Field, Hugh J., and Graham Darby.

"Pathogenicity in Mice of Strains of Herpes Simplex Virus

Which Are Resistant to Acyclovir In Vitro and In Vivo." Antimicrobial Agents and
Chemotherapy 17 (1980): 209-16. Print.
Mice infected with three different isolates of herpes simplex virus (HSV) and treated with
acyclovir (ACV) showed low levels of virus replication during the phase of infection. However,
virus from mice did not show increased resistance to ACV. In contrast, resistant virus was
passaging HSV in the presence of the drug. The majority of ACV-resistant genes put
undetectable levels of HSV-specified thymidine kinase (TK), the enzyme responsible for
phosphorylating ACV in infected cells. The TK--resistant genes were weakened when injected
into mice. One mutant gene is described which was highly resistant to ACV and continued
virulence for mice. The speculation all started when the researchers were performing in vitro
cultures for different HSV strains. Then, they found strains of HSV which are poor TK inducers
which may be resistance to drugs, especially to Acyclovir. At first they were only present in cell
cultures, then they found strains in mice that were also resistant to Acyclovir. They used 3-weeks
old female mice for the experiments. Since they were not testing with HSV-2, but with HSV-1,
the main area of infection was the ear. They took consider of the thickness of the ears and other
factors that might influence the results. Despite the effective reduction, virus replication in the
ear continued and reached a peak 4 to 6 days after inducing with drugs.
The article was very interesting; the virus cannot be treated completely, especially HSV.
The idea of researching in depth about the cause of immunity and resistant to certain drugs was
fascinating to read about. Even though the type of HSV we are focusing on was different, this
article help show the specific details of drug-resistant strains. This article supports the reasons
behind why people start developing tolerance over certain drugs, and eventually have to switch
products or take higher doses in order to get the same effect. Also, this experiment can be
supported by Darwin's Natural Selection theory; drug-resistant strains will survive, reproduce,
and eventually cause drugs to not work as efficiently as before anymore. Overall, this paper can
be very helpful in my research, since it deals with HSV strains that are ineffective of Acyclovir.
Using their research, we can maybe expand on the reasons behind and try to find something out
to avoid situations like this.

Kimberlin, David W. "Safety and Efficacy of High-Dose Intravenous Acyclovir in the

Management of Neonatal Herpes Simplex Virus Infections." Pediatrics (2006): 230-38.
Print.
In this article, the safety of high-dose (HD) acyclovir for the treatment of neonatal herpes
simplex virus (HSV) disease was tested. In addition to the safety, the virologic efficacy of HD
acyclovir was also tested during the treatment. Neonatal herpes simplex virus (HSV) infection
continues to cause significant morbidity and mortality despite significant advances in treatment;
the baby can be infected with HSV when having direct contact with infected vaginal secretions
during delivery. The researchers try to figure out a way to reduce mortality and morbidity of
infants. They try different way to treat the virus on neonatal babies, including antiviral therapy,
Polymerase chain reaction (PCR)-guided therapy, and oral suppression therapy. However, in this
article, it focuses on investigating the therapeutic efficacy and safety of high-dose acyclovir in
the treatment of neonatal HSV disease. In this study, a course of 21 days was used. Sixteen
patients received intermediate-dose of acyclovir (45 mg/kg/day) and 72 patients received highdose of acyclovir (60 mg/kg/day). Data were later compared to see any effects. Interestingly,
babies of high-dose acyclovir had an increased survival rate compared to babies treated with
standard-dose acyclovir. Also, there wasn't any severe or significant impacts of high-dose
acyclovir. The babies were in normal condition. However, depending on the types of virus
(HSV-1 or HSV-2), there was a significant difference in the number of babies returning to
normal state between high-dose and standard-dose acyclovir groups.
Even though this study focuses primarily on pediatric aspects of how to deal with herpes
virus, it was interesting to read about how herpes affect people in different age groups. Treating
babies with any virus infections are difficult and dangerous due to the fragility of the newborns.
They cannot go through the same process adults go through in treating viruses. Especially they
need to be more cautious about using drugs on babies and watch out for not overdosing it. I was
surprised to see that giving higher dosage on Acyclovir to 12 months old baby works better than
those who were given standard dosage. However, I assume that the effectiveness is also
influenced by the severity of the infection. Using this source, we could study in depth about
treating herpes on newborn babies and different ways to release drugs so it can be effective in
killing most of the virus present in children.

Mindel, Adrian. et al. "Intravenous Acyclovir for the Treatment of Primary Genital Herpes."
Lancet (1982): 697-700. Print.
Genital infection with herpes simplex virus (HSV) is a major and increasing cause of
morbidity in many countries. The primary infection may be severe enough to hospitalize
patients, and recurrences are frequent. The virus has association with fatal diseases such as
carcinoma and other cancer-causing viruses. Patients were informed of the experiment, and some
were excluded from doing so due to age or pregnancy issues. Patients with a severe first attack of
genital herpes were treated with intravenous acyclovir in a randomized, double-blind, placebocontrolled trial. They were taken blood tests to check if other parts of the body was healthy. The
actual drug tests were repeated on the 4th and 7th days of the hospital stay. Patients conditions
were recorded daily for 7 days, and then twice weekly until healing occurred. 15 Patients
received the drug and 15 placebo, and the result showed faster rate of healing time for the
Acyclovir. The healing time, duration of vesicles, new lesion formation, viral shedding, and all
symptoms were significantly shorter in patients treated with acyclovir than in the controls.
Intravenous acyclovir seems to be a safe and effective therapy for patients having their first
attack of genital herpes.
This experiments follows Mindel's previous research on how Acyclovir is more effective
than inosine pranobex. He went farther and tried to see if Acyclovir is actually effective on firstattack genital herpes patients. With the same method and same procedure, Mindel successfully
proved the effectiveness of the drug. The procedure helps to support the validity of the research
because Mindel and contributors highlighted all the exceptions and details that directs the readers
to an answer with little or no assumptions. The paper includes specific details of the methods,
how patients were gathered, the routines, etc. Like the previous paper, one thing readers might be
unsure is the date of publication. Since this was published more than 20 years ago, current
researches might reject this experiment.

Mindel, A. et al. "Treatment of First-Attack Genital HerpesAcyclovir versus Inosine

Pranobex." Lancet (1987): 1171-73. Print.
77 patients with a first attack of genital herpes were entered into a double-blind trial to
compare the efficacy of acyclovir with that of inosine pranobex. 24 patients received acyclovir,
25 inosine pranobex, and 28 both drugs. First-attack genital herpes is a severe illness lasting two
to three weeks, characterized by genital pain and dysuria and often accompanied by systemic
symptoms including malaise, fever, and headaches. Acyclovir is a specific antiherpetic drug
which acts by competing with viral thymidine kinase and also inhibits DNA polymerase.
Unfortunately, the drug does not seem to prevent subsequent recurrences. Inosine pranobex is an
immunomodulator whose action depends upon stimulation of the bodys own immune
mechanism. It is not a specific antiviral agent, but studies have shown that the drug might reduce
the time to heal in patients with first-attack genital herpes. Patients all agreed to sign the
informed consent. Some of the patients were excused due to their age, time availability, use of
other antiviral drugs, etc. Patients were randomly divided to three treatment groups. One group
received active acyclovir and "dummy" inosine pranobex, one received active inosine pranobex
and dummy acyclovir, and the third group received both active acyclovir and active inosine
pranobex. Patients were required to see the doctors every three days a week for six months. The
collected data show that patients treated with acyclovir or both drugs healed more quickly and
had a shorter duration of viral shedding than those treated with inosine pranobex. The usual
symptoms were also shorter with acyclovir than with inosine pranobex. The time of subsequent
recurrences were similar but acyclovir took longer for the virus to recur. This experiment proved
that Acyclovir is the treatment of choice for patients with a first attack of genital herpes.
This source supports the use of the drug Acyclovir, which we are currently using for
making our own implants. The use of double-blind method increases the validity of the
experiment results. The rate of which the virus decreased was significantly faster with Acyclovir
than with inosine pranobex, which shows how much Acyclovir is effective in treating first-attack
genital herpes. Even though this does not mean we can completely eliminate the virus, it can help
slow down the recurrence of the virus and heal the wounds faster. The doctors obtained the data
through a long-term experiment with different types of patients. They also used various methods
to collect results, such as lesioning and blood test. One thing unsure about this is that the paper
was published in 1987, and the current data might show different results.

Wald, Anna. et al. "Frequent Genital Herpes Simplex Virus 2 Shedding in Immunocompetent
Women; Effect of Acyclovir Treatment." Journal of Clinical Investigation 99 (1997):
1092-97. Print.
The researchers performed a series of studies to evaluate the frequency and pattern of
HSV-2 reactivation using both viral isolation and HSV PCR assay. Viral shedding refers to the
expulsion and release of virus progeny following successful reproduction during a host-cell
infection. Herpes simplex virus type 2 (HSV-2) is the major cause of genital herpes and one of
the most frequent sexually transmitted diseases worldwide. For the research, four women with
clinical evidence of genital herpes were pilot trialed and were followed without antiviral therapy
for 4060 consecutive days. The tissues of HSV-2 area were removed to perform lesioning. After
the pilot trial, the results demonstrated a much higher frequency of HSV detection in genital
area. Then they evaluated whether HSV shedding was altered by antiviral chemotherapy. The 24
of 34 women who participated in a double-blind, placebo-controlled, crossover study took oral
acyclovir twice a day to evaluate the effect of antiviral therapy on subclinical shedding of HSV.
It turns out Acyclovir blocks HSV replication, but some of the viral genes have never been
detected during latent infections. If PCR positivity by acyclovir is shown, that would indicate the
presence of replicating potentially infectious virus on mucosal surfaces, which are linings of
mostly endodermal origin. The researchers used various methods (laboratory, in vivo, statistical)
to measure why there are HSV-2 shedding on mucosal surfaces and what are the pathogenic
mechanisms.
The wording of the paper was very hard to comprehend. The research they have done was
also confusing to follow because there were multiples of different experiments explained at the
same time. Most of the terms they used were unfamiliar to me, so I had to frequently look up the
words. They included many statistical data, but they failed to thoroughly explain what each table
was talking about. The research was well-planned. There was enough sample size, performing
different tests. The researchers used different methods to collect and analyze data so they are as
accurate as possible. They were still unsure of the pathogenic mechanisms causing HSV-2
shedding on mucosal surfaces after the research, but they did find that acyclovir slows down the
virus. It would have been nicer if the paper included explanations of general methods and terms
they included.