation.1,2
====================================================================
CIDOFOVIR
====================================================================
Source: HARRISON'S 14
Cidofovir is a phosphonomethylether derivative
of cytosine that is highly active against CMV, including some
ganciclovir- and foscarnet-resistant strains. This agent is administered
intravenously and is cleared largely by the kidney, with a serum
half-life of 2.6 h. Concomitant administration with probenecid markedly
prolongs the half-life of cidofovir and protects recipients against the
major form of toxicity elicited by the drug (nephrotoxicity). The
intracellular half-life of cidofovir diphosphate;17 to 30
h;is the basis for its infrequent administration (once a week or
once every other week). Cidofovir is currently being evaluated for the
treatment of CMV retinitis in patients with AIDS.
====================================================================
19.) Trifluridine, cidofovir, and penciclovir in the treatment of
experimental herpetic keratitis.
====================================================================
Author
Kaufman HE; Varnell ED; Thompson HW
Address
LSU Eye
Center, Louisiana State University Medical Center School of Medicine,
New Orleans 70112-2234, USA.
Source
Arch Ophthalmol, 116(6):777-80
1998 Jun
Abstract
OBJECTIVE: To compare trifluridine eyedrops,
cidofovir eyedrops, and penciclovir ophthalmic ointment for the
treatment of herpes simplex virus type 1 keratitis.
METHODS: New Zealand
white rabbits were infected with the McKrae strain of herpes simplex
virus type 1. Three days after viral inoculation, the rabbits were
randomly assigned to treatment with 1% trifluridine, 0.2% cidofovir, 3%
penciclovir ointment, or phosphate-buffered saline (for control) on
various schedules. The severity of keratitis was graded in a masked
manner.
RESULTS: Treatment with any of the antiviral drugs resulted in
significantly less severe keratitis than treatment with
phosphate-buffered saline. There was no statistically significant
difference between eyes given trifluridine 2, 4, or 7 times a day and
eyes given cidofovir 2 times a day (P=.06, P=.43, and P=.19,
respectively, using the F test of the analysis of variance). Cidofovir
given twice a day was significantly more effective than penciclovir given
either 2 or 4 times a day (P<.001 and P=.002, respectively).
Even with
once-a-day dosage, all 3 drugs were significantly more effective than
phosphate-buffered saline (P<.001 for all). There was no significant
difference between once-a-day trifluridine and cidofovir treatments
(P=.17). Trifluridine administered 5 times a day was as effective as 1%
cidofovir. A similar degree of punctate keratitis was seen after 4 to 5
days in eyes treated with trifluridine at the highest frequency, 1%
cidofovir, or penciclovir ointment.
CONCLUSION: Trifluridine treatment was
highly effective in this rabbit model, even when given only once a day.
Treatment with cidofovir was as effective as that with trifluridine.
CLINICAL RELEVANCE: Cidofovir and penciclovir treatments may prove to be
effective against epithelial keratitis. Clinical trials of trifluridine,
cidofovir, and penciclovir with lower treatment frequencies appear to be
warranted.
====================================================================
20.) Bioavailability and metabolism of cidofovir following topical
administration to rabbits.
====================================================================
Author
Cundy KC; Lynch G; Lee WA
Address
Gilead Sciences, Foster
City, CA 94404, USA.
Source
Antiviral Res, 35(2):113-22 1997 Jul
Abstract
The bioavailability and metabolism of the antiviral nucleotide
analog cidofovir (HPMPC) were examined in New Zealand white rabbits
following topical administration to normal and abraded skin. Male
rabbits (four per group) received 14C-cidofovir (100 microCi/kg)
intravenously (1 mg/kg) as a solution or topically (2 mg/animal) as a 1%
w/w gel containing hydroxyethylcellulose (HEC) with or without propylene
glycol (PG).
The same PG/HEC formulation was applied topically to an
abraded skin site in a fourth group of animals. All radioactivity
detected in plasma and skin was accounted for by cidofovir. Plasma
concentrations of radioactivity declined multiexponentially following
intravenous administration, with a terminal half-life of 5.4 h. For
intact skin, the absolute bioavailabilities of the HEC and PG/HEC
formulations were 0.2 and 2.1%, respectively. For abraded skin, the
bioavailability for the PG/HEC gel was 41%.
Radioactivity in kidneys was
attributed to cidofovir ( > 95%) and cyclic HPMPC. Concentrations in
kidney following topical administration of cidofovir to normal skin were
< 4% of those following intravenous dosing. Topical application of
cidofovir to intact skin led to negligible systemic exposure to the
drug. The topical bioavailability and hence the flux of cidofovir
through intact skin was enhanced by the presence of PG in the formulation.
Abrasion of the skin removed the principal barrier to absorption and led to
significant systemic exposure to cidofovir.
====================================================================
21.) Cidofovir: a new therapy for cytomegalovirus retinitis.
====================================================================
Author
Lalezari JP
Address
Department of Medicine, University of
California, San Francisco 94115, U.S.A.
Source
J Acquir Immune Defic
Syndr Hum Retrovirol, 14 Suppl 1():S22-6 1997
Abstract
Cidofovir,
(S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine, formerly known as
HPMPC, is the first antiviral nucleotide analogue available for the
treatment of cytomegalovirus (CMV) retinitis. Because cidofovir does not
require viral activation, it has two advantages over nucleoside
analogues such as ganciclovir and acyclovir. Cidofovir is active in
uninfected cells and may act preemptively, and it may retain activity
against ganciclovir-resistant strains.
Preclinical studies showed the major
toxicity of cidofovir to be dose-, schedule-, and species-dependent
nephrotoxicity.
These studies also showed that concomitant administration
of probenecid protects animal models against cidofovir-induced
nephrotoxicity. Two phase I-II studies were undertaken in HIV-positive
patients with asymptomatic CMV excretion to evaluate several
dose-escalation regimens. Data from both phase I-II studies showed that in
patients receiving cidofovir at > or =3 mg/kg, the virologic response rate
(> or =2 log reduction in CMV titer) was 93% for urine and 74% for semen.
In addition, four treatment modifications were indicated to reduce the
incidence of cidofovir-related nephrotoxicity:
(a) dose reduction or
interruption for changes in renal function;
(b) concomitant administration
of probenecid;
(c) administration of 1 L of normal saline 1 h before
infusion of cidofovir; and
(d) extension of the dosing interval.
====================================================================
22.) Parenteral cidofovir for cytomegalovirus retinitis in patients with
AIDS: the HPMPC peripheral cytomegalovirus retinitis trial. A
randomized, controlled trial. Studies of Ocular complications of AIDS
Research Group in Collaboration with the AIDS Clinical Trials Group.
====================================================================
Source
Ann Intern Med, 126(4):264-74 1997 Feb 15
Abstract
BACKGROUND: Cytomegalovirus (CMV) retinitis is a common infection and a
major cause of visual loss in patients with the acquired immunodeficiency
syndrome (AIDS).
OBJECTIVE: To evaluate intravenous cidofovir as a
treatment for CMV retinitis. DESIGN: Two-stage, multicenter, phase II/III,
randomized, controlled clinical trial.
SETTING: Ophthalmology and AIDS
services at tertiary care medical centers.
PATIENTS: 64 patients with AIDS
and previously untreated, small, peripheral CMV retinitis lesions (that is,
patients at low risk for loss of visual acuity).
INTERVENTION: Patients
were randomly assigned to one of three groups: the deferral group, in which
treatment was deferred until retinitis progressed; the low-dose cidofovir
group, which received cidofovir, 5 mg/kg of body weight once weekly for 2
weeks, then maintenance therapy with cidofovir, 3 mg/kg once every 2 weeks;
or the high-dose cidofovir group, which received cidofovir, 5 mg/kg once
weekly for 2 weeks, then maintenance therapy with cidofovir, 5 mg/kg once
every 2 weeks. To minimize nephrotoxicity, cidofovir was administered with
hydration and probenecid.
MEASUREMENTS: Progression of retinitis, evaluated
in a masked manner by a fundus photograph reading center; the amount of
retinal area involved by CMV; the loss of visual acuity; and morbidity.
RESULTS: Median time to progression was 64 days in the low-dose cidofovir
group and 21 days in the deferral group (P = 0.052, log-rank test). The
median time to progression was not reached in the high-dose cidofovir group
but was 20 days in the deferral group (P = 0.009, log-rank test). Analysis
of the rates of increase in the retinal area affected by CMV confirmed the
data on time to progression.
The three groups had similar rates of visual
loss. Proteinuria of 2+ or more occurred at rates of 2.6 per person-year in
the deferral group, 2.8 per person-year in the low-dose cidofovir group (P
> 0.02), and 6.8 per person-year in the high-dose cidofovir group (P =
0.135). No patient developed 4+ proteinuria, but two cidofovir recipients
developed persistent elevations of serum creatinine levels at more than 177
mumol/L (2.0 mg/dL). Reactions to probenecid occurred at a rate of 0.70 per
person-year.
CONCLUSIONS: Intravenous cidofovir, high- or low-dose,
effectively slowed the progression of CMV retinitis. Concomitant probenecid
and hydration therapy, intermittent dosing, and monitoring for proteinuria
seemed to minimize but not eliminate the risk for nephrotoxicity.
====================================================================
23.) Cidofovir and experimental herpetic stromal disease.
====================================================================
Author
Kaufman HE; Varnell ED; Thompson HW
Address
LSU Eye
Center, Louisiana State University Medical Center School of Medicine,
New Orleans 70112-2234, USA.
Source
Arch Ophthalmol, 117(7):925-8
1999 Jul
Abstract
OBJECTIVE: To compare topical cidofovir with
topical trifluridine for the prevention and treatment of herpes simplex
type 1 stromal keratitis in rabbits.
METHODS: The RE strain of herpes
simplex virus 1 was injected into the central stroma of both eyes of New
Zealand white rabbits. Two to 3 days after virus inoculation, the
rabbits were randomized to treatment groups of 10 each and treated with
1% trifluridine administered 5 or 7 times a day, 1%, 0.5%, or 0.2%
cidofovir administered twice a day, fluorometholone administered twice a
day, or balanced salt solution (BSS) administered twice a day (control)
until day 21 after injection. The treated corneas were examined 3 times
a week and the severity of stromal keratitis was graded in a masked
fashion. To evaluate the ability of cidofovir to treat established
stromal disease, groups of 10 rabbits each were inoculated with herpes
simplex virus and treated with 1% cidofovir twice a day, 1% trifluridine
5 times a day, fluorometholone twice a day, or BSS twice a day beginning
on day 7 after virus inoculation through day 21.
RESULTS: Treatment with
0.2% cidofovir twice a day was not effective in preventing the
appearance of stromal disease (P = .89), whereas treatment with 0.5%
(P<.001) or 1% (P<.001) cidofovir twice a day or 1% trifluridine 5 times a
day (P<.001) or 7 times a day (P = .006) significantly reduced the
appearance of stromal keratitis on the 8 evaluation days, compared with BSS
treatment (F test analysis of variance). There was no difference between
the eyes treated with 0.5% cidofovir twice a day and those treated with 1%
trifluridine 5 times a day. Treatment with 1% cidofovir was not effective
in treating established stromal disease.
CONCLUSIONS: Cidofovir and
trifluridine are highly effective in preventing the appearance of herpetic
stromal disease. Cidofovir is as effective as, but no more effective than,
trifluridine in this model. Neither cidofovir nor trifluridine benefits
established stromal disease, however.
CLINICAL RELEVANCE: Cidofovir is a
new, potent antiviral that seems similar in efficacy to trifluridine and is
effective in the prevention of the development of stromal herpes, but is
not effective in the treatment of established stromal disease in which
hypersensitivity predominates.
====================================================================
24.) Clinical pharmacokinetics of the antiviral nucleotide analogues
cidofovir and adefovir.
====================================================================
Author
Cundy KC
Address
Gilead Sciences Inc., Foster City,
California, USA. [email protected]
Source
Clin Pharmacokinet,
36(2):127-43 1999 Feb
Abstract
Cidofovir and adefovir are members of
a new class of antiviral compounds. They are acyclic phosphonate
analogues of deoxynucleoside monophosphates. Both compounds undergo
intracellular activation to form diphosphates that are potent inhibitors
of viral DNA polymerases.
Cidofovir has broad spectrum antiviral
activity against herpesviruses, papillomaviruses and poxviruses, whereas
adefovir has potent activity against retroviruses and certain DNA
viruses, including herpesviruses and hepadnaviruses. Intravenous
cidofovir is approved for treatment of cytomegalovirus retinitis in
patients with AIDS.
Cidofovir and adefovir are dianionic at
physiological pH and have low oral bioavailability in animals and humans.
After intravenous administration to HIV-infected patients, the
pharmacokinetics of both drugs are independent of dose and are consistent
with preclinical data. Systemic exposure is proportional to the intravenous
dose and both drugs are cleared by the kidney and excreted extensively as
unchanged drug in the urine.
Intracellular activation of a small fraction
(< 10%) of the dose by cellular kinases leads to prolonged antiviral
effects that are not easily predicted from conventional pharmacokinetic
studies. The observed rate of elimination of cidofovir and adefovir from
serum may not reflect the true duration of action of these drugs, since the
antiviral effect is dependent on concentrations of the active
phosphorylated metabolites that are present within cells. For both drugs, >
90% of an intravenous dose is recovered unchanged in the urine over 24
hours. Metabolism does not contribute significantly to the total clearance
of either drug.
Concomitant oral probenecid decreases both the renal
clearance of cidofovir and the incidence of nephrotoxicity, presumably by
blocking its active tubular secretion. This is the basis of the clinical
use of concomitant probenecid as a nephroprotectant during cidofovir
therapy. Subcutaneous administration produces exposure equivalent to that
following intravenous administration. Drug interaction studies with
cidofovir are ongoing, but there is no evidence of an interaction between
zidovudine and either cidofovir or adefovir.
Clearance of cidofovir in
patients with renal impairment showed a linear relationship to creatinine
clearance. The low oral bioavailability of adefovir has led to the
development of an oral prodrug, adefovir dipivoxil, currently in
development for the treatment of HIV and hepatitis B infections.
====================================================================
25.) Cidofovir in the treatment of cytomegaloviral disease.
====================================================================
Author
Kendle JB; Fan-Havard P
Address
Division of Pharmacy
Practice and Administration, College of Pharmacy, Ohio State University,
Columbus 43210, USA.
Source
Ann Pharmacother, 32(11):1181-92 1998
Nov
Abstract
OBJECTIVE: To review the clinical pharmacology and
microbiology of cidofovir in the therapy of cytomegalovirus (CMV)
disease. DATA SOURCES: Pertinent literature was identified via a MEDLINE
search (October 1986-February 1997), and data from abstracts presented
at recent scientific meetings were also included; unpublished
information was provided by the manufacturer.
STUDY SELECTION: Antiviral
activity data were included if widely accepted methodology was used. All
clinical data currently available from human studies were also included.
DATA SYNTHESIS: Cidofovir is similar to ganciclovir in mechanism of
action; however, cidofovir does not require viral enzymes for
activation. Although the half-life of cidofovir in plasma is only 2.6
hours, the intracellular half-life may be much longer, allowing efficacy
with biweekly maintenance dosing. In vitro, cidofovir appears to be
equally or more effective than the other agents currently available for
the treatment of CMV. In vivo, cidofovir appears to be effective in
delaying the progression of CMV retinitis, although no clinical trials to
date have directly compared cidofovir with either ganciclovir or foscarnet.
Current intravenous dose recommendations are 5 mg/kg once weekly for two
doses (induction), and then 5 mg/kg once every other week (maintenance).
Since cidofovir is cleared almost entirely by the kidneys, dosage
adjustments must be made in patients with impaired renal function.
Disadvantages of cidofovir primarily include its risks of adverse drug
reactions, such as nephrotoxicity, which is likely to occur in up to 50% of
patients if appropriate preventative measures are not taken. Neutropenia
and constitutional reactions to probenecid are also commonly encountered
during the course of cidofovir therapy.
CONCLUSIONS: Cidofovir is the first
acyclic phosphonate nucleoside antiviral agent to be approved for general
use in the US. In addition to delaying the progression of CMV retinitis,
cidofovir may provide some protective benefits to patients at risk for
developing the disease and may be active against certain strains of virus
resistant to other currently available therapies.
Another advantage of
cidofovir is its infrequent dosage schedule, which may prove beneficial in
patients who are not compliant with daily intravenous dosing regimens. When
determining the appropriate treatment for a patient with CMV retinitis, the
benefits of using cidofovir must be weighed carefully against the risk of
potentially serious adverse effects.
====================================================================
26.) Antitumor potential of acyclic nucleoside phosphonates.
====================================================================
Nucleosides Nucleotides 1999 Apr-May;18(4-5):759-71
De Clercq E,
Andrei G, Balzarini J, Hatse S, Liekens S, Naesens L, Neyts J, Snoeck R
Rega Institute for Medical Research, K.U. Leuven, Belgium.
Acyclic
nucleoside phosphonates such as HPMPC (cidofovir) and PMEA (adefovir)
have been identified as broad-spectrum antiviral agents that are
effective against herpes-, retro- and hepadnavirus infections (PMEA) and
herpes-, pox-, adeno-, polyoma-, and papillomavirus infections (HPMPC).
Here we show that HPMPC and PMEA also offer great potential as antitumor
agents, through the induction of tumor cell differentiation (PMEA),
inhibition of angiogenesis (HPMPC) and induction of apoptosis (HPMPC). In
vivo tumor regressions have been noted for choriocarcinoma (PMEA) in rats,
hemangioma (HPMPC) in rats and papillomatous lesions (HPMPC) in humans.
Acyclic nucleoside phosphonates can be considered as a new dimension to the
discipline of chemotherapy.
They have a unique mode of action that is
targeted at (viral or tumoral) DNA synthesis. They exhibit a pronounced and
prolonged anti-viral and/or tumoral activity that can persist for days or
weeks after a single administration.
Most importantly, they have a uniquely
broad spectrum of indications for clinical use, encompassing both DNA- and
retrovirus infections, as well as various forms of cancer of both viral and
non-viral origin.
====================================================================
27.) Clinical uses of cidofovir.
====================================================================
Rev
Med Virol 1997 Sep;7(3):145-156
Safrin S, Cherrington J, Jaffe HS
Gilead Sciences, Foster City, CA, USA.
Cidofovir is a cytidine
nucleotide analogue recently licensed as an intravenous treatment for
CMV retinitis in AIDS patients.
Three controlled clinical trials have
demonstrated efficacy of cidofovir for this indication, and have
generated data useful as a guideline to prevent potential toxicity.
Although de novo emergence of resistance to cidofovir has not been
observed clinically in patients receiving cidofovir, cross-resistance to
cidofovir in ganciclovir-resistant clinical DNA polymerase mutants has
been identified. Cross-resistance of cidofovir and foscarnet has not
been identified to date.
A broad spectrum agent with in vitro activity
against human herpesviruses, adenovirus, HPV, polyomaviruses and human
poxviruses, cidofovir is under clinical investigation for a variety of
potential applications.
Examples include intravenous administration of
cidofovir for treatment of progressive multifocal leukoencephalopathy
and Kaposi's sarcoma, intraocular injection for treatment of CMV
retinitis, intralesional injection for treatment of respiratory
papillomatosis, topical application for treatment of molluscum
contagiosum, anogenital condyloma acuminata, and recurrent genital herpes,
and ophthalmic instillation for treatment of viral keratoconjunctivitis.
====================================================================
28.) Characterization of the DNA polymerase and thymidine kinase genesof
herpes simplex virus isolates from AIDS patients in whom acyclovirand
foscarnet therapy sequentially failed.
====================================================================
J
Infect Dis 1999 Aug;180(2):487-90
Schmit I, Boivin G
Infectious
Disease Research Center, Centre Hospitalier de l'Universite Laval,
Quebec, Canada, G1V 4G2. [email protected].
Herpes simplex
virus (HSV) isolates were characterized from 8 AIDS patients in whom
acyclovir and foscarnet therapy sequentially failed. The 6 postacyclovir
(prefoscarnet) HSV isolates were resistant to acyclovir and susceptible
to foscarnet. Of the 9 postfoscarnet isolates, 8 were
foscarnet-resistant and acyclovir-susceptible, 1 was resistant to both
drugs.
Acyclovir- or foscarnet-resistant isolates retained susceptibility
to cidofovir. The acyclovir-resistant isolates contained single-base
substitutions or frameshift mutations in G or C homopolymer nucleotide
repeats of the thymidine kinase gene. In contrast, the foscarnet-resistant
strains contained single-base substitutions in conserved (II, III, or VI)
or, more rarely, nonconserved (between I and VII) regions of the DNA
polymerase (pol) gene.
The single isolate exhibiting resistance to
acyclovir and foscarnet contained mutations in both genes. In this study of
clinical HSV isolates, DNA pol mutations conferring foscarnet resistance
were not associated with decreased acyclovir or cidofovir susceptibility.
====================================================================
29.) A case study: the use of cidofovir for the management of progressive
multifocal leukoencephalopathy.
====================================================================
J
Assoc Nurses AIDS Care 1999 Jul-Aug;10(4):70-4
Dodge RT
Max
Robinson Center, Whitman-Walker Clinic, Inc.
Progressive Multifocal
Leukoencephalopathy (PML) is an opportunistic infection of the brain in
advanced stages of AIDS. PML is caused by the JC virus, which leads to a
decline in mental acuity and motor functions over a period of weeks or
months.
Currently, there is no treatment or cure for PML. Cidofovir, an
antiviral agent, at the standard dosages for the treatment of
cytomegalovirus (CMV) was implemented in the treatment and management of
a 35-year-old, newly diagnosed AIDS, White male with PML. The patient
presented with impaired motor functions of the left upper and lower
extremities, which resulted in hemiparalysis and hemiparesis. The use of
cidofovir infusions at standard recommendations for treatment and
management of CMV has resulted in improvement and some resolution of the
patient's paralysis and paresthesia.
The patient has remained on the
cidofovir for more than a year, with no signs of advancement of his PML or
AIDS. Further investigation and extensive clinical trials are needed in the
treatment and management of PML with the use of cidofovir.
====================================================================
30.) Antiinfectives update: focus on treatment and prevention of viral and
associated infections.
====================================================================
Ann
Pharmacother 1999 May;33(5):607-14
McNicholl IR, Palmer SM, Ziska
DS, Cleary JD
Division of Pharmacy Practice, St. Louis College of
Pharmacy, MO, USA.
OBJECTIVE: To review the clinically significant
antiinfectives approved by the Food and Drug Administration (FDA) since
1996, with an emphasis on agents used for treatment, prevention, or
suppression of infection in immunocompromised individuals.
DATA SOURCES:
A MEDLINE search covering November 1994 to March 1998 was conducted to
identify all antiinfectives (new medications and old medications with
new indications) and the pertinent literature for review. The search was
updated in August 1998 and supplemented with an FDA listing of approved
drugs to enhance completeness.
STUDY SELECTION: Clinically relevant
studies were selected to highlight specific points about each
medication. Preclinical publications were used when sufficient
information was not available from clinical trials and this information
was needed for clinical practice.
CONCLUSIONS: Several new and promising
antiretroviral agents (stavudine, lamivudine, saquinavir soft-gel
capsules, nelfinavir, efavirenz) have been approved, which may allow more
options to control HIV viremia.
New options for treatment, prevention, and
suppression of infections in immunocompromised individuals include
azithromycin, cidofovir, famciclovir, valacyclovir, and itraconazole
suspension. Liposomal-based amphotericin products may be associated with
less toxicity than conventional amphotericin B; however, superior efficacy
has not been proven.
====================================================================
31.) Identification and rapid quantification of early- and late-lytic human
herpesvirus 8 infection in single cells by flow cytometric analysis:
characterization of antiherpesvirus agents.
====================================================================
J
Virol 1999 Jul;73(7):5894-902
Zoeteweij JP, Eyes ST, Orenstein JM,
Kawamura T, Wu L, Chandran B, Forghani B, Blauvelt A
Dermatology
Branch, National Cancer Institute,National Institutes of Health,
Bethesda, Maryland 20892, USA.
Human herpesvirus 8 (HHV-8) infection
is associated with Kaposi's sarcoma, primary effusion lymphoma (PEL),
and multicentric Castleman's disease.
In this study, we used monoclonal
antibodies (MAbs) directed against HHV-8 lytic cycle-associated proteins
encoded by open reading frame (ORF) 59 (nuclear PF-8 protein) and ORF
K8.1 (viral envelope glycoprotein K8.1 [gpK8.1]) to investigate HHV-8
lytic infection in single cells. Lytically infected cells were labeled
with MAbs, stained with fluorescently conjugated secondary Abs, and
analyzed by flow cytometry.
A 3-day stimulation of HHV-8-positive PEL
cell lines (BCBL-1 and BC-3) with 12-O-tetradecanoylphorbol-13-acetate
(30 nM) or n-butyric acid (0.3 mM) maximized the expression of
lytic-phase viral proteins and minimized cell toxicity. The absolute
number of expressing cells was inducer and cell line dependent.
Expression of PF-8 occurred earlier and more frequently (in up to 20% of
cells) than did expression of gpK8.1. A subset of PF-8 positive cells
(25%) co-expressed gpK8.1, representing the majority of gpK8.1
expressing cells.
Acyclovir, foscarnet, cidofovir, and PMEA reduced the
number of cells expressing gpK8.1, but not the number expressing the
nonstructural early lytic gene product PF-8. By contrast, alpha interferon
(IFN-alpha) and IFN-beta reduced expression of both PF-8 and gpK8.1,
implying an overall inhibitory effect on viral gene transcription or
translation. In summary, we have characterized and quantified HHV-8 lytic
infection in single cells by dual measurement of early- and
late-lytic-cycle HHV-8 protein expression. This technique should prove
useful for screening of possible antiherpesvirus agents and for detailed
phenotypic characterization of HHV-8-infected cells in vitro and in
patients with HHV-8-associated diseases.
====================================================================
32.)Inhibiting effects of cidofovir (HPMPC) on the growth of the human
cervical carcinoma (SiHa) xenografts in athymic nude mice.
====================================================================
Oncol Res 1998;10(10):533-9
Andrei G, Snoeck R, Piette J, Delvenne
P, De Clercq E
Rega Institute for Medical Research, Katholieke
Universiteit, Leuven, Belgium. [email protected]
At present more than 70 human papillomaviruses (HPV) genotypes have
been described and each shows a predilection for a cutaneous or mucosal
surface.
There is a strong association between infection with specific
genital viruses (i.e., types 16 and 18) and the development of cervical
cancer. Thus, intervention with the natural history of HPV infection in
the genital tract may form the basis for an effective anticancer
strategy. We have shown that treatment of cell lines derived from human
cervical carcinomas [i.e., SiHa and CaSki (HPV-16-positive)] and HeLa
(HPV-18-positive)] with HPMPC (cidofovir) results in a concentration-
and time-dependent inhibition of cell proliferation. We report here the
effects of HPMPC on the growth of cervical carcinoma (SiHa) xenografts
in athymic nude mice. Athymic mice between the age of 6 and 8 weeks were
injected SC with 5 to 10x10(6) cells.
Once tumors were established, the
mice were injected with PBS (placebo), HPMPC, or cytarabine (AraC) at
the tumor site. Animals that were injected intratumorally with HPMPC at
a dose of 5 mg/ml (0.25 mg/injection) or 10 mg/ml (0.5 mg/injection)
three or five times per week, once daily, during 4 weeks showed a
statistically significant reduction in tumor size compared to the
placebo group or AraC group.
However, when HMPC was administered
topically (as a cream) or systemically (intraperitoneally), no reduction of
tumor growth was observed at nontoxic concentrations, suggesting that a
high local concentration of HPMPC is required to achieve a significant
decrease of tumor growth.
====================================================================
33.) Antiproliferative effects of acyclic nucleoside phosphonates on human
papillomavirus (HPV)-harboring cell lines compared with HPV-negative cell
lines.
====================================================================
Oncol Res 1998;10(10):523-31
Andrei G, Snoeck R, Piette J, Delvenne
P, De Clercq E
Rega Institute for Medical Research, Katholieke
Universiteit, Leuven, Belgium. [email protected]
Acyclic nucleoside phosphonates (ANPs) possess a broad-spectrum
activity against DNA viruses and retroviruses. HPMPC (cidofovir) has
proved to be effective in the treatment of HPV-associated diseases. We
have evaluated the effects of various ANPs [i.e.,
3-hydroxy-2-phosphonylmethoxypropyl derivatives of adenine (HPMPA) and
cytosine (HPMPC, cidofovir)]; cyclic HPMPC (cHPMPC);
9-(2-phosphonylmethoxyethyl) derivatives of adenine (PMEA, adefovir),
guanine (PMEG), and 2,6-diaminopurine (PMEDAP); and cyclo-propyl PMEDAP
(cPr-PMEDAP), several other antiviral drugs [i.e., acyclovir (ACV),
ganciclovir (GCV), foscarnet (PFA), and ribavirin]; the antitumor agents
cytarabine (AraC) and 5-fluorouracil (5-FU); and the immunosuppressant
mycophenolic acid (MPA) on the proliferation of human cervical
keratinocytes immortalized by HPV-33 (CK-1 cells) and the cervical
carcinoma cell lines containing HPV-16 (CaSki and SiHa) or HPV-18 (HeLa).
In vitro incubation of these cell lines with ANPs resulted in a
concentration- and time-dependent inhibition of cell proliferation. This
inhibitory effect was most striking for HPMPC. The 50% inhibitory
concentration (IC50) of HPMPC decreased from 20-50 microg/ml at day 3 to
0.6-2 microg/ml at day 7.
When the IC50 values of the ANPs for the various
HPV-harboring cells were compared with those for primary human
keratinocytes isolated from normal cervix, HPMPC emerged as the most
selective ANP, with a selectivity index (SI) in the range of 15-42. When
IC50 values as a function of time were determined for several tumor cell
lines (i.e., human melanomas, lung, colon, and breast carcinomas), ANPs
again showed an antiproliferative effect as a function of time, although of
a lower extent (5- to 25-fold decrease in the IC50 values between days 3
and 7) than for the HPV-positive cells.
Treatment of SV40- and
adenovirus-transformed cells with ANPs resulted in the inhibition of cell
proliferation as a function of time, similar to that observed with
HPV-positive cells, HPMPC and cHPMPC being the most potent
antiproliferative agents.
These results suggest that the antiproliferative
activity of ANPs, in particular HPMPC, against HPV-bearing tumor cells may
be explained, at least in part, by a specific inhibitory effect on rapidly
proliferating cells, and the presence of the HPV genome might enhance the
sensitivity of cells to HPMPC due to interactions of the viral-transforming
proteins with products of the tumor suppressor genes.
====================================================================
34.) Resolution of recalcitrant molluscum contagiosum virus lesions in
human immunodeficiency virus-infected patients treated with cidofovir.
====================================================================
Arch Dermatol 1997 Aug;133(8):987-90
Meadows KP, Tyring SK, Pavia
AT, Rallis TM
Department of Dermatology, University of Utah Health
Sciences Center, Salt Lake City, USA.
BACKGROUND: Molluscum
contagiosum virus (MCV) causes cutaneous skin growths that mainly affect
children, sexually active adults, and immunocompromised individuals.
Lesions of MCV in patients infected with human immunodeficiency virus
can be large and numerous, and response to available treatments is often
unsatisfactory.
OBSERVATIONS: We describe 3 men infected with human
immunodeficiency virus who presented with extensive MCV lesions that
were not responsive to various treatments. Patient 1 demonstrated
dramatic clearing of his MCV lesions when intravenous cidofovir therapy
was started for his treatment-resistant bilateral CMV retinitis and
because of cidofovir's possible activity against MCV.
In case 2,
cidofovir was compounded as a 3% cream in a combination vehicle
(Dermovan) for extensive facial involvement, and complete resolution of MCV
was seen after 1 month of therapy. In case 3, intravenous cidofovir therapy
was started both for CMV retinitis and in an attempt to clear 90% facial
MCV involvement; after 1 month of treatment, all clinical evidence of MCV
had resolved. All 3 patients remain clear of recurrence.
CONCLUSIONS:
Cidofovir, a nucleotide analog of deoxycytidine monophosphate, appears to
have contributed to clearing of advanced MCV lesions in these 3 patients,
thus providing suggestive evidence of clinical activity against MCV.
Controlled trials of cidofovir therapy for MCV in persons infected with
human immunodeficiency virus are warranted.
====================================================================
35.) Therapeutic potential of Cidofovir (HPMPC, Vistide) for the treatment
of DNA virus (i.e. herpes-, papova-, pox- and adenovirus) infections.
====================================================================
Verh K Acad Geneeskd Belg 1996;58(1):19-47; discussion 47-9
De
Clercq E
Rega Institute for Medical Research, Katholieke Universiteit,
Leuven.
(S)-1-(3-Hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC,
Cidofovir, Vistide) is an acyclic nucleoside phosphonate with
broad-spectrum activity against a wide variety of DNA viruses including
herpesviruses [Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2),
varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus
(EBV), human herpesvirus type 6 (HHV-6) and equine and bovine
herpesviruses], papovaviruses [human polyoma virus and human papilloma
virus (HPV)], adeno-, irido-, hepadna-, and poxviruses. HPMPC has proved
effective against these viruses in different cell culture systems and/or
animal models.
The mechanism of action of HPMPC is based upon the
interaction of its active intracellular metabolite, the diphosphorylated
HPMPC derivative HPMPCpp, with the viral DNA polymerase. HPMPCpp has
been shown to block CMV DNA synthesis by DNA chain termination following
incorporation of two consecutive HPMPC molecules at the 3'-end of the
DNA chain. HPMPC confers a prolonged antiviral action, which lasts for
several days or weeks, thus allowing infrequent dosing (i.e. every week
or every two weeks).
This prolonged antiviral action is probably due to
the very long intracellular half-life of the HPMPC metabolites,
particularly the HPMPCp-choline adduct. In clinical studies, HPMPC has
proved efficacious in the treatment of CMV retinitis, following both
intravenous injection (3 or 5 mg/kg, every other week) and intravitreal
injection (single dose of 20 micrograms per eye).
Initial clinical
trials also point to the efficacy of both systemic (intravenous) and
topical HPMPC (1% ointment) in the treatment of acyclovir-resistant HSV
infections, and of topical HPMPC (ointment or injection) in the
treatment of pharyngeal, laryngeal and anogenital HPV infections. HPMPC
is now being pursued in the topical and/or systemic (intravenous)
treatment of various infections due to CMV, HSV, VZV, EBV, HPV,
polyoma-, adeno- and poxviruses.
====================================================================
36.) Topical and intralesional cidofovir: a review of pharmacology and
therapeutic effects.
====================================================================
J
Am Acad Dermatol 1998 Nov;39(5 Pt 1):741-5
Zabawski EJ Jr, Cockerell
CJ
University of Texas Southwestern Medical Center, Dallas, USA.
BACKGROUND: Cidofovir is a potent nucleoside analog antiviral drug
approved for the treatment of cytomegalovirus (CMV) retinitis in
patients with AIDS. It is currently available only for intravenous
infusion. Several small studies and case reports describe the successful
use of cidofovir applied either topically or intralesionally in several
virally induced cutaneous diseases.
OBJECTIVE: Our purpose was to review
the usefulness of topical and intralesional cidofovir for the treatment
of viral infections caused by human papillomavirus, herpesviruses
(including acyclovir-resistant strains), Kaposi's sarcoma-associated
herpesvirus, and molluscum contagiosum. METHODS: We performed a review
of recent literature.
RESULTS: Cidofovir is a potent topical
intralesional antiviral agent with activity against several DNA viruses
that cause cutaneous disease. No significant systemic side effects have
been noted, although application site reactions are common and can
occasionally be severe.
CONCLUSION: The effective use of topical and
intralesional cidofovir for the treatment of diseases of the skin caused
by DNA viruses has been demonstrated in a limited number of patients
including those infected with HIV. Although larger studies will be
necessary to determine the specific function that topical cidofovir will
have in the treatment of cutaneous diseases caused by DNA viruses, the drug
offers significant promise.
====================================================================
37.) Treatment of classical Kaposi's sarcoma with intralesional injections
of cidofovir: report of a case.
====================================================================
J
Med Virol 1998 Jul;55(3):215-8
Simonart T, Noel JC, De Dobbeleer G,
Parent D, Van Vooren JP, De Clercq E, Snoeck R
Department of
Dermatology, Erasme University Hospital, Brussels, Belgium.
The
effect of intralesional injections of cidofovir, a nucleotide analog
with potent in vitro activity against human herpesvirus 8 (HHV-8), was
studied in vivo in an HIV-negative patient with classical Kaposi's sarcoma
(KS).
After five weekly injections of the drug, no clinical, histological,
immunohistological, or virological changes could be detected in comparison
with saline-injected lesions. These findings suggest that, once the KS
tumor has developed, active viral replication is no longer involved in the
pathogenesis of the disease. Alternative hypotheses are that HHV-8
replication in blood-borne cells may foster growth of spindle cells in the
skin, or that blocking HHV-8 may not affect existing lesions but may
prevent new lesions from developing.
====================================================================
38.) Selective inhibition of human papillomavirus-induced cell
proliferation by (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine.
====================================================================
Antimicrob Agents Chemother 1999 May;43(5):1198-205
Johnson JA,
Gangemi JD
Department of Microbiology and Molecular Medicine and the
Greenville
Hospital System Biomedical Cooperative, Clemson University,
Clemson, South Carolina 29634, USA.
(S)-1-[3-Hydroxy-2-(phosphonylmethoxy)propyl]cytosine (HPMPC) is a
nucleoside phosphonate analog which in its active diphosphorylated form is
known to inhibit herpesvirus DNA polymerase. In this study, we have
demonstrated that, in a dose-dependent manner, this compound irreversibly
suppressed proliferation of cells infected with human papillomavirus (HPV),
which does not possess a viral DNA polymerase.
To elucidate the mechanism
of cell growth inhibition, cell cycle indicator-regulator expression,
thymidine incorporation, transcript levels of apoptosis factors, and
anabolic products of HPMPC following drug treatment were evaluated. HPMPC
treatment reduced WAF1 (p21) levels independent of those of p53, while
proliferating cell nuclear antigen increased. However, in comparison to
controls, HPMPC-treated cells displayed a decrease in thymidine
incorporation, indicating an inhibition of host DNA polymerase activity. In
normal primary keratinocytes, HPMPC predominantly accumulated in the form
of the choline adduct HPMPCp-choline.
However, in HPV type 16-transformed
keratinocytes, HPMPCpp was the most abundant anabolic product, with little
HPMPCp-choline having formed. The data imply that an unrecognized viral
factor is modulating the conversion of nucleotides, including HPMPC, to the
triphosphorylated form.
====================================================================
39.) Resistance of human cytomegalovirus to antiviral drugs.
====================================================================
Clin Microbiol Rev 1999 Apr;12(2):286-97
Erice A
Department of
Laboratory Medicine & Pathology and Department of Medicine,
University
of Minnesota Medical School, Minneapolis, Minnesota 55455,
[email protected]
Resistance of cytomegalovirus (CMV) to
antiviral agents is a well-recognized phenomenon that has been observed
in the laboratory and in the clinical setting.
Infections caused by
antiviral-resistant CMV have been found exclusively among
immunocompromised individuals, including patients with AIDS, bone marrow
and solid-organ transplant recipients, and patients with hematologic
malignancies, and in individuals with primary immunodeficiencies. The
majority of these infections have been described to occur in patients
with AIDS receiving prolonged antiviral therapy for CMV end-organ
disease.
Antiviral agents currently licensed for the treatment of CMV
infections include ganciclovir, foscarnet, and cidofovir. Resistance of
CMV to ganciclovir is related to mutations in the UL97 region of the viral
genome and/or mutations in the viral DNA polymerase. Resistance to
foscarnet and cidofovir is associated with mutations in the viral DNA
polymerase. Antiviral susceptibility of CMV strains containing DNA
polymerase mutations is dependent on the region of the DNA polymerase where
the mutations are located.
Some DNA polymerase mutant viruses are
cross-resistant to ganciclovir, foscarnet, and cidofovir. The recognition
that specific UL97 and UL54 mutations are associated with resistance to
antiviral agents has led to the development of molecular methods for
detection of mutant viruses.
This article reviews the mechanisms of
resistance of CMV to antiviral agents, the laboratory methods for detection
of resistant CMV, and the clinical aspects of infections caused by
antiviral-resistant CMV.
====================================================================
40.) Comparative antiviral efficacies of cidofovir, trifluridine, and
acyclovir in the HSV-1 rabbit keratitis model.
====================================================================
Invest Ophthalmol Vis Sci 1999 Feb;40(2):378-84
Romanowski EG,
Bartels SP, Gordon YJ
Department of Ophthalmology, University of
Pittsburgh School of Medicine, Pennsylvania, USA.
PURPOSE: To
determine the relative antiviral inhibitory activity of topical 1% and
0.5% cidofovir, topical trifluridine (Viroptic; Burroughs-Wellcome,
Research Triangle Park, NC), and topical acyclovir (Zovirax; The Wellcome
Foundation, London, UK) during a 7-day period for the treatment of herpes
simplex virus type 1 (HSV-1) keratitis and HSV-1 replication in the New
Zealand rabbit ocular model.
METHODS: In a series of four experiments using
a two-eye design, a total of 80 New Zealand rabbits were inoculated in both
eyes with HSV-1 McKrae after epithelial scarification. Forty-eight hours
after inoculation, the rabbits were randomly assigned to a treatment group.
Five treatment groups (16 rabbits/group) were evaluated: I, 1% cidofovir,
twice daily for 7 days; II, 0.5% cidofovir, twice daily for 7 days; III, 3%
acyclovir ointment, five times daily for 7 days; IV, 1% trifluridine, nine
times daily for 3 days, then 4 times daily for 4 days; and V, control
vehicle twice daily for 7 days. HSV-1 dendritic keratitis was graded in a
masked fashion by slit-lamp examination on days 2, 3, 5, 7, 9, 11, and 14.
Ocular viral cultures were obtained after slit-lamp examination on days 1,
3, 5, 7, 9, 11, and 14.
RESULTS: Compared with the control group, all four
treatment groups demonstrated significantly lower viral titers, fewer
HSV-1-positive eyes/total during the treatment period, lower keratitis
scores, fewer eyes with keratitis/total, and a shorter time to resolution
of keratitis. Within the treatment groups, the 1% and 0.5% cidofovir
treatments were significantly more effective than acyclovir and
trifluridine as measured by the previous viral and keratitis parameters.
CONCLUSIONS: Topical 1% and 0.5% cidofovir both appeared to be
significantly more efficacious than topical trifluridine and acyclovir,
during a 7-day course, in the treatment of experimental HSV-1 ocular
disease in the New Zealand rabbit keratitis model.
====================================================================
41.) [Human herpesvirus 8 (HHV8). II. Pathogenic role and sensitivity to
antiviral drugs].
====================================================================
Ann
Biol Clin (Paris) 1999 Jan-Feb;57(1):19-28
Boulanger E
Service
d'hematologie clinique, hopital Saint-Louis, Paris.
Human
herpesvirus 8 (HHV8) has been found to be associated with three
different diseases observed in Aids patients: Kaposi's sarcoma, primary
effusion lymphoma, which is a rare type of non-Hodgkin lymphomas affecting
the body cavities, and multicentric Castleman's disease.
The role of this
new herpesvirus and other lymphoid proliferations, like angioimmunoblastic
lymphadenopathy or multiple myeloma, is much debatable. To date, there are
several evidences for a direct role of this virus in the occurrence of the
Kaposi's sarcoma, although the hypothesis of a passenger virus hypothesis
cannot be totally excluded. In vitro, HHV8 is sensitive to some
anti-herpesvirus drugs like foscarnet, cidofovir and adefovir, but the
indications of these therapies in the prevention or the treatment of the
Kaposi's sarcoma have not been documented so far.
====================================================================
42.) Inhibitory effects of novel nucleoside and nucleotide analogues on
Epstein-Barr virus replication.
====================================================================
Antivir Chem Chemother 1998 May;9(3):275-82
Meerbach A, Holy A,
Wutzler P, De Clercq E, Neyts J
Institute for Antiviral Chemotherapy,
Friedrich-Schiller-University Jena, Erfurt, Germany.
The
anti-Epstein-Barr virus (EBV) activity of different classes of compounds
was assessed by means of an EBV DNA hybridization assay using a
digoxigenin-labelled probe specific for the BamHI W fragment of the EBV
genome, as well as by measuring viral capsid antigen (VCA) expression after
a 7 day incubation period of P3HR-1 producer cells with the test
substances.
Acyclovir, ganciclovir, cidofovir and zidovudine were included
as reference compounds. Several compounds proved to be potent and selective
inhibitors of EBV DNA synthesis and VCA expression.
Of the new compounds
that were evaluated for their anti-EBV activity, the highest efficacy
(lowest EC50) and highest selectivity index (SI) were shown by the purine
nucleoside analogue 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine
(S2242) (EC50 0.6 ng/ml; SI 600), the acyclic nucleoside phosphonate
analogues 9-(2-phosphono -methoxyethyl)-6-dimethylaminopurine (EC50 1.1
micrograms/ml; SI 91), 9-(2-phosphonomethoxyethyl)-2-
amino-6-benzhydrylaminopurine (EC50 1.3 micrograms/ml; SI 29),
7-(2-phosphonomethoxyethyl)-6-dimethyl-aminopurine (EC50 0.8 microgram/ml;
SI 56), 9-(R)-(2-phosphonomethoxypropyl)-6-(2-dimethylaminoethyl)-aminopur
ine (EC50 0.5 microgram/ml; SI 42), the 2',3'-dideoxythymidine derivative
3'-oximino-2',3'-dideoxythymidine (EC50 1.5 micrograms/ml; SI 65), and
1-(2,3- dideoxy-3-N-hydroxyamino-beta-D-threo-pentafuranyl)pentafuranos
yl)thymine (EC50 4.1 micrograms/ml; SI > 24).
====================================================================
43.) Comparison of antiviral compounds against human herpesvirus 6 and 7.
====================================================================
Antiviral Res 1998 Dec;40(1-2):73-84
Yoshida M, Yamada M, Tsukazaki
T, Chatterjee S, Lakeman FD, Nii S, Whitley RJ
Department of Virology,
Okayama University Medical School, Japan.
[email protected]
Four classes of antiviral compounds were evaluated for inhibitory
activity against two variants of human herpesvirus 6 (HHV-6A and -6B)
and human herpesvirus 7 (HHV-7). These included:
(1) a pyrophosphate
analog, phosphonoformic acid (PFA);
(2) beta-guanine analogs,
9-(2-hydroxyethoxymethyl)guanine (acyclovir or ACV),
9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (ganciclovir or GCV) and
9-(4-hydroxy-3-hydroxy-3-hydroxymethylbutylyl)guanine (penciclovir or PCV);
(3) acyclic nucleoside phosphonates,
(S)-1-[(3-hydroxy-2-phosphonylmethoxy)propyl]cytosine [cidofovir or
(S)-HPMPC] and its cyclic derivative (S)-cyclic-HPMPC (cHPMPC),
9-[[2-hydroxy-1-phosphonomethoxy)ethoxy]methyl]guanine (HPMEMG) and
9-[(2-phosphonylmethoxy)ethyl]-2,6-diaminopurine (PMEDAP), and the seven
other related compounds; and
(4) a series of benzimidazole ribonucleosides,
including 2-bromo-5,6-dichloro-1-(beta-D-ribofuranosyl)benzimidazole
(BDCRB). End-point inhibitory concentration (EPC) and 50% effective
inhibitory concentration (EC50) values were determined by a dot-blot
antigen detection method in cord blood mononuclear cells infected with
HHV-6A, HHV-6B or HHV-7 at a multiplicity of infection of 0.004
CCID50/cell. (S)-HPMPC and cHPMPC had an EC50 value of approximately 0.3
microg/ml for HHV-6A, 1.2 microg/ml for HHV-6B and 3.0 microg/ml for HHV-7.
These compounds were the most active of those tested against each virus.
The EC50 value of GCV for HHV-6A was 0.65 microg/ml, 1.33 microg/ml for
HHV-6B, and >7 microg/ml for HHV-7. The EC50 values of ACV and PCV were
approximately 6-8 microg/ml for HHV-6A, 16-24 microg/ml for HHV-6B and
121-128 microg/ml for HHV-7. These drugs were the least active. The
sensitivity of HHV-7 to the guanine analogs was different from HHV-6,
suggesting a difference in selectivity of specific viral enzymes.
====================================================================
44.) [Advances in the diagnosis and treatment of infections caused by
herpesvirus and JC virus].
====================================================================
Enferm Infecc Microbiol Clin 1998;16 Suppl 1:11-9
Arribas JR,
Arrizabalaga J, Mallolas J, Lopez-Cortes LF
Hospital La Paz, Madrid.
[email protected]
During the last two years important advances in the
diagnosis and treatment of cytomegalovirus (CMV) disease have occurred.
Several studies have suggested that biologic markers of CMV viremia
(PCR, branched DNA and pp65 antigenemia) might be useful both to
stratify the risk of developing CMV disease and to follow the response
of CMV retinitis to therapy. It has been shown that patients who are
plasma CMV PCR positive have a risk of developing CMV disease three
times higher than patients who are plasma CMV PCR negative. In addition,
for each log10 increase of the CMV viral load there is a 3-fold higher
risk of developing CMV disease.
Currently, therapeutic options for
induction treatment of CMV retinitis (CMVR) are: i.v. ganciclovir (GCV),
i.v. foscarnet, i.v. cidofovir or GCV intraocular implant combined with
oral GCV. For maintenance therapy options are: i.v. GCV (3, 5 or 7 days
per week), oral GCV (only for peripheral retinitis), i.v. foscarnet
(daily), i.v. cidofovir (biweekly) and GCV intraocular implant (replaced
every 6-8 months) combined with oral GCV.
There is currently enough
evidence to allow the diagnosis of progressive multifocal
leukoencephalopathy (PML) based on the finding of JC virus DNA in CSF by
PCR. There are still no drugs with proven clinical efficacy against JC
virus but the possibility that HAART treatments might improve the control
of this disease appear promising.
====================================================================
45.) A multicenter phase I/II dose escalation study of single-dose
cidofovir gel for treatment of recurrent genital herpes.
====================================================================
Antimicrob Agents Chemother 1998 Nov;42(11):2996-9
Sacks SL, Shafran
SD, Diaz-Mitoma F, Trottier S, Sibbald RG, Hughes A, Safrin S, Rudy J,
McGuire B, Jaffe HS
Viridae Clinical Sciences, Inc., and Department of
Pharmacology and Therapeutics, Faculty of Medicine, The University of
British Columbia, Vancouver, British Columbia, Canada.
[email protected]
A randomized, double-blind, clinic-initiated,
sequential dose-escalation pilot study was performed to compare the
safety and efficacy of single applications of 1, 3, and 5% cidofovir gel
with placebo in the treatment of early, lesional, recurrent genital
herpes at five Canadian outpatient sites.
Ninety-six patients began
treatment within 12 h of lesion appearance and were evaluated twice
daily until healing of the lesion occurred. Cidofovir gel at all
strengths significantly decreased the median time to negative virus
culture in a dose-dependent fashion (3.0 days in the placebo group
versus 2.2, 1.3, and 1.1 days in the 1, 3, and 5% cidofovir gel
treatment groups, respectively; P = 0.02, 0.0001, and 0.0003,
respectively). A trend toward a reduction in the median time to complete
healing in association with treatment was present, but the differences were
not statistically significant (5.0 days in the placebo group versus 4.3,
4.1, and 4.6 days in the 1, 3, and 5% cidofovir gel treatment groups,
respectively).
Application site reactions occurred in 3, 5, 19, and 22% of
the patients in these four groups, respectively. Treatment-associated
lesion recrudescence with delayed healing, which is suggestive of local
toxicity, was observed in three patients treated with 5% cidofovir gel and
one patient treated with 3% cidofovir gel. In summary, single-dose
application of cidofovir gel confers a significant antiviral effect on
lesions of recurrent genital herpes.
Additional studies are warranted to
further identify the optimal efficacious dose of cidofovir in association
with the maximum gel strength that can be tolerated.
====================================================================
46.) Cidofovir use in acyclovir-resistant herpes infection.
====================================================================
Ann
Pharmacother 1997 Dec;31(12):1519-21
Martinez CM, Luks-Golger DB
Montefiore Medical Center, Bronx, NY, USA.
Herpes infections
continue to be prevalent, especially in immunocompromised patients. Some
of these patients will develop resistant HSV infections. Therefore, it
is important to explore new treatment options. Animal studies have shown
cidofovir to be effective in the treatment and prevention of HSV
infections. Human data are limited, with only one randomized, double-blind,
placebo-controlled trial performed to date. The results from this study
look promising; however, due to the small sample size, a larger clinical
trial is warranted.
The human data available as case reports are suboptimal
in the quality of reporting time frames for resolution of lesions/symptoms
and outcomes of therapy. Another problem with the case report data is that
the TK status of the herpes simplex isolates was not reported. This would
have helped substantiate the acyclovir resistance seen in these patients.
It was evident in these case reports that acyclovir resistance can be
overcome, as acyclovir-resistant strains became sensitive following
cidofovir therapy. This may be because TK(+) viruses have been shown to
establish latency more readily than do TK(-) viruses. This pattern suggests
that alternating between acyclovir and cidofovir therapies may provide a
strategy to manage the emergence of alternatively acyclovir-sensitive and
-resistant infections.
At present, only the intravenous formulation of
cidofovir is commercially available. Advantages of the intravenous
formulation include weekly dosing and efficacy. Disadvantages are the
complexity of administration and the adverse effect profile. The most
common adverse effects with this formulation include nephrotoxicity
manifested as proteinuria (12%), and increased creatinine (5%) and
neutropenia (15%).
Administration of probenecid and NaCl 0.9% hydration are
used to reduce the incidence and severity of nephrotoxicity in patients who
are receiving cidofovir. Probenecid also has toxicities, including nausea,
vomiting, headache, fever, and flushing. The topical formulation of
cidofovir looks promising for mucocutaneous HSV infection because it is
usually undetectable in the blood following topical administration.
Therefore, systemic adverse effects should be minimized.
A cidofovir gel
product (Forvade, Gilead Sciences) is currently being reviewed by the Food
and Drug Administration for the treatment of refractory HSV. Ultimately,
more controlled clinical studies are necessary to determine whether routine
cidofovir use can be justified in patients with acyclovir-resistant HSV
infection.
====================================================================
47.) A randomized, double-blind, placebo-controlled trial of cidofovir gel
for the treatment of acyclovir-unresponsive mucocutaneous herpes simplex
virus infection in patients with AIDS.
====================================================================
J
Infect Dis 1997 Oct;176(4):892-8
Lalezari J, Schacker T, Feinberg J,
Gathe J, Lee S, Cheung T, Kramer F, Kessler H, Corey L, Drew WL, Boggs
J, McGuire B, Jaffe HS, Safrin S Mt.
Zion Medical Center and San
Francisco General Hospital, University of California, USA.
The
safety and efficacy of cidofovir gel for treatment of
acyclovir-unresponsive herpes simplex virus infections in AIDS patients was
evaluated in a randomized, double-blind, multicenter trial. Cidofovir (0.3%
or 1%) or placebo gel was applied once daily for 5 days.
Ten of 20
cidofovir-treated and none of 10 placebo-treated patients had complete
healing or >50% decreased area (P = .008); 30% of cidofovir-treated
patients versus 0 placebo recipients had complete healing (P = .031). Viral
shedding ceased in 13 (87%) of 15 cidofovir-treated and 0 of 9
placebo-treated patients (P = .00004). For cidofovir-treated patients,
median time to complete or good response was 21 days, and median time to
negative viral culture was 2 days (P = .025, P = .0001, respectively).
Median lesion area decreases were 58% for cidofovir-treated versus 0 for
placebo-treated patients (P = .005), and mean pain score changes were -1.84
versus -0.34 (P = .042).
Application site reactions occurred in 25% of
cidofovir-treated and 20% of placebo-treated patients; none was
dose-limiting. Cidofovir therapy provided significant benefits in lesion
healing, virologic effect, and pain reduction.
====================================================================
48.) Isolation of human adenovirus type 5 variants resistant to the
antiviral cidofovir.
====================================================================
Invest Ophthalmol Vis Sci 1996 Dec;37(13):2774-8
Gordon YJ,
Araullo-Cruz TP, Johnson YF, Romanowski EG, Kinchington PR
Department of
Ophthalmology, Eye and Ear Institute, University of Pittsburgh Medical
Center, Pennsylvania 15213, USA.
PURPOSE: Cidofovir (S-HPMPC) is a
potent broad-spectrum antiviral drug with potential clinical application
against infections caused by human cytomegalovirus, herpes simplex
virus, and adenovirus (AD). This study sought to determine whether
variants of AD5 could be isolated in vitro that demonstrated increased
resistance to this new antiviral drug.
METHODS: Homogenous stocks of
wild-type AD5 (ATCC strain VR-5) were generated from isolated plaques
grown in A549 cells. The stocks subsequently were serially passaged in
cells containing increasing levels (from 5 to 75 micrograms/ml) of
cidofovir. The recovered virus either was passaged, titrated, or assayed
for 50% inhibitory concentration (IC50) of cidofovir.
RESULTS: Three
independently isolated variants were obtained that demonstrated increased
resistance to cidofovir. Viral resistance to the drug increased on stepwise
passage in higher concentrations. Compared to the ATCC AD5 reference (IC50
= 6.2 micrograms/ml), stable cidofovir-resistant variants showed fivefold
to eightfold resistance (AD5 RI IC50 = 36.5 micrograms/ml; AD5 R2 IC50 =
36.7 micrograms/ml; and AD5 R3 IC50 = 32.6 micrograms/ml; analysis of
variance, P = 0.000001).
However, a variable number of passages (1 to 13)
at each concentration of cidofovir was performed to obtain robust
infectious virus suitable for testing at the next higher concentration. All
resistant virus isolates grew to levels of virus titer comparable to the
parental virus and showed no apparent phenotypic changes in growth rates,
plaque size, or efficiency of plaque formation.
CONCLUSIONS: The successful
isolation of AD5 variants in tissue culture resistant to cidofovir has
important clinical implications with respect to the anticipated use of this
antiviral drug in treating adenoviral ocular infections.
====================================================================
49.) Herpesvirus resistance to antiviral drugs: a review of the mechanisms,
clinical importance and therapeutic options.
====================================================================
J
Hosp Infect 1996 Aug;33(4):235-48
Reusser P
Department of
Medicine, University Hospital, Basel, Switzerland.
During the past
decade, potent agents against herpes simplex virus (HSV) types 1 and 2,
varicella zoster virus (VZV), and cytomegalovirus (CMV) have become
available. The increasing clinical use of acyclovir, ganciclovir, and
foscarnet has been associated with the emergence of drug-resistant
herpesvirus strains.
Resistance to acyclovir or ganciclovir most frequently
results from deficient intracellular phosphorylation of these agents which
is required for drug activation. Resistance to foscarnet is due to viral
DNA polymerase mutants that permit viral replication despite the presence
of the drug.
In immunocompetent patients, herpesvirus resistance is rare
and generally does not correlate with clinical outcome. In contrast, in
immunocompromised hosts, resistance of HSV, VZV, and CMV is increasingly
detected, and may be associated with disease refractory to antiviral
therapy.
Foscarnet treatment has been used with some clinical benefit in
patients with acyclovir-resistant HSV or VZV, or ganciclovir-resistant CMV.
For therapy of resistant mucocutaneous HSV disease, topical
trifluorothymidine, and topical or intravenous cidofovir (HPMPC) have
yielded encouraging results that warrant further investigation. Improved
methods for detection of herpesvirus resistance, and validation of
alternative therapy for patients with documented resistance are required to
reduce the clinical impact of drug-resistant herpesviruses.
====================================================================
50.) Topical cidofovir for severe molluscum contagiosum. Lancet 1999 Jun
12;353(9169):2042
Davies EG, Thrasher A, Lacey K, Harper J
====================================================================
====================================================================
51.) Abatement of cutaneous Kaposi's sarcoma associated with cidofovir
treatment.
Clin Infect Dis 1998 Dec;27(6):1562
Simonart T, Noel
JC, De Clercq E, Snoeck R
====================================================================
====================================================================
52.) Treatment of verruca vulgaris with topical cidofovir.
JAMA 1997 Oct
15;278(15):1236
Zabawski EJ Jr, Sands B, Goetz D, Naylor M,
Cockerell CJ
====================================================================
====================================================================
53.) Topical cidofovir for severe molluscum contagiosum.
Lancet 1999 Jun
12;353(9169):2042
Davies EG, Thrasher A, Lacey K, Harper J
====================================================================
====================================================================
54.) CIDOFOVIR, The product
====================================================================
VA
CLASSIFICATION (Primary/Secondary);AM800
Commonly used brand
name(s):
Vistide.
Note: For a listing of dosage forms and
brand names by country
availability, see Dosage Forms section(s).
Category
Antiviral (systemic).
Indications
General considerations
All cidofovir-resistant cytomegalovirus (CMV)
isolates have been found to be resistant to ganciclovir, but remained
susceptible to foscarnet1.
Accepted
Cytomegalovirus
retinitis (treatment);Cidofovir is indicated, in combination with
probenecid, for the treatment of cytomegalovirus (CMV) retinitis in
patients with acquired immunodeficiency syndrome1. Safety and efficacy
have not been established for the treatment of CMV disease in non-HIV
infected people, other CMV infections, or congenital or neonatal CMV
disease1.
Pharmacology/Pharmacokinetics
Physicochemical
characteristics:
Molecular weight; Cidofovir: 315.221
Cidofovir anhydrous: 279.191
Mechanism of action/Effect:
Cidofovir diphosphate, the active intracellular metabolite of cidofovir,
suppresses cytomegalovirus (CMV) replication by selectively inhibiting
viral DNA polymerase1. Cidofovir diphosphate inhibits herpesvirus
polymerases at concentrations that are 8- to 600-fold lower than those
needed to inhibit the human cellular polymerases alpha, beta, and gamma1.
Reduction in the rate of viral DNA synthesis is due to incorporation of
cidofovir into the growing viral DNA chain1.
Distribution:
Volume of distribution is 537 mL per kg (mL/kg) without concurrent
probenecid administration and 410 mL/kg with concurrent probenecid
administration1.
Concentrations of cidofovir were undetectable 15
minutes after the end of a 1-hour infusion in one patient who had a
corresponding serum concentration of 8.7 mcg per mL (mcg/mL)1.
Protein binding:
Low (less than 6%)1.
Time to peak
concentration:
End of infusion1.
Peak serum concentration:
With concurrent probenecid administration; 3 mg per kg of
body weight (mg/kg): 9.8 mcg/mL1.
5 mg/kg: 19.6 mcg/mL1.
Without concurrent probenecid administration; 3 mg/kg: 7.3
mcg/mL1.
5 mg/kg: 11.5 mcg/mL1.
Elimination:
Renal
(without concurrent probenecid administration);Approximately 80 to
100% of an administered cidofovir dose was recovered unchanged in the urine
within 24 hours1.
Renal (with concurrent probenecid
administration);Approximately 70 to 85% of an administered
cidofovir dose was recovered unchanged in the urine within 24 hours. The
renal clearance of cidofovir was reduced to that of creatinine
clearance, suggesting that probenecid blocks active renal tubular
secretion of cidofovir1.
In dialysis;The effect of
hemodialysis on the pharmacokinetics of cidofovir is not known1.
Precautions to Consider
Carcinogenicity
Cidofovir should
be considered a carcinogen in rats and a potential carcinogen in
humans1.
Chronic, two-year carcinogenicity studies in rats and mice
have not been done. However, a 26-week toxicology study was done in rats
evaluating once weekly subscapular subcutaneous injections of cidofovir.
The study was terminated at 19 weeks because palpable mammary
adenocarcinomas were detected in females after only six doses. These
masses developed at doses as low as 0.6 mg per kg (mg/kg) per week,
which is equivalent to 0.04 times the human systemic exposure at the
recommended cidofovir dose based on area under the plasma
concentration-time curve (AUC) comparisons.1
There was also a
significant increase in mammary adenocarcinomas in female rats and a
significant incidence of Zymbal's gland carcinomas in male and female
rats administered 15 mg/kg of cidofovir once weekly; this was not seen
at the 0.6 or 3 mg/kg doses. The 15 mg/kg dose is equivalent to 1.1
times the human systemic exposure at the recommended dose of cidofovir,
based on AUC.1
Tumorigenicity
No tumors were detected in
cynomologus monkeys who received intravenous cidofovir, alone and in
conjunction with concomitant oral probenecid, once a week for 52 weeks.
This dose is equivalent to approximately 0.7 times the human systemic
exposure. However, due to the small number of animals and the short
duration of treatment, this study was not designed as a carcinogenicity
study.1
Mutagenicity
There was no mutagenic response
observed in microbial mutagenicity assays involving Salmonella
typhimurium (Ames) and Escherichia coli in the presence and absence of
metabolic activation. There was an increase in micronucleated
polychromatic erythrocytes in vivo seen in mice receiving ³ 2000
mg/kg, a dose approximately 65-times higher than the maximum recommended
clincial dose of cidofovir, based on body surface area estimations.
Cidofovir induced chromosomal aberrations in human peripheral blood
lymphocytes in vitro without metabolic activation. At the four doses tested, the percentage of damaged metaphases and the number of aberrations per cell increased in a concentration-dependent manner.1
Pregnancy/Reproduction
Fertility;; Cidofovir was
shown to cause inhibition of spermatogenesis in rats and monkeys.
However, there were no reported adverse effects on fertility or
reproduction in male rats administered once-weekly intravenous injections
for thirteen consecutive weeks at doses up to 15 mg/kg per week; this is
equivalent to 1.1 times the recommended human dose based on AUC
comparisons. Female rats dosed intravenously at 1.2 mg/kg per week
(equivalent to 0.09 times the recommended human dose based on AUC) or
higher for up to six weeks prior to mating, and for two weeks after mating,
had decreased litter size and live births per litter, as well as an
increased incidence of early resorptions per litter. Peri- and postnatal
development studies in which female rats were administered subcutaneous
cidofovir at doses up to 1 mg/kg per day from day 7 of gestation through
day 21 postpartum (approximately five weeks) resulted in no adverse effects
on viability, growth, behavior, sexual maturation, or reproductive capacity
in the offspring.1
Pregnancy;Adequate and well-controlled
studies in humans have not been done. Cidofovir should be administered
only if the potential benefit justifies the potential risk to the
fetus.1
Cidofovir was found to be embryotoxic (reduced fetal body
weight) in rats administered 1.5 mg/kg per day and in rabbits given 1
mg/kg per day during the period of organogenesis; these doses were also
maternotoxic. There was also an increased incidence of fetal external
soft tissue and skeletal anomalies, such as meningocele, short snout,
and short maxillary bones, seen in rabbits administered 1 mg/kg per day,
which was also maternally toxic. The no-observable-effect levels for
embryotoxicity in rats (0.5 mg/kg per day) and in rabbits (0.25 mg/kg
per day) were approximately 0.04 and 0.05 times the human maintenance
dose, respectively, based on AUC.
FDA Pregnancy Category C.1
Breast-feeding
It is not known whether cidofovir is distributed
into breast milk. However, it is recommended that HIV-infected women not
breast-feed their infants to avoid postnatal transmission of HIV to a
child who may not be infected.1
Pediatrics
No information is
available on the relationship of age to the effects of cidofovir in
pediatric patients. Safety and efficacy have not been established.
However, cidofovir should be used with caution in children with HIV
infection because of the potential risk of long-term carcinogenicity and
reproductive toxicity.1
Geriatrics
No studies have been done
assessing the safety and efficacy of cidofovir in patients over the age
of 601. However, elderly patients are more likely to have age-related
renal function impairment, which may require adjustment of dosage in
patients receiving cidofovir1.
Drug interactions and/or related
problems
The following drug interactions and/or related problems
have been selected on the basis of their potential clinical significance
(possible mechanism in parentheses where appropriate);not
necessarily inclusive (>> = major clinical significance):
Note:
Combinations containing any of the following medications, depending on
the amount present, may also interact with this medication. >>
Nephrotoxic medications (see Appendix II);(because cidofovir has
been reported to be associated with severe renal function impairment,
concurrent use with other nephrotoxic medications, such as
aminoglycosides, amphotericin B, foscarnet, nonsteroidal
anti-inflammatory drugs, and pentamidine, may increase the risk of
nephrotoxicity and is contraindicated; it is recommended that patients
undergo at least a 7-day washout period before receiving cidofovir2)
>> Probenecid;(probenecid must be administered concurrently with
cidofovir; probenecid is known to interact with the metabolism or renal
tubular excretion of many medications, such as acetaminophen, acyclovir,
aminosalicylic acid, angiotensin-converting enzyme inhibitors,
barbiturates, benzodiazepines, bumetanide, clofibrate, famotidine,
furosemide, methotrexate, nonsteroidal anti-inflammatory agents,
theophylline, and zidovudine; these medications should be used with caution
when used concurrently with probenecid1)
Zidovudine;(concurrent use with cidofovir, without probenecid, showed
no evidence of an effect on the pharmacokinetics of zidovudine1)
Laboratory value alterations
The following have been selected on
the basis of their potential clinical significance (possible effect in
parentheses where appropriate);not necessarily inclusive (>> =
major clinical significance):
With physiology/laboratory test
values Creatinine, serum and1 Protein, urine1;(may be
increased)
Bicarbonate, serum and1 Neutrophils1;(may be
decreased)
Medical considerations/Contraindications
The
medical considerations/contraindications included have been selected on
the basis of their potential clinical significance (reasons given in
parentheses where appropriate);not necessarily inclusive (>> = major
clinical significance).
Except under special circumstances, this
medication should not be used when the following medical problem exists
>> Hypersensitivity to cidofovir or probenecid1;
Risk-benefit should be considered when the following medical problem exists
>> Renal function impairment1;(because cidofovir has been
reported to be associated with severe renal function impairment,
cidofovir is contraindicated in patients with a serum creatinine > 1.5
mL per dL, a creatinine clearance £ 55 mL per minute [0.92 mL per
second], or a urine protein ³ 100 mg per dL [equivalent to ³
2+ proteinuria]2)
Patient monitoring
The following may be
especially important in patient monitoring (other tests may be warranted
in some patients, depending on condition; >> = major clinical
significance):
>> Creatinine, serum and1 >> Protein, urine and1
>> White blood cell count with differential1;(because cidofovir has
been reported to cause severe renal function impairment and cause
neutropenia, these laboratory parameters should be monitored prior to
each dose of cidofovir)
>> Intraocular pressure1 >> Visual
acuity1;(because cidofovir can cause ocular hypotony, especially
in patients with preexisting diabetes, intraocular pressure and visual
acuity should be monitored periodically)
Side/Adverse Effects
Note: Nephrotoxicity, the major dose-limiting toxicity of cidofovir
therapy, was manifested as > 1+ proteinuria, serum creatinine concentration
³ 0.4 mg per dL, or a decrease in creatinine clearance to £ 55 mL
per min (0.92 mL per second) in 53% of patients receiving a maintenance
dose of 5 mg per kg of body weight every other week1. Proteinuria may be
an early indicator of cidofovir-related nephrotoxicity and continued
administration may lead to additional proximal tubular cell injury,
resulting in glycosuria, decreases in serum phosphate, uric acid, and
bicarbonate, and elevations in serum creatinine. Patients with these
side effects and meeting a criteria of Fanconi's syndrome have been
reported.1 There have also been reports of severe renal function
impairment associated with cidofovir use2. To help reduce the risk of
nephrotoxicity, patients must be pre-hydrated with at least 1 liter of
0.9% sodium chloride solution and probenecid must be administered at
proper times.2 Dosage adjustment or discontinuation is necessary when
changes in renal function occur during therapy.
Neutropenia
(£ 500 cells/mm3) occurred in 20% of patients receiving the 5 mg
per kg of body weight maintenance dose in clinical trials. Granulocyte
colony stimulating factor was used in 34% of patients.1
Ocular
hypotony (³ 50% change from baseline) was reported in 5 of 42
patients receiving the 5 mg per kg of body weight maintenance dose in
clinical studies. Hypotony was reported in one patient with concomitant
diabetes mellitus; the risk of ocular hypotony may be increased in patients
with pre-existing diabetes.1
Two percent of study patients were
diagnosed with Fanconi's syndrome, manifested by multiple abnormalities
of proximal tubule function. Decreases in serum bicarbonate to £
16 milliequivalents per liter associated with evidence of renal tubular
damage occurred in approximately 9% of patients.1
The following
side/adverse effects have been selected on the basis of their potential
clinical significance (possible signs and symptoms in parentheses where
appropriate);not necessarily inclusive:
Those indicating need
for medical attention
Incidence more frequent Nephrotoxicity1
decreased urination; increased thirst and urination); neutropenia1
(fever, chills, or sore throat)
Incidence less frequent; Fever
Incidence rare Ocular hypotony decreased vision or any change in
vision)
Those indicating need for medical attention only if they
continue or are bothersome
Incidence more frequent:
Gastrointestinal effects (diarrhea; loss of appetite; nausea; vomiting);
headache
Incidence less frequent Asthenia (generalized weakness;
loss of strength)
Overdose
Overdosage with cidofovir has not
been reported. However, probenecid may reduce potential nephrotoxicity
through reduction of active tubular secretion. Hemodialysis and
hydration may reduce plasma cidofovir concentrations.1
For more
information on the management of overdose or unintentional ingestion,
contact a Poison Control Center (see Poison Control Center Listing).
Patient Consultation
In providing consultation, consider
emphasizing the following selected information (>> = major clinical
significance)
Before using this medication
>> Conditions
affecting use, especially:
Hypersensitivity to cidofovir or
probenecid
CarcinogenicityCidofovir is a carcinogen in animals and
should be considered a potential carcinogen in humans
Pregnancy;Cidofovir was embryotoxic and maternotoxic in animals;
cidofovir should be administered only if the potential benefit justifies
the potential risk to the fetus
Breast-feeding;It is not
known whether cidofovir is distributed into breast milk; however, it is
recommended that HIV-infected women not breast-feed their infants to
avoid postnatal transmission of HIV to a child who may not be infected
Use in children;Safety and efficacy have not been established;
however, cidofovir should be used with caution in HIV-infected children
because of the potential risk of long-term carcinogenicity and
reproductive toxicity
Other medications, especially nephrotoxic
medications and probenecid
Other medical problems, especially renal
function impairment
Proper use of this medication
>>
Importance of receiving medication for full course of therapy and on a
regular schedule
>> Proper dosing
Precautions while using
this medication
>> Regular visits to physician to check blood
counts
>> Regular visits to ophthalmologist to examine eyes since
progression of retinitis and visual loss may occur during cidofovir
therapy
Side/adverse effects
Signs of potential side
effects, especially, nephrotoxicity, neutropenia, fever, and ocular
hypotony
General Dosing Information
Cidofovir must not be
administered by intraocular injection. Direct injection may result in
significant decreases in intraocular pressure and vision impairment.1
Because cidofovir has been reported to be associated with severe renal
function impairment, the recommended dosage, frequency, or infusion rate
must not be exceeded. Cidofovir must be diluted in 100 mL of 0.9% sodium
chloride injection prior to administration. Probenecid and intravenous
sodium chloride prehydration must be administered with each cidofovir
infusion to minimize potential nephrotoxicity. The dose of cidofovir must
be reduced or discontinued if changes in renal function occur during
therapy. Serum creatinine and urine protein must be monitored within 48
hours prior to each dose of cidofovir.1,2
The dose of cidofovir must
be reduced or discontinued if changes in renal function occur during
therapy. For increases in serum creatinine of 0.3 to 0.4 mg per dL
(mg/dL) above baseline, the dose of cidofovir must be reduced from 5 mg
per kg (mg/kg) to 3 mg/kg. Cidofovir must be discontinued for an increase in serum creatinine of 0.5 mg/dL above baseline or development of
3+ proteinuria. Patients with 2+ proteinuria should be observed carefully; dose reduction or temporary discontinuation of treatment should be considered.2
Two grams of probenecid should be administered 3 hours
prior to each dose of cidofovir and 1 gram should be administered 2 and
8 hours after the completion of the 1-hour infusion (total 4 grams)1.
Each dose of cidofovir should be administered with 1 liter of 0.9%
sodium chloride injection, infused over 1 to 2 hours immediately before
the cidofovir infusion. If the patient can tolerate the fluid load, a
second liter of 0.9% sodium chloride injection should be started either
at the beginning of the cidofovir infusion or immediately afterwards,
over a 1- to 3-hour period.1
Ingestion of food before each dose
of probenecid may reduce nausea and vomiting associated with probenecid
administration. Administration of an antiemetic may also reduce the
potential for nausea.
Safety considerations for handling this
medication
Due to the mutagenic potential of cidofovir, use of
appropriate safety equipment is recommended for the preparation,
administration, and disposal of cidofovir. The National Institutes of
Health recommends that cidofovir be prepared in a Class II laminar flow
biological safety cabinet and that personnel preparing this medication
wear surgical gloves and a closed-front surgical-type gown with knit
cuffs. If cidofovir contacts the skin, membranes should be washed and
flushed thoroughly with water. Excess cidofovir and materials used in
the admixture and administration procedures should be placed in a
leak-proof, puncture-proof container. High temperature incineration is
the recommended method of disposal.1
Parenteral Dosage Forms
CIDOFOVIR INJECTION
Usual adult dose
Antiviral;
Induction: Intravenous infusion, 5 mg per kg of body weight, administered
continuously over one hour, once a week for two consecutive weeks.
Probenecid must be administered with each dose of cidofovir. Two grams of
probenecid should be administered three hours prior to each dose of
cidofovir and 1 gram should be administered two and eight hours after the
completion of the one-hour infusion (total 4 grams).1
Maintenance:
Intravenous infusion, 5 mg per kg of body weight, administered
continuously over one hour, once every two weeks. Probenecid must be
administered with each dose of cidofovir. Two grams of probenecid should be
administered three hours prior to each dose of cidofovir and 1 gram should
be administered two and eight hours after the completion of the one-hour
infusion (total 4 grams).1
Note: Cidofovir has not been studied in
patients with pre-existing renal function impairment. The most
appropriate dose of cidofovir for patients with a serum creatinine > 1.5
mg per mL or a creatinine clearance £ 55 mL per min (mL/min) is
not known. However, the following doses (in mg per kg of body weight)
are recommended when the benefits of cidofovir exceed the potential
risks1:
Creatinine Induction (once Maintenance (once every
2 Clearance weekly for 2 weeks) (mL/min) weeks) 41-55 2 mg per
kg 2 mg per kg 30-40 1.5 mg per kg 1.5 mg per kg 20-29 1 mg per kg 1
mg per kg £ 19 0.5 mg per kg 0.5 mg per kg
Usual
pediatric dose
Safety and efficacy have not been established.1
Strength(s) usually available
U.S.; 375 mg per 5 mL
(Rx)[Vistide].
Packaging and storage:
Store at room
temperature between 20 and 25 °C (68 and 77 °F).1
Preparation of dosage form:
The vial should be visually inspected
for particulate matter and discoloration prior to administration and
discarded if particulate matter or discoloration is observed.1
The appropriate volume of cidofovir should be extracted from the vial and
the dose transferred to an infusion bag containing 100 mL of 0.9% sodium
chloride solution. The entire volume should be infused into the patient at
a constant rate over a 1-hour period. It is recommended that a standard
infusion pump be used for administration.1
Stability:
It is
recommended that cidofovir admixtures be administered within 24 hours of
preparation and that refrigeration or freezer storage not be used to
extend this 24-hour limit.1
If admixtures are not intended for
immediate use, they may be refrigerated (between 2 and 8 °C [36 and
46 °F]) for no more than 24 hours. Refrigerated admixtures should be
allowed to equilibrate to room temperature prior to use.1
Incompatibilities:
Compatibility with Ringer's solution, Lactated
Ringer's solution, or bacteriostatic infusion fluids has not been
evaluated.1
The chemical stability of cidofovir admixtures was
determined in polyvinyl chloride composition and ethylene/propylene
copolymer composition commercial infusion bags, and in glass bottles.1
Note: Great care should be taken to prevent exposure of the skin to
cidofovir. The use of gloves is recommended. Any cidofovir that comes in
contact with the skin should be washed off thoroughly with soap and water.1
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DATA-MEDICOS/DERMAGIC-EXPRESS No (70) 15/09/99 DR. JOSE LAPENTA R.
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Produced by Dr. José Lapenta R.
Dermatologist
Maracay Estado Aragua Venezuela 1999-2026
Telf.:
04142976087 - 04127766810
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