Action And Clinical Pharmacology
Mechanism Of Action
ZOVIRAX® (acyclovir), a synthetic acyclic purine
nucleoside analog, is a substrate with a high degree of specificity for herpes
simplex and varicella-zoster specified thymidine kinase. Acyclovir is a poor
substrate for host cell-specified thymidine kinase. Herpes simplex and
varicella-zoster specified thymidine kinase transform acyclovir to its
monophosphate which is then transformed by a number of cellular enzymes to
acyclovir diphosphate and acyclovir triphosphate. Acyclovir triphosphate is
both an inhibitor of, and a substrate for, herpesvirus-specified DNA
polymerase. Although the cellular α-DNA polymerase in infected cells may
also be inhibited by acyclovir triphosphate, this occurs only at concentrations
of acyclovir triphosphate which are higher than those which inhibit the
herpesvirus-specified DNA polymerase. Acyclovir is selectively converted to its
active form in herpesvirus-infected cells and is thus preferentially taken up by
these cells. Acyclovir has demonstrated a very much lower toxic potential in
vitro for normal uninfected cells because: 1) less is taken up; 2) less is
converted to the active form; and 3) cellular α-DNA polymerase has a lower
sensitivity to the action of the active form of the drug. A combination of the
thymidine kinase specificity, inhibition of DNA polymerase and premature
termination of DNA synthesis results in inhibition of herpes virus replication.
No effect on latent non-replicating virus has been demonstrated. Inhibition of
the virus reduces the period of viral shedding, limits the degree of spread and
level of pathology, and thereby facilitates healing. During suppression there
is no evidence that acyclovir prevents neural migration of the virus. It aborts
episodes of recurrent herpes due to inhibition of viral replication following
The pharmacokinetics of acyclovir after oral
administration have been evaluated in 6 clinical studies involving 110 adult
In one study of 35 immunocompromised patients with herpes
simplex or varicella-zoster infection given ZOVIRAX® Capsules in doses of 200
to 1,000 mg every 4 hours, 6 times daily for 5 days, the bioavailability was estimated
to be 15 to 20%. In this study, steady-state plasma levels were reached by the
second day of dosing. Mean steady-state peak and trough concentrations
following the last 200 mg dose were 0.49 μg/mL (0.47 to 0.54 μg/mL)
and 0.31 μg/mL (0.18 to 0.41 μg/mL), respectively and following the
last 800 mg dose were 2.8 μg/mL (2.3 to 3.1 μg/mL) and 1.8 μg/mL
(1.3 to 2.5 μg/mL). In another study, 20 immunocompetent patients with
recurrent genital herpes simplex infections given ZOVIRAX® Capsules in dose of
800 mg every 6 hours, 4 times daily for 5 days, the mean steady-state peak and
trough concentrations were 1.4 μg/mL (0.66 to 1.8 μg/mL) and 0.55
μg/mL (0.14 to 1.1 μg/mL).
In a multiple-dose crossover study where 23 volunteers
received ZOVIRAX® as one 200 mg capsule, one 400 mg tablet and one 800 mg
tablet 6 times daily, absorption decreased with increasing dose and the
estimated bioavailabilities of acyclovir were 20, 15 and 10%, respectively. The
decrease in bioavailability is believed to be a function of the dose and not
the dosage form. It was demonstrated that acyclovir is not dose proportional
over the dosing range 200 to 800 mg. In this study, steady-state peak and
trough concentrations of acyclovir were 0.83 and 0.46 μg/mL, 1.21 and 0.63
μg/mL, and 1.61 and 0.83 μg/mL for the 200, 400 and 800 mg dosage
In another study in 6 volunteers, the influence of food
on the absorption of acyclovir was not apparent.
A single oral dose bioavailability study in 23 normal
volunteers showed that ZOVIRAX® Capsules 200 mg are bioequivalent to 200 mg
acyclovir in aqueous solution. In a separate study in 20 volunteers, it was
shown that ZOVIRAX® Suspension is bioequivalent to ZOVIRAX® Capsules. In a
different single-dose bioavailability/ bioequivalence study in 24 volunteers,
one ZOVIRAX® 800 mg Tablet was demonstrated to be bioequivalent to four ZOVIRAX®
200 mg Capsules.
Plasma protein binding is relatively low (9 to 33%) and
drug interactions involving binding site displacement are not anticipated.
Following oral administration, the mean plasma half-life
of acyclovir in volunteers and patients with normal renal function ranged from
2.5 to 3.3 hours. The mean renal excretion of unchanged drug accounts for 14.4%
(8.6 to 19.8%) of the orally administered dose. The only urinary metabolite
(identified by high performance liquid chromatography) is
Special Populations And Conditions
In general, the pharmacokinetics of acyclovir in children
is similar to adults. Mean half-life after oral doses of 300 and 600 mg/m², in
children aged 7 months to 7 years, was 2.6 hours (range 1.59 to 3.74 hours).
Orally administered acyclovir in children less than 2 years
of age has not yet been fully studied.
In the elderly, total body clearance falls with
increasing age, associated with decreases in creatinine clearance, although
there is little change in the terminal plasma half-life. Dosage reduction may
be required in geriatric patients with reduced renal function (see DOSAGE
The half-life and total body clearance of acyclovir are
dependent on renal function.
A dosage adjustment is recommended for patients with
reduced renal function (see DOSAGE AND ADMINISTRATION).
Initial Genital Herpes
Double blind, placebo controlled studies have
demonstrated that orally administered ZOVIRAX® significantly reduced the
duration of acute infection and duration of lesion healing. The duration of
pain and new lesion formation was decreased in some patient groups.
Recurrent Genital Herpes
In a study of patients who received ZOVIRAX® 400 mg twice
daily for 3 years, 45, 52, and 63% of patients remained free of recurrences in
the first, second, and third years, respectively. Serial analyses of the 3
month recurrence rates for the patients showed that 71 to 87% were recurrence
free in each quarter.
Herpes Zoster Infections
In a double blind, placebo controlled study of
immunocompetent patients with localized cutaneous zoster infection, ZOVIRAX® (800
mg 5 times daily for 10 days) shortened the times to lesion scabbing, healing,
and complete cessation of pain, and reduced the duration of viral shedding and
the duration of new lesion formation.
In a similar double blind, placebo controlled study,
ZOVIRAX® (800 mg 5 times daily for 7 days) shortened the times to complete
lesion scabbing, healing, and cessation of pain, and reduced the duration of
new lesion formation.
Treatment was begun within 72 hours of rash onset and was
most effective if started within the first 48 hours. Adults greater than 50
years of age showed greater benefit.
Three randomized, double-blind, placebo-controlled trials
were conducted in 993 pediatric patients aged 2 to 18 years with chickenpox.
All patients were treated within 24 hours after the onset of rash. In two
trials, ZOVIRAX® was administered at 20 mg/kg four times daily (up to 3,200 mg
per day) for 5 days. In the third trial, doses of 10, 15, or 20 mg/kg were
administered four times daily for 5 to 7 days. Treatment with ZOVIRAX® shortened
the time to 50% healing, reduced the maximum number of lesions, reduced the
median number of vesicles, decreased the median number of residual lesions on
day 28, and decreased the proportion of patients with fever, anorexia, and
lethargy by day 2. Treatment with ZOVIRAX® did not affect varicella zoster
virus specific humoral or cellular immune responses at 1 month or 1 year
See Action And Clinical Pharmacology.
The quantitative relationship between the in vitro susceptibility
of herpes simplex virus (HSV) and varicella-zoster viruses (VZV) to acyclovir
and the clinical response to therapy has not been established in man, and virus
sensitivity testing has not been standardized. Sensitivity testing results,
expressed as the concentration of drug required to inhibit by 50% the growth of
virus in cell culture (ID50), vary greatly depending upon the particular assay
used, the cell type employed, and the laboratory performing the test. The ID50 of
acyclovir against HSV-1 isolates may range from 0.02 μg/mL (plaque
reduction in Vero cells) to 5.9-13.5 μg/mL (plaque reduction in green
monkey kidney [GMK] cells). The ID50 against HSV-2 ranges from 0.01 to 9.9
μg/mL (plaque reduction in Vero and GMK cells, respectively).
Using a dye-uptake method in Vero cells, which gives ID50
values approximately 5 to 10-fold higher than plaque reduction assays, 1,417
HSV isolates (553 HSV-1 and 864 HSV-2) from approximately 500 patients were
examined over a 5-year period. These assays found that 90% of HSV-1 isolates
were sensitive to ≤ 0.9 μg/mL acyclovir and 50% of all isolates were
sensitive to ≤ 0.2 μg/mL acyclovir. For HSV-2 isolates, 90% were
sensitive to ≤ 2.2 μg/mL and 50% of all isolates were sensitive to
≤ 0.7 μg/mL of acyclovir. Isolates with significantly diminished
sensitivity were found in 44 patients. It must be emphasized that neither the
patients nor the isolates were randomly selected and, therefore, do not
represent the general population. Most of the less sensitive HSV clinical
isolates have been relatively deficient in the viral thymidine kinase (TK).
Strains with alterations in viral TK or viral DNA polymerase have also been
The ID50 against VZV ranges from 0.17-1.53 μg/mL
(yield reduction, human foreskin fibroblasts) to 1.85-3.98 μg/mL (foci
reduction, human embryo fibroblasts [HEF]). Reproduction of EBV genome is
suppressed by 50% in superinfected Raji cells or P3HR-1 lymphoblastoid cells by
1.5 μg/mL acyclovir. Cytomegalovirus (CMV) is relatively resistant to
acyclovir with ID50 values ranging from 2.3-17.6 μg/mL (plaque reduction,
HEF cells) to 1.82-56.8 μg/mL (DNA hybridization, HEF cells). The latent
state of the genome of any of the human herpesviruses is not known to be
sensitive to acyclovir.
Prolonged exposure of HSV to subinhibitory concentrations
(0.1 μg/mL) of acyclovir in cell culture has resulted in the emergence of
a variety of acyclovir-resistant strains. The emergence of resistant strains is
believed to occur by “selection” of naturally occurring viruses with
relatively low susceptibility to acyclovir. Such strains have been reported in
pre-therapy isolates from several clinical studies.
Two resistance mechanisms involving viral thymidine
kinase (required for acyclovir activation) have been described. These are: (a)
selection of thymidine-kinase-deficient mutants that induce little or no enzyme
activity after infection, and (b) selection of mutants possessing a thymidine
kinase of altered substrate specificity that is able to phosphorylate the
natural nucleoside thymidine but not acyclovir. The majority of less susceptible
viruses arising in vitro are of the thymidine-kinase-deficient type which have
reduced infectivity and pathogenicity and less likelihood of inducing latency
However, an acyclovir-resistant HSV infection in an
immunosuppressed bone marrow transplant recipient on extended acyclovir therapy
was found to be due to a clinical isolate which had a normal thymidine kinase
but an altered DNA polymerase. This third mechanism of resistance involving
herpes simplex virus DNA polymerase is due to the selection of mutants encoding
an altered enzyme, which is resistant to inactivation by acyclovir
VZV appears to manifest resistance to acyclovir via
mechanisms similar to those seen in HSV.
However, limited clinical investigation has revealed no
evidence of a significant change in in vitro susceptibility of VZV with
acyclovir therapy, although resistant mutants of this virus can be isolated in
vitro in a manner analogous to HSV. Analysis of a small number of clinical
isolates from patients who received oral acyclovir or placebo for acute herpes
zoster suggests that in vivo emergence of resistant VZV may occur infrequently.
Prolonged acyclovir treatment of highly immunocompromised patients with
acquired immunodeficiency syndrome and severe VZV may lead to the appearance of
Cross-resistance to other antivirals occurs in vitro in
acyclovir-resistant mutants. HSV mutants which are resistant to acyclovir due
to an absence of viral thymidine kinase are cross-resistant to other agents
which are phosphorylated by herpesvirus thymidine kinase, such as
bromovinyldeoxyuridine, ganciclovir and the 2'-fluoropyrimidine nucleosides,
such as, 2'-fluoro-5-iodoarabinosyl-cytosine (FIAC).
The clinical response to acyclovir treatment has usually
been good for patients with normal immunity from whom HSV having reduced
susceptibility to acyclovir has been recovered, either before, during or after
therapy. However, certain patient groups, such as the severely immunocompromised
(especially bone marrow transplant recipients) and those undergoing chronic
suppressive regimens have been identified as being most frequently associated
with the emergence of resistant herpes simplex strains, which may or may not
accompany a poor response to the drug. The possibility of the appearance of
less sensitive viruses must be recognized when treating such patients, and
susceptibility monitoring of clinical isolates from these patients should be
In summary, the quantitative relationship between the in
vitro susceptibility of HSV and VZV to acyclovir and the clinical response to
therapy has not been clearly established in man. Standardized methods of virus
sensitivity testing are required to allow more precise correlations between in
vitro virus sensitivity and clinical response to acyclovir therapy.
Acute Toxicity Studies
Adult Mice and Rats: The acute toxicity of oral acyclovir
was determined as shown in Table 6.
Table 6 : Acute Toxicity Studies
||95% Conf. Level
|| > 10 000
|| > 20 000
Neonatal, Immature, and Adult Rats
Groups of 10 male and 10 female Charles River CD
(Sprague-Dawley) rats were given single large doses (5 different dose levels)
of a solution (pH 11.0) of acyclovir by subcutaneous injection when they were
3, 10, 28 and 71 days of age. They were observed for 14 days after treatment
and LD50 values were calculated by the Litchfield and Wilcoxon method (see
Table 7 below). This study was done to determine if age at exposure affects the
acute toxicity of acyclovir; there was no evidence that young rats were more
sensitive than older rats to the acute toxic effects of acyclovir.
Table 7 :LD50 in Rats
|Age When Treated
||LD50 (mg/kg body weight)
There was no apparent relationship between length of
survival after treatment and age at which treatment was given. Clinical signs
for the rats treated at 3 and 10 days of age included red and purple cutaneous
blisters, blue areas, scabs, scars, necrotic and sloughed skin, open wounds,
body tremors and alopecia. Decreased activity, lacrimation, closed eyelids,
red-brown or brown material around the eyes, nose and mouth, ataxia,
prostration, body tremors, urine stains around the abdomen or genital area,
scabbed or necrotic areas and alopecia were observed in rats treated at 28 and
71 days of age.
Subchronic Oral Toxicity Study
Four groups each consisting of 28 male and 28 female
Charles River CD-1 (ICR) mice were orally dosed by stomach tube for 33 days with
suspensions of acyclovir. Daily dose levels were 0, 50, 150 and 450 mg/kg.
Hematology and clinical chemistry measurements were made on an additional 8
male and 8 female mice per group (dosed in the same manner) after the first and
fourth weeks of dosing and during the 3rd postdose week.
Plasma drug concentrations were measured in pooled
samples from an additional 4 male and 4 female mice per group on dose days 1,
15 and 30.
Based on preliminary experiments with rats and mice, the
high dose of 450 mg/kg was selected to produce the highest drug plasma levels
attainable, in a practical manner, by oral dosing in a rodent species. Averaged
drug plasma concentrations ranged from approximately 3.4 (at the low dose) to
11.0 (at the high dose) μg/mL of plasma one hour after oral dosing.
No changes in health, growth rate, hematology and
clinical chemistry measurements occurred that could be definitely attributed to
dosing with acyclovir. Gross and histopathologic examinations of 16 male and 16
female rats from the high-dose and control groups at the end of the dose period
revealed nothing remarkable.
Chronic Toxicity Studies
Lifetime Oral Toxicity Study in Rats Given Acyclovir by
Charles River CD (Sprague-Dawley) rats were given
suspensions of acyclovir by gavage. There were 50 male and 50 female rats at
each of the following dose levels: 0, 50, 150 and 450 mg/kg. After 30 and 52
weeks of treatment, 10 male and 10 female rats from each group were necropsied.
The remaining rats were dosed each day until natural mortality decreased a
group size to approximately 20% of the number of animals of that sex present in
the test groups when the study was started. All remaining rats were killed and
necropsied when the 20% cut-off point was reached. This was during week 110 for
the male rats and week 122 for the female rats. Tissues from control rats and
those in the high-dose group were evaluated by light microscopy. Tissues from
rats in the low and mid-dose groups having masses, nodules or unusual lesions
were also examined by light microscopy. Fixed tissues from rats that were found
dead during the first 52 weeks of the study were also evaluated by light
No signs of toxicosis were observed. Plasma samples were
collected 1.5 hours after dosing on days 7, 90, 209, 369, 771 (males only) and
852 (females only). Mean plasma levels found in high-dose males (450 mg/kg/day)
at the times indicated above were as follows: 1.54, 1.63, 1.39, 1.60 and 1.70
μg/mL (6.84, 7.26, 6.17, 7.10 and 7.56 μM). Corresponding mean plasma
levels for the high-dose females for the corresponding time periods were 1.76,
2.38, 2.12, 1.71 and 1.81 μg/mL (7.82, 10.58, 9.44, 7.62 and 8.03
μM). Plasma levels in both males and females at all dose levels after one
year of treatment were generally comparable to plasma levels obtained at
earlier samplings. Values for laboratory tests including hematology, clinical
chemistry and ophthalmoscopy were all within the normal range. There were no
drug-induced gross or microscopic lesions and there was no evidence that
acyclovir affected survival.
Lifetime Oral Carcinogenicity Study in Rats
There were no signs of toxicosis in Charles River CD
(Sprague-Dawley) rats (100 rats/sex/dose group) given acyclovir by oral gavage
at 50, 150 and 450 mg/kg in a lifetime oral carcinogenicity study. Mean plasma
levels obtained in high-dose males 1.5 hours after dosing at various sampling
times during the study were as follows: 1.54, 1.63, 1.39, 1.60 and 1.70
μg/mL (6.84, 7.26, 6.17, 7.10 and 7.56 μM) at days 7, 90, 209, 369
and 771, respectively. Corresponding mean values for the high-dose females were
1.76, 2.38, 2.12, 1.71 and 1.81 μg/mL (7.82, 10.58, 9.44, 7.62 and 8.03
μM) at days 7, 90, 209, 369 and 852, respectively.
Values for clinical laboratory tests including
hematology, clinical chemistry, urinalysis, body weight, food consumption and
ophthalmoscopy were all within normal ranges. There were no drug-induced gross
or microscopic lesions and there was no evidence that acyclovir affected
survival, temporal patterns of tumor incidence or tumor counts for benign or
Most of the relatively few rats found dead or moribund
during the first 52 weeks of this study suffered dosing accidents as evidenced
by postmortem findings of esophageal perforation causing pleural effusion,
pneumonia, or mediastinitis.
Lifetime Oral Carcinogenicity Study in Mice
There were no signs of toxicosis in Charles River CD-1
(ICR) mice (115 mice/sex/dose group) given acyclovir by oral gavage at 50, 150
and 450 mg/kg/day in a lifetime oral carcinogenicity study. Mean plasma levels
obtained in high-dose males 1.5 hours after dosing at various sampling times
during the study were as follows: 2.83, 3.17 and 1.82 μg/mL (12.59, 14.10
and 8.10 μM) at days 90, 365 and 541, respectively. Corresponding mean
values for the high-dose females were 9.81, 5.85 and 4.0 μg/mL (43.60,
26.0 and 17.79 μM).
Values for clinical laboratory tests including
hematology, body weight and food consumption were all within normal ranges.
There were no drug-induced gross or microscopic lesions. Female mice given 150
and 450 mg/kg acyclovir survived significantly longer than control female mice;
survival of treated males was comparable to survival of control males. Patterns
of tumor incidence and tumor counts for benign or malignant neoplasms were not
affected by treatment with acyclovir.
Chronic 12-Month Oral Toxicity Study in Dogs
Purebred Beagle dogs were given 0, 15, 45 or 150 mg/kg/day
of acyclovir each day for the first two weeks of a one-year study. There were 9
male and 9 female dogs in each test group. The dogs were given gelatin capsules
that contained the appropriate dose. They were treated t.i.d., hence the
dosages administered at each of three equally spaced dose periods were 0, 5, 15
and 50 mg/kg. The 45 and 150 mg/kg dose levels induced diarrhea, emesis,
decreased food consumption and weight loss in both male and female dogs during
the first two weeks of the study. For this reason, during the third week of the
study the decision was made to decrease the mid- and high-dosage levels to 30
and 60 mg/kg/day (10 and 20 mg/kg t.i.d.). The low dose of 15 mg/kg/day (5
mg/kg t.i.d.) was unchanged. Dogs given 60 mg/kg/day occasionally vomited and
occasionally had diarrhea but did well for the duration of the test, and values
for body weight gain and food consumption were comparable to control values.
During the toxicosis induced by the larger doses of
acyclovir, plasma levels of the drug were likely very high (as indicated by
initial mean values of 24.0 μg/mL (106.6 μM) for high-dose males and
17.4 μg/mL (77.2 μM) for high-dose females when determined 1 hour
after the third dose on day 1 of the study). When measured on day 15, plasma
levels of acyclovir in high-dose dogs (150 mg/kg/day) were still very high but
they decreased later when the dosages were decreased. Values for plasma levels
after 12 months of treatment were generally comparable to values recorded after
1, 3 and 6 months of treatment. Thus, there was no indication of enhanced
metabolism of acyclovir as a result of chronic treatment.
During the 13th week, some male and female dogs at both
the mid- and high-dosage levels had the following signs: tenderness in
forepaws, erosion of footpads, and breaking and loosening of nails.
Regeneration of lost nails began a few weeks later. Nails regenerated by 6
months (when 3 males and 3 females from each group were killed for an interim
sacrifice) and by the end of the study were of generally good quality. There
were never any signs of an effect on paws or nails in dogs in the low dose
group (15 mg/kg/day).
It is accepted that injury of the corial epithelium that
produces nail keratin can result in arrested production of keratin and
production of abnormal keratin. The transient toxicosis induced by the large
doses (45 and 150 mg/kg/day) of acyclovir given during the first two weeks of
the study may have affected the corial epithelium. If there was a transient
effect on the corial epithelium (possibly related to direct effects or
secondary to drug-induced illness during the first two weeks of the study)
later loss of the nail could be a sequella. No discernible effects upon other
keratin-producing or keratin-containing tissues were observed. It should be
emphasized that the alterations in the nails appeared to be related to the
transient toxicosis induced by dose levels of 50 and 150 mg/kg/day tested
during the first two weeks of the study and not to the 30 and 60 mg/kg/day dose
levels tested subsequently.
There were no important drug-induced alterations in
values for serum biochemical tests, urinalyses and electrocardiographic tests
done at appropriate intervals during this study. Values for serum albumin and
total protein were slightly decreased in dogs treated at 30 and 60 mg/kg/day
for 6 and 12 months. However, all values for these parameters remained within
limits accepted as normal.
With the exception of residual alterations in old keratin
at the tips of the claws, there were no signs of treatment-related effects in
any of the tissues examined by light microscopy. Nor were there meaningful
alterations in values for the organs weighed at necropsy. Thus, dose levels up
to 60 mg/kg/day were well tolerated for one year. The “no dose
effect” dose level of acyclovir was 15 mg/kg/day (5 mg/kg t.i.d.);
however, the only adverse effects at 30 or 60 mg/kg/day were changes in nails
and footpads (30 and 60 mg/kg/day) and mild gastrointestinal signs (60 mg/kg/day).
Teratology – Rats
Acyclovir was administered to pregnant A.R.S.
Sprague-Dawley female rats by subcutaneous injection during the period of
organogenesis (day 6 through day 15 of gestation) at dose levels of 0.0, 6.0,
12.5 and 25.0 mg/kg body weight twice daily.
Criteria evaluated for compound effect included maternal
body weights, weight gains, appearance and behaviour, survival rates, eye
changes, pregnancy rates, and reproduction data. Offspring viability and
development were also evaluated.
In addition to the above measurements, designated animals
were sacrificed 1 hour after the first dose on day 15 in order to collect
samples of maternal blood, amniotic fluid and fetuses for measurements of drug
concentration. Mean values from these samples are listed in Table 8.
Table 8 : Acyclovir Concentrations in a Teratology
Study in Rats
|Dose mg/kg b.i.d., s.c.
|Amniotic Fluid fag/mL)
||(nmoles/g wet wt)
The values obtained for plasma would represent about 30%
of initial plasma levels as judged by the plasma half-life in rodents.
No effects attributable to the administration of
acyclovir were noted in comparisons of maternal body weight values, appearance
and behaviour, survival rates, pregnancy rates, or implantation efficiencies.
In addition, no compound-related differences were noted in evaluations of fetal
size, sex and development.
Although the incidences of resorption and fetal viability
were within the range of normal variability in all of the groups, slightly
greater incidences of resorptions were noted in the high-dose animals
sacrificed on days 15 and 19 of gestation; however, clear dose-related trends
did not eventuate.
Therefore, acyclovir was not considered teratogenic or
embryotoxic when administered to rats at levels up to 50.0 mg/kg of body weight
per day during organogenesis.
Teratology – Rabbits
A teratology study was done in New Zealand White rabbits
using essentially the same experimental design as in the rat, except that
dosing was from day 6 through day 18 of gestation. Also, collection of fetuses,
amniotic fluid and samples of maternal blood occurred on day 18 rather than day
No signs of maternal toxicity were observed at any dose,
but there was a statistically significant (p < 0.05) lower implantation
efficiency in the high-dose group. While there were a few terata observed in
the study (in both control and treated animals), there was no apparent association
with drug treatment. There was, however, an apparent dose-related response in
the number of fetuses having supernumerary ribs. No similar effect was noted in
the rat teratology study (see above) or in a reproduction-fertility experiment
Concentrations of acyclovir were detected in plasma and
amniotic fluid samples, as well as in homogenates of fetal tissues. All samples
were taken one hour after the first dose on day 18 of gestation. Drug
concentrations in amniotic fluid were substantially higher than that of plasma
(see Table 9).
Table 9 : Acyclovir Concentrations in a Teratology
Study in Rabbits
|Dose mg/kg b.i.d., s.c.
||Acyclovir Concentrations (Mean and S.E.)
|Amniotic Fluid fag/mL)
||(nmoles/g wet wt)
Reproduction – Fertility
Acyclovir was shown not to impair fertility or
reproduction in groups of 15 male and 30 female mice in a two-generation
fertility study. The mice in this study were given acyclovir by gastric
intubation at dosage levels of 50, 150 and 450 mg/kg/day. Males were dosed for
64 consecutive days prior to mating and females for 21 days prior to mating.
In a rat fertility study where groups of 20 male and 20
female rats were given 0, 12.5, 25.0 and 50.0 mg/kg/day by subcutaneous
injection, acyclovir was shown not to have an effect on mating or fertility.
The males were dosed for 60 days prior to mating and until their mating
schedule was completed. Female rats were dosed for 14 days prior to mating and
until day 7 of pregnancy. At 50 mg/kg/day s.c. there was a statistically
significant increase in post-implantation loss, but no concomitant decrease in
In 25 female rabbits treated subcutaneously with 50
mg/kg/day acyclovir on days 6 to 18 of gestation, there was a statistically
significant decrease in implantation efficiency but no concomitant decrease in
litter size. There was also a dose-related increase in the number of fetuses
with supernumerary ribs in all drug-treated groups. This increase was not
dose-related when the incidence of supernumerary ribs per litter was examined.
In 15 female rabbits treated intravenously with 50
mg/kg/day acyclovir on days 6 to 18 of gestation, there was no effect on either
implantation efficiency or litter size.
In a rat peri- and postnatal study (20 female rats per
group), acyclovir was given subcutaneously at 0, 12.5, 25 and 50 mg/kg/day from
17 days of gestation to 21 days postpartum. At 50 mg/kg/day s.c. there was a
statistically significant decrease in the group mean numbers of corpora lutea,
total implantation sites and live fetuses in the F1 generation. Although not
statistically significant, there was also a dose-related decrease in group mean
numbers of live fetuses and implantation sites at 12.5 mg/kg/day and 25 mg/kg/day
In a dose-range finding study with 5 female rabbits the
intravenous administration of acyclovir at a dose of 100 mg/kg/day from days 6
to 8 of pregnancy, a dose known to cause obstructive nephropathy, caused a
significant increase in fetal resorptions and a corresponding decrease in
litter size. At a maximum tolerated intravenous dose of 50 mg/kg/day in rabbits
there were no drug-related reproductive effects.
In a subchronic toxicity study where groups of 20 male
and 20 female rats were given intraperitoneal doses of acyclovir at 0, 20, 80
or 320 mg/kg/day for one month, and followed for a one-month postdose period,
there was testicular atrophy. Some histologic evidence of recovery of sperm
production was evident 30 days postdose, but this was insufficient time to
demonstrate full reversibility.
Groups of 25 male and 25 female rats were administered
intraperitoneal doses of acyclovir at 0, 5, 20 or 80 mg/kg/day for 6 months.
Ten male and 10 female rats in each group were continued undosed for 13 weeks.
Testicular atrophy was limited to high-dose rats given 80 mg/kg/day for 6
months. Organ weight data and light microscopy defined full reversibility of
the testicular atrophy by the end of the postdose recovery period.
In a 31-day dog study (16 males and 16 females per group)
where acyclovir was administered intravenously at levels of 50, 100 and 200
mg/kg/day, testicles were normal in dogs at 50 mg/kg. Doses of 100 or 200
mg/kg/day caused death of some dogs due to cytostatic effects (bone marrow and
gastrointestinal epithelium) and aspermic testes or testes with scattered
aspermic tubules. It cannot be ruled out that the testicular change may have
been primary, however, similar changes can be observed secondary to severe
stress in moribund dogs.
Developmental Toxicity Studies
Neonatal Rats - Subchronic Study
Acyclovir dissolved in 0.4% sterile saline was given by
subcutaneous injection to Charles River CD (Sprague-Dawley) neonatal rats for
19 consecutive days, beginning on the 3rd post-partum day. The dose levels
tested were 0, 5, 20 and 80 mg/kg body weight. There were 12 litters (each
consisting of 5 male and 5 female neonates nursing the natural dam) at each
dose level. The dams were not treated. Neonates were removed from each group
for necropsy and microscopic evaluation of a wide variety of tissues, including
eyes and multiple sections of brain, after they had been treated for 5, 12 or
19 days and after a 3-week postdose drug-free period (at which time they were 45
days of age). Hematologic (hemoglobin, packed cell volume, RBC, WBC and
differential cell counts) and clinical chemistry (BUN) tests were done after 16
days of treatment and repeated 18 days after the last (19th) dose was given.
Blood was collected from some neonates 30 minutes after
treatment on day 1, on day 9 and at the end of the dose period for the
determination of concentrations of acyclovir in plasma. The largest
concentration of acyclovir in plasma was 99.1 μg/mL (440.5 μM) found
in pooled plasma collected from 6 female high-dose (80 mg/kg) neonates 30
minutes after the first dose was given. Treatment with acyclovir did not
increase mortality in the neonatal period.
Rats in the low-dose group gained as much body weight as
the respective control rats. Significant (p < 0.05) reductions in mean body
weight values were observed in mid- and high-dose group male and female
neonates during the treatment period. Rats in the high-dose group partially
compensated by gaining significantly more body weight than the controls during
the postdose recovery period. There was a minimal but significant increase in
BUN for male (p < 0.01) and female (p < 0.05) neonates in the high-dose group
on dose day 16. This finding may be of biological importance because there were
minimal accumulations of nuclear debris in renal collecting ducts and loops of
Henle in kidney sections taken from high-dose neonates after 19 days of
treatment and examined by light microscopy. This was the only time period (and
the kidney was the only organ) in which minimal effects on developing organ
systems were detected. Thus, 5 mg/kg was clearly a no effect dose level and 20
mg/kg caused only minimal decreases in body weight gain.
Eye examinations and light microscopy did not reveal
adverse effects on ocular development. It should be emphasized that there was
no morphologic or functional evidence of adverse effects on developing brain or
other portions of the central nervous system. Thus, acyclovir is distinctly
different than cytosine arabinoside which was reported to produce prominent
cerebellar and retinal dysplasia in neonatal rats.
Mutagenicity And Other Short-Term Studies
Acyclovir has been tested for mutagenic potential in a
number of in vitro and in vivo systems:November 10, 2014 Page 27 of 38
Acyclovir was tested for mutagenic activity in the Ames
Salmonella plate assay; in a preincubation modification of the Ames assay; in
the Rosenkrantz E. coli polA+/polA- DNA repair assay; and in the eukaryote S.
cerevisiae, D-4. All studies were performed both in the presence and absence of
exogenous mammalian metabolic activation. Acyclovir gave no positive responses
in any of these systems.
The previous Salmonella studies were extended to
extremely high concentrations in order to achieve toxicity. No positive effects
were observed either in the presence or absence of exogenous mammalian
metabolic activation, at concentrations of acyclovir up to 300 mg/plate or 80
Acyclovir was tested for mutagenic activity in cultured
L5178Y mouse lymphoma cells, heterozygous at the thymidine kinase (TK) locus,
by measuring the forward mutation rate to TK-deficiency (TK+/- → TK-/-;
additional studies were performed at the HGPRT locus and at the
Ouabain-resistance marker in these same cells. All studies were performed in
the presence and in the absence of exogenous mammalian metabolic activation.
The test compound was mutagenic at the TK locus at high concentrations (400
-2,400 μg/mL). (By comparison, the upper limit of acyclovir peak plasma
levels following oral dosing of 200 mg q4h is 0.9 μg/mL). It was negative
at the HGPRT locus and Ouabain-resistance marker. Identical results were
obtained with and without metabolic activation.
Inconclusive results with no apparent dose-related
response were obtained when acyclovir mutagenicity was studied at each of 3
loci (APRT, HGPRT and Ouabain-resistance) in Chinese hamster ovary (CHO) cells,
both in the presence and absence of exogenous metabolic activation.
Acyclovir, at a concentration of 50 μg/mL (222
μM) for a 72-hour exposure, has been shown to cause a statistically
significant increase in the incidence of morphologically-transformed foci
resulting from treating BALB/C-3T3 cells in vitro in the absence of exogenous metabolic
activation. The morphologically transformed foci have been shown to grow as
tumours following transplantation into immunosuppressed, syngeneic, weanling
mice. Tumour tissues were diagnosed as being either undifferentiated sarcomas
Acyclovir, at concentrations between 8 and 64 μg/mL
for 18 hours' exposure, did not induce any morphologically-transformed foci
among C3H/10T ½ cells treated in vitro in the absence of exogenous metabolic
Acyclovir, at concentrations of 62.5 and 125 μg/mL
for a 48-hour exposure, did not induce any chromosome aberrations in cultured
human lymphocytes in the absence of exogenous metabolic activation. At higher
concentrations, 250 and 500 μg/mL for 48 hours exposure, acyclovir caused
a significant increase in the incidence of chromosome breakage. There was also
a significant dose-related decrease in mitotic index with exposure to
Acyclovir, at doses of 25 and 50 mg/kg/day i.p. for 5
consecutive days, did not produce a dominant lethal effect in male BKA (CPLP)
mice. Further, there was no evidence of a dominant lethal effect on Charles
River CD-1 (ICR) male and female mice treated orally at dose levels of 50, 150
and 450 mg/kg/day as summarized for the Two Generation Reproduction/ Fertility
Acyclovir, at single intraperitoneal doses of 25, 50 and
100 mg/kg, failed to induce chromosome aberrations in bone marrow cells of
Chinese hamsters when examined 24 hours after dosing. At higher nephrotoxic doses
(500 and 1,000 mg/kg), a blastogenic effect was seen. (An intraperitoneal dose
of 500 mg/kg produces mean peak plasma levels in Chinese hamsters of 611
μg/mL (2.72 mM) which is 680 times higher than the upper limit of human
peak plasma levels during oral dosing of 200 mg q4h).
Acyclovir, at single intravenous doses of 25, 50 and 100
mg/kg, failed to induce chromosome aberrations in bone marrow cells of male and
female rats when examined at 6, 24 and 48 hours after treatment.
Thus, all these studies showed that acyclovir does not
cause single-gene mutations but is capable of breaking chromosomes.
Acyclovir was subjected to a number of in vitro and in
vivo immunological tests.
In two in vivo tests, lymphocyte-mediated cytotoxicity
and neutrophil chemotaxis, acyclovir showed no inhibitory effects at
concentrations as high as 135 μg/mL (600 μM). The compound inhibited
rosette formation approximately 50% at 0.9 μg/mL (4 μM).
In four in vivo tests in mice which measured cell-mediated
immunity (complement-dependent cellular cytotoxicity, complement-independent
cellular cytotoxicity, delayed hypersensitivity and graft vs. host reaction)
acyclovir showed no inhibitory effects at single doses up to 200 mg/kg given on
day 2 after antigenic stimulation.
Four daily doses of 100 mg/kg/day had no significant
effect on Jerne hemolysin plaques or circulating antibody on day 7 after
antigenic stimulation. When the Jerne hemolysin plaques and antibody titers
were examined four days after antigenic challenge and one day after the last
drug dose, 100 mg/kg showed only a slight suppressive effect. However, 200
mg/kg produced some weight loss (-2.2 g), a moderate reduction in the number of
Jerne hemolysin plaques (PFC/spleen were reduced to 33% of control, PFC/107 WBC
to 46.5% of control). However, there was only a small reduction in the
circulating hemagglutinin titer (from 8.3 to 6.5) and the circulating hemolysin
titer (from 9.5 to 8.3) at 200 mg/kg.
In experiments in mice designed to test whether acyclovir
would potentiate the immunosuppressive effect of azathioprine on antibody
formation, it was found that the effects of the two drugs were no more than
additive. Only the 200 mg/kg dose of acyclovir showed an increased suppression
of antibody response when given in combination with azathioprine at doses above
Studies were carried out to evaluate the influence of
acyclovir in vitro on human lymphocyte function. Inhibitory effects on
blastogenesis were seen only in assays examining peak concentrations of potent
mitogens, phytohemagglutinin (PHA) and concanavalin A (Con A), and only at
concentrations of drug above 50 μg/mL (222 μM) and were much less
with monilia and tetanus toxoid antigens, where the blastogenic response is
characteristically less vigorous. There was very little effect on cytotoxicity
or LIF production except at concentrations of 200 μg/mL (890 μM)
where there has already been demonstrated to be a direct cytotoxic effect.
These inhibitory concentrations are far in excess of anticipated levels from
doses selected for clinical application and over 1,000-fold higher than the
concentration required to inhibit herpesvirus multiplication in vitro.
The effect of acyclovir on human cells was measured. A
concentration of 11.2 - 22.5 μg/mL (50-100 μM) inhibits the division
of fibroblasts to a variable extent, depending on the experimental design and
the confluency of the monolayer. The magnitude of this effect was less than that
caused by adenine arabinoside or human leukocyte interferon when these three
antiviral agents were compared at clinically relevant concentrations. Acyclovir
also inhibited thymidine incorporation by peripheral blood mononuclear cells
stimulated by PHA or three different herpesvirus antigens. A linear
dose-response curve was observed with these cells, and their proliferation was
50% inhibited by 22.5 μg/mL (100 μM) acyclovir. Inhibition was
exerted on T-cell proliferation without apparent effect on the release of lymphokines
or on monocyte function.
It should also be mentioned that there was no evidence of
adverse effects on the immune system in the detailed subchronic and chronic
animal tests covered earlier in this summary except at excessively high doses
(50 to 100 mg/kg b.i.d.) in dogs where marked lymphoid hypoplasia occurred.
1. Balfour HH, Jr., Kelly JM, Suarez CS, Heussner RC,
Englund JA, Crane DD et al. Acyclovir treatment of varicella in otherwise
healthy children. J Pediatr 1990; 116(4):633-639.
2. Balfour HH, Jr., Rotbart HA, Feldman S, Dunkle LM,
Feder HM, Jr., Prober CG et al. Acyclovir treatment of varicella in otherwise
healthy adolescents. The Collaborative Acyclovir Varicella Study Group. J
Pediatr 1992; 120(4 Pt 1):627-633.
3. Barry DW, Blum MR. Antiviral drugs: acyclovir, in
Recent Advances in Clinical Pharmacology. Turner P, Shand DG (eds) Churchill
Livingstone, Edinburgh 1983.
4. Barry DW, Nusinoff-Lehrman S. Viral resistance in
clinical practice: summary of five years experience with acyclovir.
Pharmacological and Clinical Approaches to Herpesviruses and Virus
Chemotherapy, Aiso, Japan, September 10-13 1984.
5. Barry DW, Nusinoff-Lehrman S, Ellis MN, Biron KK,
Furman PA. Viral resistance, clinical experience. Scand J Infect Dis Suppl
6. Barry DW, Nusinoff-Lehrman S. Viral resistance in
clinical practice: summary of five years experience with acyclovir. Proceedings
of the International Symposium on Pharmacological and Clinical Approches to
Herpes Viruses and Virus Chemotherapy, Elsever, Amsterdam 1985;269-270.
7. Biron KK, Elion GB. Effect of acyclovir combined with
other antiherpetic agents on varicella zoster virus in vitro. Am J Med 1982;
8. Boelaert J, Schurgers M, Daneels R, Van Landuyt HW,
Weatherley BC. Multiple dose pharmacokinetics of intravenous acyclovir in
patients on continuous ambulatory peritoneal dialysis. J Antimicrob Chemother
9. Bryson YJ, Dillon M, Lovett M, Acuna G, Taylor S,
Cherry JD et al. Treatment of first episodes of genital herpes simplex virus
infection with oral acyclovir. A randomized double-blind controlled trial in
normal subjects. N Engl J Med 1983; 308(16):916-921.
10. Burns WH, Saral R, Santos GW, Laskin OL, Lietman PS,
McLaren C et al. Isolation and characterisation of resistant Herpes simplex
virus after acyclovir therapy. Lancet 1982; 1(8269):421-423.
11. Christophers J, Sutton RN. Characterisation of
acyclovir-resistant and -sensitive clinical herpes simplex virus isolates from
an immunocompromised patient. J Antimicrob Chemother 1987; 20(3):389-398.
12. Cole NL, Balfour HH, Jr. Varicella-Zoster virus does
not become more resistant to acyclovir during therapy. J Infect Dis 1986; 153(3):605-608.
13. Collins P, Bauer DJ. The activity in vitro against
herpes virus of 9-(2-hydroxyethoxymethyl)guanine (acycloguanosine), a new
antiviral agent. J Antimicrob Chemother 1979; 5(4):431-436.
14. Collins P, Oliver NM. Sensitivity monitoring of herpes
simplex virus isolates from patients receiving acyclovir. J Antimicrob
Chemother 1986; 18 Suppl B:103-112.
15. Collins P. Viral sensitivity following the
introduction of acyclovir. Am J Med 1988; 85(2A):129-134.
16. Collins P, Larder BA, Oliver NM, Kemp S, Smith IW,
Darby G. Characterization of a DNA polymerase mutant of herpes simplex virus
from a severely immunocompromised patient receiving acyclovir. J Gen Virol
1989; 70 ( Pt 2):375-382.
17. Crumpacker CS, Schnipper LE, Zaia JA, Levin MJ.
Growth inhibition by acycloguanosine of herpesviruses isolated from human
infections. Antimicrob Agents Chemother 1979; 15(5):642-645.
18. Crumpacker CS, Schnipper LE, Marlowe SI, Kowalsky PN,
Hershey BJ, Levin MJ. Resistance to antiviral drugs of herpes simplex virus
isolated from a patient treated with acyclovir. N Engl J Med 1982;
19. Darby G, Inglis MM, Larder BA. Mechanisms of
resistance to nucleoside analogue inhibitors of herpes simplex virus. 6th Int
Congr Virol 1984;(Abstract #W34-5).
20. De Clercq E, Descamps J, Verhelst G, Walker RT, Jones
AS, Torrence PF et al. Comparative efficacy of antiherpes drugs against
different strains of herpes simplex virus. J Infect Dis 1980; 141(5):563-574.
21. De Clercq E. Comparative efficacy of antiherpes drugs
in different cell lines. Antimicrob Agents Chemother 1982; 21(4):661-663.
22. Dekker C, Ellis MN, McLaren C, Hunter G, Rogers J,
Barry DW. Virus resistance in clinical practice. J Antimicrob Chemother 1983;
12 Suppl B:137-152.
23. Douglas JM, Davis LG, Remington ML, Paulsen CA,
Perrin EB, Goodman P et al. A double-blind, placebo-controlled trial to the
effect of chronically administered oral acyclovir on sperm production in men
with frequently recurrent genital herpes. J Infect Dis 1988 Mar; 157:588-93.
24. Douglas JM, Critchlow C, Benedetti J, Mertz GJ,
Connor JD, Hintz MA et al. A double-blind study of oral acyclovir for
suppression of recurrences of genital herpes simplex virus infection. N Engl J
Med 1984; 310(24):1551-1556.
25. Dunkle LM, Arvin AM, Whitley RJ, Rotbart HA, Feder
HM, Jr., Feldman S et al. A controlled trial of acyclovir for chickenpox in
normal children. N Engl J Med 1991; 325(22):1539-1544.
26. Ellis MN, Keller PM, Martin JL, Strauss SE,
Nusinoff-Lehrman S etal. Characterization of an HSV-2 clinical isolate
containing an ACV-resistant mutant which produces a thymidine kinase with
altered substrate specificity. Ninth Int Herpesvirus Workshop, Seattle, Washington,
August 24-29 1984.
27. Ellis MN, Keller PM, Fyfe JA, Martin JL, Rooney JF,
Straus SE et al. Clinical isolate of herpes simplex virus type 2 that induces a
thymidine kinase with altered substrate specificity. Antimicrob Agents
Chemother 1987; 31(7):1117-1125.
28. Englund JA, Zimmerman ME, Swierkosz EM, Goodman JL,
Scholl DR, Balfour HH, Jr. Herpes simplex virus resistant to acyclovir. A study
in a tertiary care center. Ann Intern Med 1990; 112(6):416-422.
29. Erlich KS, Jacobson MA, Koehler JE, Follansbee SE,
Drennan DP, Gooze L et al. Foscarnet therapy for severe acyclovir-resistant
herpes simplex virus type-2 infections in patients with the acquired
immunodeficiency syndrome (AIDS). An uncontrolled trial. Ann Intern Med 1989;
30. Erlich KS, Mills J, Chatis P, Mertz GJ, Busch DF,
Follansbee SE et al. Acyclovir-resistant herpes simplex virus infections in
patients with the acquired immunodeficiency syndrome. N Engl J Med 1989;
31. Field HJ, Darby G, Wildy P. Isolation and
characterization of acyclovir-resistant mutants of herpes simplex virus. J Gen
Virol 1980; 49(1):115-124.
32. Field HJ. The problem of drug-induced resistance in
viruses, in Problems of Antiviral Therapy. Stuart-Harris CH, Oxford J (Eds)
Academic Press, London 1983.
33. Fyfe K. Recurrence patterns of genital herpes after
cessation of more then 5 years of chronic acyclovir suppression. VIII Int Conf
AIDS/III Std Wrld Cong 1992;(B240).
34. Huff JC, Bean B, Balfour HH, Jr., Laskin OL, Connor
JD, Corey L et al. Therapy of herpes zoster with oral acyclovir. Am J Med 1988;
35. Jacobson MA, Berger TG, Fikrig S, Becherer P, Moohr
JW, Stanat SC et al. Acyclovir-resistant varicella zoster virus infection after
chronic oral acyclovir therapy in patients with the acquired immunodeficiency
syndrome (AIDS). Ann Intern Med 1990; 112(3):187-191.
36. Kaplowitz LG, Baker D, Gelb L, Blythe J, Hale R,
Frost P et al. Prolonged continuous acyclovir treatment of normal adults with
frequently recurring genital herpes simplex virus infection. The Acyclovir
Study Group. JAMA 1991; 265(6):747-751.
37. Krasny HC, Liao SH, de Miranda P, Laskin OL, Whelton
A, Lietman PS. Influence of hemodialysis on acyclovir pharmacokinetics in
patients with chronic renal failure. Am J Med 1982; 73(1A):202-204.
38. Kurtz T. Safety and efficacy of long-term suppressive
cyclovir treatment of frequently recurring genital herpes: year 5 results. 30th
Intersci Conf Antimicrob Agents Chemother 1990;270.
39. Laskin OL, Longstreth JA, Whelton A, Krasny HC,
Keeney RE, Rocco L et al. Effect of renal failure on the pharmacokinetics of
acyclovir. Am J Med 1982; 73(1A):197-201.
40. Lau RJ, Emery MG, Galinsky RE. Unexpected
accumulation of acyclovir in breast milk with estimation of infant exposure.
Obstet Gynecol 1987; 69(3 Pt 2):468-471.
41. Lehrman SN, Douglas JM, Corey L, Barry DW. Recurrent
genital herpes and suppressive oral acyclovir therapy. Relation between
clinical outcome and in-vitro drug sensitivity. Ann Intern Med 1986;
42. Marlowe S, Douglas J, Corey L, Schnipper L,
Crumpacker C. Sensitivity of HSV genital isolates after oral acyclovir. 24th
Interscience Conf Antimicrob Ag Chemother, Washington, DC, October 8-10 1984.
43. Mattison HR, Reichman RC, Benedetti J, Bolgiano D,
Davis LG, Bailey-Farchione A et al. Double-blind, placebo-controlled trial
comparing long-term suppressive with short-term oral acyclovir therapy for
management of recurrent genital herpes. Am J Med 1988; 85(2A):20-25.
44. McLaren C, Sibrack CD, Barry DW. Spectrum of
sensitivity of acyclovir of herpes simplex virus clinical isolates. Am J Med
45. McLaren C, Ellis MN, Hunter GA. A colorimetric assay
for the measurement of the sensitivity of herpes simplex viruses to antiviral
agents. Antiviral Res 1983; 3(4):223-234.
46. McLaren C, Corey L, Dekket C, Barry DW. In vitro sensitivity to acyclovir in genital herpes simplex viruses from
acyclovir-treated patients. J Infect Dis 1983; 148(5):868-875.
47. Mertz GJ, Critchlow CW, Benedetti J, Reichman RC,
Dolin R, Connor J et al. Double-blind placebo-controlled trial of oral
acyclovir in first-episode genital herpes simplex virus infection. JAMA 1984;
48. Mertz GJ, Jones CC, Mills J, Fife KH, Lemon SM,
Stapleton JT et al. Long-term acyclovir suppression of frequently recurring
genital herpes simplex virus infection. A multicenter double-blind trial. JAMA
49. Mertz GJ, Eron L, Kaufman R, Goldberg L, Raab B,
Conant M et al. Prolonged continuous versus intermittent oral acyclovir
treatment in normal adults with frequently recurring genital herpes simplex
virus infection. Am J Med 1988; 85(2A):14-19.
50. Meyer LJ, de Miranda P, Sheth N, Spruance S.
Acyclovir in human breast milk. Am J Obstet Gynecol 1988; 158(3 Pt 1):586-588.
51. Mindel A, Weller IV, Faherty A, Sutherland S, Hindley
D, Fiddian AP et al. Prophylactic oral acyclovir in recurrent genital herpes.
Lancet 1984; 2(8394):57-59.
52. Morton P, Thomson AN. Oral acyclovir in the treatment
of herpes zoster in general practice. N Z Med J 1989; 102(863):93-95.
53. Naib ZM, Nahmias AJ, Josey WE, Zaki SA. Relation of
cytohistopathology of genital herpesvirus infection to cervical anaplasia.
Cancer Res 1973; 33(6):1452-1463.
54. Nilsen AE, Aasen T, Halsos AM, Kinge BR, Tjotta EA,
Wikstrom K et al. Efficacy of oral acyclovir in the treatment of initial and
recurrent genital herpes. Lancet 1982; 2(8298):571-573.
55. Nusinoff-Lehrman S, Hunter G, Rogers J, Corey L,
Davis G. The in vitro acyclovir sensitivity of herpesvirus shed by patients
receiving suppressive oral therapy. 24th Interscience Conf Antimicrob Ag
Chemother, Washington, DC, October 8-10 1984;(Abstract #1015).
56. O'Brien JJ, Campoli-Richards DM. Acyclovir. An
updated review of its antiviral activity, pharmacokinetic properties and
therapeutic efficacy. Drugs 1989; 37(3):233-309.
57. Pahwa S, Biron K, Lim W, Swenson P, Kaplan MH, Sadick
N et al. Continuous varicella-zoster infection associated with acyclovir
resistance in a child with AIDS. JAMA 1988; 260(19):2879-2882.
58. Parker AC, Craig JI, Collins P, Oliver N, Smith I.
Acyclovir-resistant herpes simplex virus infection due to altered DNA polymerase.
Lancet 1987; 2(8573):1461.
59. Parris DS, Harrington JE. Herpes simplex virus
variants restraint to high concentrations of acyclovir exist in clinical
isolates. Antimicrob Agents Chemother 1982; 22(1):71-77.
60. Preblud SR, Arbeter AM, Proctor EA, Starr SE, Plotkin
SA. Susceptibility of vaccine strains of varicella-zoster virus to antiviral
compounds. Antimicrob Agents Chemother 1984; 25(4):417-421.
61. Reichman RC, Badger GJ, Mertz GJ, Corey L, Richman
DD, Connor JD et al. Treatment of recurrent genital herpes simplex infections
with oral acyclovir. A controlled trial. JAMA 1984; 251(16):2103-2107.
62. Shah GM, Winer RL, Krasny HC. Acyclovir
pharmacokinetics in a patient on continuous ambulatory peritoneal dialysis. Am
J Kidney Dis 1986; 7(6):507-510.
63. Sibrack CD, Gutman LT, Wilfert CM, McLaren C, St
Clair MH, Keller PM et al. Pathogenicity of acyclovir-resistant herpes simplex
virus type 1 from an immunodeficient child. J Infect Dis 1982; 146(5):673-682.
64. Straus SE, Seidlin M, Takiff H, Jacobs D, Bowen D,
Smith HA. Oral acyclovir to suppress recurring herpes simplex virus infections
in immunodeficient patients. Ann Intern Med 1984; 100(4):522-524.
65. Straus SE, Takiff HE, Seidlin M, Bachrach S, Lininger
L, DiGiovanna JJ et al. Suppression of frequently recurring genital herpes. A
placebo-controlled double-blind trial of oral acyclovir. N Engl J Med 1984;
66. Straus SE, Croen KD, Sawyer MH, Freifeld AG, Felser
JM, Dale JK et al. Acyclovir suppression of frequently recurring genital
herpes. Efficacy and diminishing need during successive years of treatment.
JAMA 1988; 260(15):2227-2230.
67. Vinckier F, Boogaerts M, De Clerck D, De Clercq E.
Chronic herpetic infection in an immunocompromised patient: report of a case. J
Oral Maxillofac Surg 1987; 45(8):723-728.
68. Wade JC, Newton B, McLaren C, Flournoy N, Keeney RE,
Meyers JD. Intravenous acyclovir to treat mucocutaneous herpes simplex virus
infection after marrow transplantation: a double-blind trial. Ann Intern Med
69. Wade JC, McLaren C, Meyers JD. Frequency and
significance of acyclovir-resistant herpes simplex virus isolated from marrow
transplant patients receiving multiple courses of treatment with acyclovir. J
Infect Dis 1983; 148(6):1077-1082.