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The Imiquimod I. El Imiquimod I.
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EDITORIAL ESPAÑOL Es un modificador de la
respuesta inmunológica y tiene actividad antitumoral: eleva los niveles del
factor de necrosis tumoral (TNF), e induce la producción de interferón (INF)
alfa, los primeros estudios que encontré datan de 1.992, con el nombre de
R-837, En noviembre 1.997 STAURT MADDIN hace una revisión del producto, en
enero de 1.998 se publica un artículo sobre su efectividad en verrugas
genitales.
AB-A: Imiquimod has been identified as a potent antiviral and antitumor agent
in animal models. The biological activity associated with imiquimod has been
attributed to its induction of interferon (IFN)-alpha . The present studies
evaluated imiquimod administered orally for its ability to stimulate
production of IFN and other cytokines in mice. The cytokine profile induced by
imiquimod was compared with other known immunomodulators. Imiquimod was found
to stimulate increased serum IFN in mice. Daily dosing of imiquimod for five
consecutive days led to diminished production of IFN in mice as measured after
the final dose. Elevated levels of serum tumor necrosis factor (TNF)-alpha and
interleukin (IL)-6 but not IL-1 alpha were found in serum from mice treated
with imiquimod. Imiquimod produced significantly higher levels of IFN but
lower levels of TNF and IL-6 and IL-1 alpha than lipopolysaccharide.
Polyinosinic acid:polycytidylic acid induced significantly higher amounts of
IFN but lower levels of TNF and IL-6 than imiquimod. Imiquimod stimulated
significantly higher levels of IFN when compared with 2-amino-5-bromo-6-phenyl-4(3H)-pyrimidinone
(ABPP) and similar levels of IFN when compared with tilorone. Neither ABPP nor
tilorone-induced TNF or IL-6. Finally, imiquimod stimulated TNF, IFN, and IL-6
production in cultures of mouse spleen and bone marrow cells. These studies
demonstrate that imiquimod induces not only IFN but other cytokines as well,
all of which may contribute to its biological activity.
AB-A: 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (imiquimod) is a
low mol wt oral inducer of interferon-alpha. Treatment with imiquimod reduced
the growth of MC-26 colon carcinoma, RIF-1 sarcoma and B16-F10 melanoma.
Treatment with 150 mg/kg imiquimod on days 1, 5, 9, 13, and 17 cured 90% of
C57BL/6 mice inoculated sc with FCB bladder carcinoma.
Oral imiquimod was also
effective in curing another mouse bladder tumor, MB49. Tumors continued to
grow until about day 15 when they started to regress and totally disappeared
by day 25. Cured mice remained tumor-free for 100 days when experiments were
terminated. MB49 was also instilled by transurethral catheter in the bladder.
In one experiment mice were sacrificed on day 17. Bladders of all
vehicle-treated mice had visible tumors of different sizes; 4/6 of the
imiquimod-treated mice had no visible tumors and the remaining two had small
tumor remnants. Bladders of vehicle-treated mice were significantly heavier
than those of mice treated with imiquimod 50.3 vs 31.7 mg (p less than 0.05).
Imiquimod as a single agent is curative for murine bladder tumors. (Abstract
from CANCERLIT)
AB-A: Imiquimod [1-(2-methylpropyl)-1H-imidazo[4,5c]quinolin-4-amine] is a
compound of low molecular weight that, when administered p.o., induces
interferon-alpha in several animal species and inhibits tumor growth in mice.
To determine maximum tolerated dose, toxicity, and biological response in
humans, a phase I clinical trial was conducted with 14 eligible cancer
patients who received 100-500 mg imiquimod p.o. either once or twice weekly.
Imiquimod induced interferon-alpha in serum in 10 of 19 doses of 200-300 mg.
Interferon serum levels peaked 8-24 h after treatment and reached a maximum of
23,000 IU/ml in one patient.
Significant mean increases (P < 0.01) in serum
beta 2-microglobulin (1.5-fold), serum neopterin (3.5-fold), and 2-5A
synthetase activity in peripheral blood mononuclear cells (7.9-fold) indicated
that 200-300 mg imiquimod had biological and immunological activity in all
evaluable patients. Increases in serum interferon, beta 2-microglobulin, and
neopterin correlated significantly with dose (P < 0.001).
No patient developed
measurable antibody to interferon-alpha. Dose-limiting side effects included
fatigue, malaise, fever, headache, and lymphocytopenia; no hepatic or renal
toxicity or other hematological changes exceeded the normal range. Patients
tolerated weekly doses of up to 500 mg, with the longest treatment lasting 4
weeks at 200 mg weekly. Twice-weekly doses up to to 300 mg were tolerated,
with the longest twice-weekly treatments being 200 mg for 9 weeks and 100 mg
for 25 weeks. No clinical responses were observed. Imiquimod, as an oral
inducer of interferon, may have therapeutic usefulness in human cancers, viral
infections, and other diseases. However, before initiation of phase II trials,
additional work will be required to establish a tolerated dose and schedule
for continued administration. (Abstract from CANCERLIT AND EMBASE)
AB-A: The low-molecular-weight imidazoquinolinamine derivative, 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine
(imiquimod, previously described as R-837), induced alpha-interferon (IFN-alpha)
in mice. IFN induction was identified at oral doses as low as 3 mg/kg. The 10%
lethal dose for daily treatment with imiquimod was 200 mg/kg.
Oral treatment
with 30 mg/kg imiquimod once every three days significantly inhibited MC-26
colon carcinoma. Delay of treatment from day 1 to day 5, when tumors were
easily palpable, did not reduce benefits.
Ten daily treatments were slightly
more effective than five. However, delivery of the same total dose of
imiquimod either once every day for 20 days, once every 4 days, once every 7
days, or once every 10 days inhibited tumor growth to the same level. The
antitumor effects of imiquimod were significantly abrogated by an antiserum to
murine IFN-alpha, suggesting that the antitumor effect was to a substantial
extent mediated by IFN induction. Imiquimod also significantly reduced the
number of lung colonies in mice inoculated i.v. with MC-26 tumor cells.
Combination of treatment with imiquimod and cyclophosphamide was significantly
(P less than 0.01) better than treatment with either drug alone. Combination
treatment with cyclophosphamide led to cures in some of the mice inoculated
either s.c. or i.v. with MC-26 cells. Treatment with imiquimod also inhibited
the growth of RIF-1 sarcoma and Lewis lung carcinoma but was ineffective for
P388 leukemia. Imiquimod is an oral IFN-alpha inducer with antitumor
effectiveness for transplantable murine tumors. (Abstract from CANCERLIT AND
EMBASE)
AB: Recently, a new class of immunomodulating agents, represented by the
molecules imiquimod and R-842, has demonstrated potent antiviral and antitumor
activities in animal models. In this study, another representative of this
class, S-28463 (4-amino-2-ethoxymethyl-alpha,alpha-dimethyl-1H-imidazo[4,5-c]quinoline-
1- ethanol) was evaluated for its immunomodulating and antiviral activities.
S-28463 induced IFN and other cytokines in vivo in mice, rats, monkeys and in
vitro in human peripheral blood mononuclear cell cultures. S-28463 showed
potent antiviral activity against herpes simplex virus-challenged guinea pigs
when given subcutaneously, dermally, or intravaginally 24 h before infection.
Antiviral activity in guinea pigs correlated with the induction of serum
2',5'-oligoadenylate synthetase activity. Thus, S-28463, like the other
imidazoquinolines, demonstrates potent antiviral and immunomodulating effects
in a number of models.
AB: The majority of current antiviral agents have become available only during
the past decade. The above mentioned antiviral drugs, especially the viral-TK-specific
agents have attempted to bring antiviral therapy on par with antimicrobial
therapy. The fact, that cells infected with viruses can be selected against
the relatively low toxicity to the patient, highlights the present state of
antiviral therapy. Since viral infection can be viewed as an integral
component of the self (i.e., a condition that cannot simply be surgically
eliminated), the science of medicine is turning to the components of the self
to overcome such conditions.
By administering immune-system-derived agents (e.g.,
interferons) or compounds that stimulate the immune system (e.g., adjuvants
like imiquimod), previously unmanageable conditions become manageable. The
future of antiviral therapy will undoubtedly be at the molecular level. With
greater understanding of the virus and the immune system with which it
interacts, more specific and efficacious antiviral agents will be added to the
arsenal of the clinician.
"This study highlights that Aldara cream, used three times a week, is a safe
and
effective patient-applied therapy," said Mary Owens, MD, associate director of
clinical research, 3M Pharmaceuticals.
The newest in a class of drugs called immune response modifiers and
representing the first new therapeutic approach to genital warts in five years,
Aldara was approved by the United States Food and Drug Administration in
March, 1997 and has been available to patients since June, 1997.
Genital warts is a sexually transmitted disease (STD) caused by the human
papillomavirus (HPV). HPV is one of the most common -- and least talked
about -- of all STDs. At least 10 to 20 percent of sexually-active Americans
are thought to be infected.
Genital warts is growing at a rate of 750,000 new cases each year, is spread
by sexual contact with an infected partner and is highly contagious. This life
long
virus can cause warts in the genital and perianal areas in females and males.
Male sexual partners of infected women often have HPV penile infection.
Genital warts may cause itching, burning, pain and tenderness. Although there
is
no cure for genital warts, treatment can alleviate physical symptoms and
psychological reactions such as problems with sexuality, shame, embarrassment
and self-blame.
Until recently, most treatment options for genital warts were tissue
destructive
Involving chemical agents, procedures such as loop electrocautery excision
(burning), surgery, cryotherapy (freezing) and tissue destructive drugs such
as
podofilox and podophyllin.
"Many patients have previously avoided treatment for genital warts because of
fear of chemical and surgical procedures," said Karl Beutner, MD, PhD,
associate clinical professor, University of California, San Francisco and
chief
investigator in the clinical trial of Aldara. "Self-administered Aldara cream
is an
effective, patient-friendly treatment that can be applied in the privacy of
home
to clear up warts."
Design: Randomized, double-blind, placebo-controlled comparison that
evaluated patients for total clearance of their warts. Patients who
experienced total clearance were evaluated for recurrence in a 12-week
follow-up.
Setting: Eleven ambulatory offices, including both private physician offices
and referral medical centers.
Patients: Three hundred eleven healthy men and women aged 18 years or
older with 2 to 50 external anogenital warts were recruited from the
practices of investigators, referring physicians, and advertisements.
Eighty-two additional patients were screened but did not qualify.
Four
patients discontinued use of the medication because of adverse effects.
Interventions: Five percent imiquimod (Aldara) cream, 1% imiquimod
cream, or vehicle cream was applied to all external warts overnight 3 times
each week for 16 weeks, or until all treated warts disappeared, whichever
occurred first.
Main Outcome Measurements: The number of patients experiencing the
elimination of all baseline warts and the recurrence rate of these warts. In
addition, the reduction in baseline wart area, the duration of therapy
required
To eliminate warts, and the frequency and severity of adverse reactions were
principal measurements.
Results: In the intent-to-treat analysis, 54 (50%) of 109 patients who
received 5% imiquimod cream, 21 (21%) of 102 of those who received 1%
imiquimod cream, and 11 (11%) of 100 patients treated with vehicle cream
experienced eradication of all treated baseline warts. The difference between
the effectiveness of 5% imiquimod cream and the vehicle cream was
statistically significant (P<.001). Of those patients whose warts cleared
during therapy, 13% of patients who received 5% imiquimod experienced a
recurrence of at least 1 wart.
Recurrences occurred in none of the patients
who used 1% imiquimod cream and in 10% of patients who used the vehicle
cream. Local erythema was the most common adverse reaction, but the
majority of patients in each group experienced no or only mild local
inflammatory reactions. There were no differences in incidences of flulike
symptoms among treatment groups.
Conclusions: Five percent imiquimod cream is an effective and safe
self-administered therapy for external anogenital warts when applied 3 times
a week overnight for up to 16 weeks. The recurrence rate is low.
Arch Dermatol. 1998;134:25-30
Although many treatments are available for genital warts caused by human
papillomavirus (HPV), none are uniformly successful in the treatment of this
disease.
Most current treatment options work by destroying affected tissue, either by
a
cytotoxic or a physically ablative mode of action. Interferons have
antiviral,
antiproliferative, and immunomodulatory activities, but these have not
translated
into a high level of cure rates against warts. With all current treatments,
recurrent warts are common.
Therapies currently being investigated include a
5-
fluorouracil/epinephrine collagen gel that achieves high concentrations of 5-
fluorouracil at the site of injection. Other new treatment modalities focus on
activating the host's immune system or improving the delivery of therapeutic
compounds to the affected site. Imiquimod, a novel immune-response modifier,
induces
interferon and a number of other endogenous cytokines.
A cream formulation
containing 5% imiquimod resulted in good total clearance rates and generally
tolerable side effects in controlled clinical trials of patients with external
genital warts. Perhaps the most effective means for managing HPV disease would
be a
vaccine that prevents the occurrence of genital warts. Although it is unlikely
that
such a vaccine will be introduced in the near future, preliminary studies
indicate
that it may be possible to develop suitable prophylactic and therapeutic
vaccines.
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Human papillomaviruses (HPVs) cause benign tumors (i.e., warts) and are
occasionally responsible for malignant tumors such as squamous-cell
carcinomas.
Therapy for most warts is commonly via surgical or cytodestructive methods.
Presently, only one antiviral/immunomodulatory drug is available for wart
therapy;
this agent, interferon alpha (IFN alpha), is approved only for genital warts
(condylomata acuminata) and is expensive, relatively difficult to use,
associated
with systemic side effects, and somewhat slow acting. Two new
antiviral/immunomodulatory drugs, imiquimod and cidofovir, have been proved to
be
effective and able to overcome many of the shortcomings of IFN alpha.
While
these
two agents are pending approval, other treatments are being evaluated, such
as
antisense oligonucleotides and therapeutic HPV vaccines. In contrast to
surgical and
cytodestructive therapies, the goal of these new antiviral/immunomodulatory
agents is
not just to remove the tumor but also to reduce sufficiently the amount of
latent and
subclinical HIV so as to reduce the rate of recurrence. (71 References)
Anogenital warts are very common,
sexually transmitted, virally induced tumors that although benign
themselves, have been associated with the development of squamous cell
carcinoma, particularly cervical carcinoma.1
Imiquimod is an immune response modifier.
Studies have shown that it has
potent immunomodulatory effects and stimulates human peripheral mononuclear
cells to release interferon alpha, sub-types alpha1,alpha2, alpha5, alpha6,
and alpha8. It also induces monocytes and macrophages to produce other
cytokines
including interleukins 1, 6, 8 and tumor necrosis factor alpha.2 The clinical
relevance of these findings is not fully understood.
Imiquimod's advantages
Low recurrence rate.
Self-application.
limited systemic effects and only mild (rarely moderate) local inflammation.
Previously available treatments (e.g. cryotherapy, laser vaporization,
electrocautery and excision) for anogenital warts are often painful and
expensive.
Local therapy with podophyllin, or podophyllotoxin or
trichloracetic acids, requires multiple applications, is slow acting and often
causes problems associated with local inflammation.1 5-Fluorouracil, although
sometimes used for external anogenital warts, is not yet approved for this
indication, has neither antiviral nor immunomodulatory effects, earlier
formulations were irritating and intralesional injections are painful.3,4
Unfortunately, recurrence often follows cessation of treatment following the
use of these therapies.1
Recent reports suggest that multiple injections of interferon alpha produce
clearance rates of 36 - 62% and are well tolerated locally; however, such
treatments are time-consuming, expensive and are associated with systemic side
effects.5,6
Efficacy
In early multicenter, double-blind, dose-ranging, vehicle controlled clinical
trials,
imiquimod 5% has proven effective in treating anogenital warts. In 311
patients, imiquimod 5% three times weekly completely cleared warts in 50% of
patients, compared to 11% clearance in patients treated with the vehicle (p <
0.0001, intent-to-treat analysis). In a subsequent trial, daily application of
the 5% cream completely cleared the warts of 52% of patients compared to 3%
clearance of
warts in patients using the vehicle alone (p < 0.0001, intent-to-treat
analysis). In these two trials, following cessation of treatment, wart
recurrence rates were 13% and 19% respectively.7
Combination treatment, using this new topical immunomodulator,
imiquimod, and ablative destructive therapy, is currently under study.8
Although results are not available, it seems logical to combine imiquimod with
and ablative therapy so that imiquimod could induce an immune response which
has the potential to affect the virus, eliminate residual lesions, and
possibly reduce recurrence rates.
Side Effects
The trials discussed above revealed that erythema and increased skin
irritation
was the most common reaction and was severe in 4% of both male and female
patients
treated three times weekly.9
Other adverse events reported by more than 1% of
patients include fatigue, fever, influenza like symptoms, headache, diarrhea,
myalgia and fungal infections.9
Safety During Pregnancy & Lactation
There are no adequate and well controlled studies in pregnancy and it is not
known whether topically applied imiquimod is excreted in breast milk.
Pharmacokinetics
Percutaneous absorption was minimal (less than 0.9%) following a single dose,
topical application of 5 mg of imiquimod to the skin of six healthy volunteers.
Dosage and Administration of Imiquimod
Prior to retiring, a thin layer of the cream is applied to the wart area,
rubbed in
until cream is no longer visible, left on the skin overnight and then in the
morning
washed off with mild soap and water. Hands should be washed before and after
being used to apply the cream.
The anogenital warts should be treated three
times per week. For those patients who respond, clearance of warts requires on
average 8 weeks for female patients and 12 weeks for male patients.
Patient Information
Local skin reactions are common but are usually mild to moderate in
severity.
Severe skin reactions should be reported to the physician
promptly. Do not occlude the treatment area. Uncircumcised males treating
warts
under the foreskin should clean the area daily.
The cream is for external use. Avoid contact with the eyes. Avoid sexual
(genital, anal, oral) contact while the cream is on the skin.
Imiquimod cream may weaken condoms and vaginal diaphragms and should not be
used concurrently.
Clinical Assessment
Imiquimod has not yet been compared to any other treatment for anogenital
warts. Podophyllin, the most frequently used topical treatment, is not a
standardised preparation10, has an unknown shelf life10, contains potentially
carcinogenic mutagens and has no known antiviral/immunomodulatory activity.
Imiquimod has no mutagenic activity, is immunomodulatory/antiviral and would
appear to be the drug of choice3 for multiple warts when cryotherapy is
inappropriate and cost is not a problem.
Imiquimod's place in therapy:
Imiquimod provides a new and practical treatment option to previously
available treatments.10 First line therapy3,8 for patients who do not demand
immediate removal of warts - it takes as long as eight weeks and sometimes
longer to
achieve clearance of warts. Alternative therapy for persons who have failed
another first line treatment and who have experienced recurrences of genital
warts.
A potential component of combination therapy for patients with
large/multiple warts.8 The immune response engendered by imiquimod
may affect the virus, eliminate residual lesions, and possibly reduce
recurrence rates. Applying imiquimod three times per week costs the patient
approximately US $100 per month for the cream.
Preliminary clinical data suggests that this new treatment approach utilizing
imiquimod to treat external genital and perianal warts/condyloma can be
justified on phamacoeconomic grounds.
Dr. Stephen Tyring, Galveston, Texas.
This review was prepared by Rodger Hall, Vancouver.
References
1.Edwards L, Ferenczy A, Eron L. Self-administered 5% imiquimod cream
for external
anogenital warts. Arch Dermatol. In press.
2.Megyeri K, Au WC, Rosztoczy I et al. Stimulation of interferon and
cytokine gene expression by imiquimod and stimulation by Sendai
virus
utilize similar signal transduction pathways. Molecular and
Cellular
Biology 1995; 15: 2207-2218.
3.Tyring SK. Personal communication. August 1997.
4.Krebs Hans-B. Treatment of genital condylomata with topical
5-fluorouracil. Dermatol Clin 1991; 9: 333-341.
5.Eron SJ, Judson F, Tucker S et al. Interferon therapy for condyloma
acuminata. N Eng J Med 1986; 315: 1059-1064
6.Friedman-Kein AE, Eron LJ, Conant M et al. Natural interferon alfa
for
treatment of condyloma acuminata. JAMA. 1988; 259: 533-538.
7.Edwards L, Beutner K, Tyring S et al. Comparison of results from two
vehicle controlled clinical trials evaluating topical imiquimod for
the
treatment of genital/perianal warts. Clinical Dermatology 2000,
Vancouver, British Columbia, May 28-31, 1996.
8.Sauder DN. Personal communication. August 1997.
9.Physician Packet Insert.
10.Beutner KR. Personal communication. October, 1997
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Produced by Dr. José Lapenta R.
Dermatologist
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