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Regression of herpes viral infection symptoms using melatonin and SB-73:

Comparison with Acyclovir

Article  in  Journal of Pineal Research · June 2008

DOI: 10.1111/j.1600-079X.2007.00538.x · Source: PubMed

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J. Pineal Res. 2008  2008 The Authors
Journal compilation  2008 Blackwell Munksgaard
Doi:10.1111/j.1600-079X.2007.00538.x
Journal of Pineal Research

Regression of herpes viral infection symptoms using melatonin

and SB-73: comparison with Acyclovir

Abstract: Infection with Herpes simplex virus type 1 (HSV-1) typically Odilon da Silva Nunes (in
causes lesions of the mouth, face, skin, esophagus, or brain. Herpes simplex memoriam) and Ricardo de Souza
virus type 2 (HSV-2) usually causes infections of the genitals, rectum, skin, Pereira
hands, or meninges. The herpes viruses are a major cause of blindness from Universidade Federal de São Carlos,
keratitis. The usual drugs used for herpes are Vidarabine, Acyclovir, Departamento de Fisioterapia, Dr. Nivaldo’s
laboratory, Rod. Washington Luı́s, São Carlos,
Penciclovir and Ganciclovir; they are associated with several complications.
SP, Brazil
The aim of this study was to investigate if a formulation containing 2.5 mg
melatonin and 100 mg SB-73 would help patients with herpes, and to Key words: antiviral properties, fatty acids,
compare the preparation with 200 mg Acyclovir. SB-73 is a mixture of herpes, immunomodulation,
magnesium, phosphate, fatty acids extracted from Aspergillus sp. which has immunostimulant, interleukin, linoleate,
magnesium, melatonin, palmitoleate,
anti-herpes virus properties. A single blind randomized study was performed phosphate, SB-73
in which 70 patients underwent treatment using the supplement cited
Address reprint requests to Prof. Dr Ricardo
above (group A) and 75 received treatment of 200 mg Acyclovir (group B). de Souza Pereira, Rua Jean Nassif Mokarzel,
Sixty-seven patients of the group A (95.7%) reported a complete regression 174 – Barão Geraldo, Campinas, SP,
Brazil – cep: 1308-070.
of symptoms after 7 days of treatment. By comparison, 64 subjects (85.3%)
E-mail: ricardodesouzapereira@yahoo.com.br
of the Acyclovir reported regression of symptoms in the same period. There
Received September 17, 2007;
was statiscally significant difference between the groups (P < 0.05). accepted October 31, 2007.

inhibitors of viral DNA synthesis. Other agents employing

Introduction
Herpes simplex virus 1 and 2 (HSV-1 and HSV-2) are two
strains of the herpes virus family, Herpesviridae, which
cause infections of the mouth, face, skin, esophagus, or
brain (HSV-1) and genitals, rectum, skin, hands, or
meninges (HSV-2). HSV-1 and 2 are also referred to as
Human Herpes Virus 1 and 2 (HHV-1 and HHV-2) [1].
Both cause serious infections in neonates [2].
Herpes infections are marked by painful, watery blisters
in the skin or mucous membranes (such as the mouth or
lips) or on the genitals. The blisters resemble those seen in
chickenpox [1]. It is estimated that as many as one in five
Americans have genital herpes, a lifelong (but manageable)
infection, yet up to 90% of those with herpes are unaware
they have it [3].
With more than 50 million adults in the US with genital
herpes and up to 1.6 million new infections each year, some
estimates suggest that by 2025 up to 40% of all men and
half of all women could be infected [4–6].
The first systemically administered anti-herpes virus
agent, Vidarabine, was approved by the Food and Drug
Administration in 1977 [2]. However, its toxicities restricted
its use to life-threatening infections of HSV and varicella
zoster virus (VZV). The discovery and development of
Acyclovir, approved in 1982, provided the first effective
treatment for less severe HSV and VZV infections in
ambulatory patients. Intravenous Acyclovir is superior to
Vidarabine in terms of efficacy and toxicity in HSV
encephalitis and in VZV infections of immunocompromised
patients. Acyclovir is the prototype of a group of antiviral
agents that are phosphorylated intracellularly by a viral
kinase and subsequently by host cell enzymes to become
this strategy include Penciclovir and Ganciclovir [2].
Acyclovir is ineffective therapeutically in established cyto-
megalovirus (CMV) infections but has been used for CMV
prophylaxis in immunocompromised patients [7].
Clinical failures of antiviral therapy may occur with
drug-sensitive virus in highly immunocompromised patients
[2]. Most drug-resistant viruses are recovered from immu-
nocompromised patients with high viral replicative loads
and repeated or prolonged courses of antiviral treatment
(influenza A virus is an exception) [2]. Current antiviral
agents do not eliminate nonreplicating or latent virus,
although some drugs have been used effectively for chronic
suppression of disease reactivation.
Interferons have been shown to have virologic and/or
clinical effects in various herpesvirus infections. However,
interferon generally is associated with additional side effects
and inferior clinical benefits compared to conventional
antiviral therapies [8].
In order to promote the regression of the symptoms of
herpes virus infection, a formulation with 2.5 mg melatonin
and 100 mg SB-73, which has no significant side effects, was
developed. This formulation is based on information
published previously [9–17] and publications indicating
that melatonin has known immunomodulatory properties.
One function of melatonin is to induce the production of
interleukin-1 beta (IL-1b) which can be beneficial in virus
infection [18, 19]. As the formula contains natural com-
pounds, it may present fewer side effects than medications
currently used in clinical medicine.
SB-73, a mixture of magnesium, phosphate, fatty acids
and protein extracted from Aspergillus oryzae; this formu-
lation has anti-herpes virus activity [10, 11, 13–15], but it

1
Nunes and Pereira
has slight adverse effects which were eliminated when
melatonin was added. The potential ability of melatonin to
act synergistically with several other medications by
enhancing their activity and reducing their adverse effects
has placed melatonin among the new and promising agents
in immunotherapy [19–22].
Materials and methods
Biochemicals
Melatonin was obtained from Galena (Campinas, SP,
Brazil). SB-73 is produced by means of the Aspergillus
oryzae fungus, cultured in a culture medium consisting of
an aqueous solution of oat and gelatin in the proportion of
10:1 oat:gelatin by weight for a period of 5 days in a
bioreactor kept between 20 and 35C, with pH stabilized in
the range of 2–4, under low aeration ()2 L/min) and slow
agitation (five rotations per hour), followed by mechanical
filtration of the culture medium. The compound was
extracted with ethyl acetate and precipitated at pH 11
using a 20% aqueous solution of sodium carbonate. It was
washed of the crystals in ethyl acetate and ether; and dried.
For use in biological systems, the compound was formu-
lated in injectable form or in the form of polymeric
microspheres. The injectable form was obtained by dissolv-
ing the compound in a phosphate-saline buffer solution
(PBS) (0.1 m), and was stable for 30 days when kept
between 5 and 8C. The form of polymeric microspheres
was achieved by preparing an emulsion containing the
compound, obtained by solvent evaporation, using a
biodegradable polymer, i.e. poly(epsilon-caprolactone),
and poly(vinyl alcohol) (PVA) as a surfactant agent
[10, 11].
The formulation was prepared by a trained pharmacist.
Melatonin and SB-73 or Acyclovir were inserted into
identical capsules to ensure a single-blind study. A set
containing seven gelatin capsules, was used to treat patients
from group A for 7 days. Patients received a 7-days supply
of medication. Another set, containing 25 gelatin capsules,
was used by patients of group B. A total of 145 sets were
prepared for use by 145 patients. The starting date of the
therapy was recorded for each patient.
Patients and inclusion criteria
Patients with herpes type 1 and 2 were enrolled into this
prospective, randomized, parallel-group comparative, sin-
gle blind, single-center study. Patients with a history of
recurrent, transient episodes were considered eligible.
Completed questionnaires about the adverse events and
compliance were obtained from all the 145 patients.
Exclusion criteria
Patients were excluded from study participation if they had
hepatic or renal impairments. Also, a history of hypersen-
sitivity to Acyclovir, conditions characterized by gastroin-
testinal malabsorption, pregnancy or nursing, receiving
immunosuppressive or other antiviral therapy, individuals
were also excluded.
2
Outcome measures
The efficacy of treatment was evaluated as the percentage of
lesions healed by day 7. The time to healing, time to
cessation of pain, discomfort or itching, the percentage of
abortive episodes and safety were also measured.
Safety and tolerability were evaluated by recording
adverse events for both groups.
Randomization
Patients who qualified were randomized; 70 patients
received the formula containing 2.5 mg melatonin and
100 mg SB-73 (group A) (it was taken as a capsule once a
day for 7 days) and 75 patients received 200 mg Acyclovir
(group B). Acyclovir was taken five times daily for 5 days.
No other medication was allowed.
University ethics committee
The data were evaluated and approved by University Ethics
Committe in December, 2005. In order to protect intellec-
tual property, a patent was registered. The study was
conducted in accordance with the Declaration of Helsinki.
Statistical analysis
The results were evaluated with per-protocol (PP) analysis
(which included only patients who completed the study)
and intention-to-treat (ITT) analysis (which included also
patients who did not complete the study). The demographic
and clinical characteristics of the two groups (A and B)
were compared by chi-squared test or Fisher¢s exact test.
The results of treatment were compared by chi-squared test.
P < 0.05 was considered statistically significant.
Results
One hundred and forty-five patients with herpes entered the
surveillance program between March, 1992, and August,
2007. Mean age at enrollment was 44.1 yr, with a range
from 18 to 80 yr; 54.3% were women in group A and and
they were 54.7% in group B. The number of patients
recruited per year increased over the course of the study as
the practice grew; the median year of enrollment was 1999.
In terms of geographical area, the subjects are from 21
different cities and towns from five Brazilian states: 141
patients (97.2%) are from São Paulo, one (0.68%) from
Minas Gerais, one (0.68%) from Paraná, one (0.68%) from
Rio de Janeiro and one (0.68%) from Goiás. In terms of
social class 32 patients (22%) are wealthy, 101 (69.7%) are
from middle class and 12 (8.3%) are poor. In terms of
education 31 (21.4%) have a university degree, 77 (53.1%)
have high school diploma, 37 (25.5%) did not high school.
The subjects were divided into two groups: seventy
patients used the formulation containing melatonin and
SB-73 for 7 days without using any other medication for
herpes (group A) and, for comparison, the remainder
(n = 75 volunteers) used Acyclovir (group B). The demo-
graphic and clinical characteristics of the 145 subjects in the
two groups are shown in Tables 1 and 2.
 Treatment of herpes virus infection

Table 1. Baseline characteristics of patients enrolled in the current Table 4. Adverse events during the treatment with melato-
study nin + SB-73 (group A) or Acyclovir (group B)

Group A (n = 70) Group B (n = 75) Group A (n = 70) Group B (n = 75)

Gender (M/F) 32/38 34/41 Diarrhea 0 (0%) 5 (6.6%)

Age (yr) (S.D.) 44.3 (18.9) 43.4 (15.8) Headache 0 (0%) 10 (13.3%)
Previous medication 64 (91.4%) 12 (16.0%) Nausea 0 (0%) 6 (8.0%)
for HSV Abdominal pain 0 (0%) 3 (4.0%)
Dizziness 0 (0%) 2 (2.6%)
HSV, Herpes simplex virus. Asthenia 0 (0%) 4 (5.3%)
Dyspepsia 0 (0%) 1 (1.3%)
Rhinitis 0 (0%) 5 (6.6%)
Pain 0 (0%) 4 (5.3%)
Table 2. Gender of the patients (M = males; F = females) and
Somnolence 63 (90%) 1 (1.3%)
type of herpes

Group A (M/F) Group B

(melatonin + SB-73) (M/F) (Acyclovir) Table 5. Lesion healing time in patients treated with melato-
nin + SB-73 (group A) or Acyclovir (group B)
Labialis 10/20 12/22
Genital 10/4 9/7 Median event duration, days
Other 12/14 13/12
Total 32/38 34/41 Type Group A (M/F) Group B (M/F)

Labialis 1.5/1.7 4.8/4.7

After finishing the 7 days of treatment, total regression of
the symptoms was observed in 95.7% of the subjects who
took the formulation. They reported total relief of the
symptoms after 7 days. Completed questionnaires about
the adverse events and compliance were obtained from all
the 145 patients. Sixty-three patients (90%) of group A
mentioned somnolence and sleep improvement.
Sixty-four patients of group B (85.3%) were healed after
5 days of treatment and the remainder continued to feel all
symptoms described before starting the treatment. Two
patients (2.7%) of group B withdrew from the study
because of persistent nausea and dyspepsia caused by
Acyclovir.
In terms of healing of all symptoms, there was a
statiscally significant difference between groups A and B;
the active healing rate was 95.7% (67 of 70) in group A
(subjects who used melatonin and SB-73), and 85.3% (64 of
75) in group B (subjects who took Acyclovir) (P < 0.05)
(Table 3).
Patients of group B related more side effects than those of
group A. Only somnolence was reported for formulation of
melatonin and SB-73 (group A) during the treatment
(Table 4). This fact may relate to the sleep-promoting
activity of melatonin [23–26].
Melatonin/SB-73 significantly reduced time to lesion
healing compared with Acyclovir (P < 0.05). Median
healing times were 2.0 and 4.9 days, respectively (Table 5).
The formulation significantly decreased the duration of
pain and discomfort compared with Acyclovir (P < 0.05).
Table 3. Healing rates of patients in the two treatment groups
Group A
(n = 70) Group B
(melatonin + (n = 75)
SB-73) (Acyclovir) P v2
PP analysis (%) 67/70 (95.7%) 64/73 (87.7%) 0.082
ITT analysis (%) 67/70 (95.7%) 64/75 (85.3%) 0.034
Genital 2.8/2.4 4.7/5.2
Other 2.9/1.7 4.9/4.6
Total mean average 2.11 4.81
At day 2, patients of group A related that pain completely
disappeared. Even three patients who had the lesions
unhealed at day 7 declared that pain disappeared.
In the first 48 hr of treatment, melatonin and SB-73 had
better effect reduction of lesion number (48%) and area
(78%) than Acyclovir: 5% and 29%, respectively (R < 0.05).
Case report 1:
A 20-yr-old white male patient with chronic Herpes simplex
type1 had ulcerations in his lips and roof of the mouth. He
had these symptoms for more than 10 yr during which he
was treated with Zovirax (GlaxoSmithKline, Rio de
Janerio, RJ, Brazil) (Acyclovir) prescribed by a physician.
The treatment did not produce even partial relief of his
symptoms. He could no longer eat properly because of the
acute pain (Fig. 1A). After many years of treatment with
Acyclovir, his physician told him to seek other advice and
he brought us his medical records. We prescribed the above
mentioned formulation encapsulated in gelatin capsules
[melatonin (2.5 mg) and SB-73 (100 mg)]. After 7 days of
treatment (taken a capsule a day), his lips were healed
(Fig. 1B). He took the formulation for 30 days. This
treatment took place 12 yr ago (September, 1995) and the
patient said that the symptoms never returned. The patient
stopped taking Acyclovir before starting the treatment with
our formulation. At the end of treatment, the patient had
taken seven capsules during a week. Fig. 1A shows patient
before the treatment and Fig. 1B after 7 days of treatment.
He experienced no side effects of the formulation.
Case report 2:
3.007
A 21-yr-old white female patient with chronic Herpes
4.473
simplex type1 had ulcerations in her lips. She had these

3
Nunes and Pereira
(A)
(B)
Fig. 1. Photographs of the face of patient (group A) with lips in-
fected by Herpes simplex at two time periods in September 1995:
(A) before treatment; (B) after 7 days of treatment (formulation
taken three times a week).
symptoms for more than 3 yr and she was treated with
Zovirax prescribed by a physician. The treatment did not
produce even partial relief of her symptoms (Fig. 2A). She
could no longer eat properly because of the acute pain.
After treating 11 months with Acyclovir, her physician told
her to seek other advice and she brought us his medical
records. We prescribed the above mentioned formulation
encapsulated in gelatin capsules [melatonin (2.5 mg) and
SB-73 (100 mg)]. After 7 days of treatment (she took a
capsule a day), her lips were healed (Fig. 2B). This event
took place 6 yr ago (July, 2001) and the patient said that
the symptoms never returned. The patient stopped taking
Acyclovir before beginning treatment with the combina-
tion. At the end of treatment, the patient had taken seven
capsules during a week. Fig. 2A shows patient before the
treatment and Fig. 2B after 7 days of treatment. She
experienced no side effects of the formulation.
Discussion
The regression or healing of viral infections may be related
to the fact that melatonin possesses immunomodulatory,
4
(A)
(B)
Fig. 2. Photographs of the face of patient (group A) with lips
infected by Herpes simplex at two time periods in June 28, 2001:
(A) before treatment; (B) after 7 days of treatment (formulation
taken daily during 7 days).
antioxidative and antiinflammatory properties [19–22].
Also, it has been shown to be beneficial in virus infection
[18, 27]. In addition, melatonin induces the production of
interleukin-1 beta (IL-1b), a cytokine capable of inducing
increased expression of inducible nitric oxide synthase; the
activity of this enzyme is increased in the brain of mice
infected with the virus [18, 27].
SB-73 has a very simple chemical structure (Fig. 3).
These are combined with palmitoleic and linoleic acids. SB-
73 contains 11.6% total lipids (22.7% of palmitoleic acid,
43.3% of linoleic acid, and 34.0% of oxidized linoleic acid),
27.0% of magnesium ions, 13.0% ammonium ions, 47.9%
phosphate, and 0.5% protein (Fig. 3) [10, 11]. Experiments
performed in vitro demonstrated that magnesium ions and
PO4– are responsible for the induction and maintenance of
cell resistance to HSV-1 infection [28]. Palmitoleic and
Linoleic acids display virucidal properties [29]. It is
assumed that the proteinaceous portion of SB-73 has no
pharmacological effect.
Currently known effects of SB-73 on immune system
components include stimulation of production of T lym-
phocytes and cytokines, particularly interleukin-2 (IL-2)
and interferon-gamma (IFN-gamma) leading to increased
activity of natural killer (NK) cells. SB-73 given either prior
or after viral infection, increased the number of bone
marrow granulocyte-macrophage progenitor cells (CFU-
GM) [9–17]. As it is known that IFN-gamma has immu-
noregulatory, antiviral activities, it may be hypothesized
that the action of SB-73 involves immunotherapeutic

–
O
–
O P
–
O Americana, SP, Brazil), for his technical support.
O
++
Mg
O O
– O
O
P
–
– O P +
O
O
– P
–
–
O USA, 2006; pp. 1119–1144.
O –
O O
++
Mg
(
–
OO
O LINOLEATE
– O
O P
– dence of herpes simplex virus type 2 infection in the United
– O
O –
( OO
PALMITOLEATE
Fig. 3. Chemical structure of SB-73. It was identified using infor-
mation of gas chromatography, X-ray diffraction and Nuclear
Magnetic Resonance [12]. The formulation used for treatment in
this study was melatonin combined with SB-73.
mechanisms. Natural killer (NK) cells and T lymphocytes
are also able to destroy virus-infected cells by directly
targeting them [9–17].
The immunosuppression reversion associated with SB-73
has also been observed in experimental models for infec-
tious diseases, and resulted in the protection of the host and
in high survival rates of animals, even for those experi-
mentally infected with lethal doses of infectious agents [9–
17]. The results shown in this paper are significant, as the
patients, who used this formulation, reported fewer side
effects than patients who used Acyclovir.
It is possible, given the anti-viral effects of melatonin [19],
that the benefits of the formulation derived primarily from
the indole. Also, the reader is reminded that the study was
blinded to the patients but not to the physician; thus, there
is same possibility of bias in interpretation of the results of
the treatment.
The herpes viruses are a major cause of blindness from
keratitis [30]. The formulation here in causes regression of
herpes infection type 1 and 2. As it is considered a
supplement, with natural ingredients, it may find utility in
the treatment of herpes infections by individuals who
cannot afford prescription drugs.
Acknowledgments
The authors wish to thank Prof. Ângela Maria Gollner,
PhD, MD (School of Medicine, Federal University of Juiz
de Fora and CITO, Serviço Médico Especializado, Anat-
omia Patológica e Citopatologia, Juiz de Fora, MG, Brazil)
and Prof. Raul Fernando Binato Lamin, PhD, MD (School
of Medicine, Federal University of Juiz de Fora and Santa
Treatment of herpes virus infection
Casa, Juiz de Fora, MG, Brazil), Prof. Dr Carol Collins
and Prof. Dr Roy Bruns (IQ, UNICAMP, Campinas, São
Paulo, Brazil) for their critical readings and Prof. Armando
Semedo Mendes, PharmD (Faculdade de Americana,
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