IE83322B1 - Method and composition for the treatment of herpes related disorders - Google Patents
Method and composition for the treatment of herpes related disordersInfo
- Publication number
- IE83322B1 IE83322B1 IE1992/1141A IE921141A IE83322B1 IE 83322 B1 IE83322 B1 IE 83322B1 IE 1992/1141 A IE1992/1141 A IE 1992/1141A IE 921141 A IE921141 A IE 921141A IE 83322 B1 IE83322 B1 IE 83322B1
- Authority
- IE
- Ireland
- Prior art keywords
- neuraminidase
- disease state
- herpes
- pharmaceutically acceptable
- acceptable carrier
- Prior art date
Links
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- 108010006232 Neuraminidase Proteins 0.000 claims description 59
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
Description
PATENTS ACT 1992
METHOD AND COMPOSITION FOR THE TREATMENT OF HERPES RELATED DISORDERS
Molecular Rx, Inc.
w E83322
METHOD AND COMPOSITION FOR THE TREATMENT
OF HERPES RELATED DISORDERS
Field of the Invention
The present invention is related to the use of
neuraminidase for the preparation of a pharmaceutical
composition for the treatment of herpes related disorders. More
particularly, the present invention relates to the use of
neuraminidase for the preparation of a pharmaceutical
composition for the treatment of a herpes related disorder at Very
low concentrations.
Background of the Invention
As used herein, the term “neuraminidase” means
any protein that has neuraminidase activity or has an amino
acid sequence that is similar to a protein which has
neuraminidase activity. The neuraminidase that can be used to
practice the present invention can also be inactivated enzyme
or part of the enzyme. The term “herpes related disorder”
means any disorder that is effected or mediated by a herpes
virus infection. The term “herpes virus” means any virus in
the herpes family. These include, but are not limited to,
herpes simplex types 1 and 2, Epstein-Barr viruses,
varicellazoster, cytomegaloviruses, Herpesvirus simiae and
human herpesvirus—6.
Herpes Virus Infections
More than 50 herpes viruses are known to infect
over 30 different species. A.J. Nahmias and B. Roizman, New
Engl. J. Med. 289, pp. 667-674 (1973). The most clinically
significant of these are the two naturally occurring variants of
herpes simplex virus (HSV). Man is the sole reservoir of this
virus. The herpes simplex virus was first isolated in 1920. B.
Lipschutz, Arch. Derm. Syph. (Berl) 136, pp.428-482 (1921).
In 1961, two serotypes were differentiated. Generally, HSV—l
infects non-genital sites while HSV-2 infects genital sites. It is
possible, however, to isolate HSV-1 in a genital herpes case.
Transmission is direct. Localized ulcers or lesions in the oral
cavity, eye, skin or reproductive tract usually develop after
infection. Dissemination can cause encephalitis in neonates and
the immunosuppressed. The virus can remain latent,
presumably for years, until a relapse is triggered by stress,
environmental factors, other medications, food additives or
food substances (see A.J. Nahmias and B. Roizman, New Engl.
J. Med. 13, pp. 667-674 (1973); W.E. Rawls, E.H. Lennette
(eds.), Laboratory Diagnosis of Viral Infections, Marcel
Dekker, Inc., N.Y., pp. 313-328 (1985)).
Another pathogen from the herpes virus group is
the Epstein-Barr virus. Discovered in the 1960’s, it is the
principal etiologic agent of infectious mononucleosis and has
been associated with Burkitt’s lymphoma and nasopharyngeal
carcinoma malignancies (see W. Henle and G. Henle, M.A.
Epstein and B.G. Achong (eds.), THE EPSTEIN-BARR VIRUS,
Springer-Verlag, Berlin, p. 297 (1979)). Infectious
mononucleosis is characterized by lymphadenopathy, fever and
pharyngitis. As with the HSV variants, the Epstein-Barr virus
may establish a latent infection which may be reactivated when
the host is immunosuppressed (see E.T. Lennette, E.H.
Lennette (eds.), LABORATORY DIAGNOSIS OF VIRAL
INFECTIONS, Marcel Dekker, Ir1c., N.Y., pp. 257-271 (1985)).
Also a herpes virus, the varicellazoster (VZ) virus
is the causative agent of both varicella (chicken pox) and
zoster (shingles). Varicella occurs primarily in childhood,
whereas the more localized zoster occurs in the elderly and
immunocompromised. Zoster is, in fact, due to a reactivation
of a latent VZ infection. Patients suffer painful, vesicular skin
lesions (see A. Gershon, E.H. Lennette (eds.), LABORATORY
DIAGNOSIS OF VIRAL INFECTIONS, Marcel Dekker, Inc.,
N.Y., pp. 329-340 (1985)). Currently, analgesics provide the
only treatment for shingles (see R. Boyd, et al., BASIC
MEDICAL MICROBIOLOGY, 2nd Edition, Little, Brown and
Company, Boston, p. 527, (1981)).
It has been reported that patients with severe
herpes simplex (HSV) infections had no antibody titers above
that observed in normal patients. This absence of immune
response was speculated to be due to a deficiency in the
patient’s cell mediated immune response (see I. W. St. Geme,
et al., New Engl. J. Med. 273, pp. 229-234 (1965)). While
there is antibody to HSV-1 in most normal adults, the humoral
immune response (antibody production) to the virus appears
not to be sufficient to fight off the disease (see C. Ching and C.
Lopez, Infect. Immun. 26, pp. 49-56 (1979)). The presence of
an immunologically recognized glycoprotein on the cell
membrane of herpes infected cells (glycoprotein C) has also
been observed. This glycoprotein C is thought to function as a
receptor for the third component of immune complement (see
M. L. Smiley and H. M. Friedman, J. Vir. 55, pp. 857-861
(1984)).
The absence of a pronounced immune response
indicates that other necessary factors are not present or
effective in herpes virus infections. In vitro studies have .
shown that HSV-1 and HSV-2 infected cells can be lysed by the
cell—mediated immune NK cells when present in significant
numbers (see C. Ching and C. Lopez, Infect. Immun. 26, pp.
49-56 (1979); M. Yasukawa and M.J. Zarling, J. Immunol.
131, pp. 2011-2016 (1983)). Many patients with severe herpes
simplex infections have very low NK cell response (see M.
Yasukawa and M.J. Zarling, J. Immunol. 131, pp. 2011-2016
(1983)).
Unlike the herpes virus, the influenza virus has
been shown experimentally to stimulate NK cells in vitro. It
has been suggested that one of the two neuraminidase
glycoproteins may be responsible for this stimulation (see J.
Arora, et al., J. Virol. 52, pp. 839-845 (1984)). To further
define the involvement of NK cell-mediated immune response,
the morbidity and mortality effect by influenza viral infections
in mice and hamsters in the presence of anti-NK antibodies
was investigated (see J. Stein-Stereilen and J. Guffee, J.
Immunol. 136, pp. 1435-1441 (1986)). The dramatic increase
in morbidity and mortality suggested that both the
neuraminidase, as well as NK cells, are necessary for this anti-
influenza viral immune response.
This anti-NK induced effect with influenza
infection is similar to that observed when HSV infections are
severe (see M. Yasukawa and M.J. Zarling, J. Immunol. 131,
pp. 2011-2016 (1983)). Another immunomodulator,
interferon, was also shown to increase several fold with
influenza virus administered intranasally to patients (see F.A.
Ennis, et a1., Lancet, p. 891-893 (1981)). The proportional
relationship between NK cells and interferon has been well
established (see G. Trinchieri, et al., J. Exp. Med. 147, pp.
1299-1313 (1978); D. Santoli and H. Koprowski, Immunol
Rev. 44 p. 125-163 (1979); T. Timonen, et al, Eur. J.
Immunol. 10, pp. 422-427 (1980); O. Haller, Curr. Top.
Microbiol. Immunol. 92, pp. 25-52 (1981); T. Timonen, J.R.
Otaldo, and R.B. Herberman, J. Exp. Med. 153, pp. 569-582
(1981); R.M. Welsh, Curr. Top. Microbiol. Immunol. 92, pp.
83-106 (1981); J. Djeu, et al., J. Exp. Med. 156, pp. 1222-
1234 (1982)). The influenza virus has neuraminidase
glycoproteins as well as hemagglutinin, all of which are
thought to play a major role in NK cell-mediated activity (see
D. Arora, et al., J. Virology 52, pp. 839-845 (1984)).
Thus, the apparent persistence of the HSV
infection is associated with the absence of the body’s immune
response to be triggered in herpes infected patients (see J. W.
St. Geme, et al., New Engl. J. Med. 273, pp.229-234 (1965);
A.J. Nahmias and B. Roizman, New Engl. J. Med. 289, pp.
667-674 (1973); C. Ching and C. Lopez, Infect. Immun. 26,
pp. 49-56 (1979); J. Stein—Stereilen and J. Guffee, J. Immunol.
136, pp. 1435-1441 (1986); M. Yasukawa and M.J. Zarling, J.
Immunol. 131, pp. 2011-2016 (1983)). The absence of natural
killer cell cell-mediated immune response in these patients has
been speculated as one possible reason for the persistence of
the disease state (see M. Yasukawa and M.J. Zarling, J.
Immunol. 131, pp. 2011-2016 (1983); C. Ching and C. Lopez,
Infect. Immun. 26, pp. 49-56 (1979); Stein-Stereilen and J.
Guffee, J. Immunol. 136, pp. 1435-1441 (1986)).
EP-A-4214 describes a pharmaceutical composition for the
treatment of viral diseases, wherein the active ingredient is a
N-acetylneuraminate glycohydrolase, extracted from
Streptococcus pneumoniae. This protein is administrated once to
4 times a day with a unit dosage between 300 and 5000 units for
the treatment of diseases, wherein viral strains with
neuraminidase are involved (i.e. myxoviruses, rhinoviruses). A
specific as well as a non-specific immunostimulating effect,
further an antitumorai activity of the pharmaceutical composition _
is described. However, herpes virus infections or HIV-infections
are not discussed in EP-A 4214.
Disorders Related to Herpes Infection
A number of disorders are thought to be related to
herpes virus infection. For example, HIV infection in vitro has
been reported to be enhanced in the presence of human herpes
virus—6 (HHV-6) (see Gallo, et al., ASM News 56, p.
(1990)). Levy, et al., reported that the HHV-6 inhibited
infection of peripheral blood mononuclear cells and purified
CD4+ lymphocytes (see Levy, et al., J Clin. Micro. 28, pp.
2362-2364 (1990)).
Nasopharyngeal carcinoma has been associated
with Epstein-Barr viral antigens. Patients with
nasopharyngeal carcinoma have been shown to exhibit
antibodies to soluble Epstein-Barr virus antigens. In addition,
antibody titers in patients suffering from nasopharyngeal
carcinoma appear when tumor growth is progressive and the
same antibodies are frequently not detectable when tumors are
regressing (see Piessens, W.F., Cancer, (Phila) 26, p. 1214
(1970)).
Herpes viruses have also been implicated in
chronic fatigue syndrome. In particular, the Epstein-Barr
virus has been associated with the disease, based in part on
several studies describing patients with atypical profiles of
antibodies to the Epstein-Barr virus. (For a review, see
Lopez, C., (ed.) Immunology and Pathogenesis of Persistent
Virus Infections, American Society for Microbiology,
Washington, D.C., p. 286 (1988)). Other diseases in which the
Herpes virus is implicated are shingles, Herpes Type I (fever
blisters), Herpes Type 2 (genital herpes), Burkitt’s lymphoma,
and mononucleosis (see Davis, et al., MICROBIOLOGY, 4th ed.,
J. B. Lippincott Company, Philadelphia, p. 929 (1990)).
As summarized hereinabove, infections by herpes-
related viruses have been implicated in a wide range of
diseases. What is needed is a method of treating disorders that
are associated with herpes virus infections so that the immune
system of the human or animal can effectively correct the
symptoms of the disease state, presumably allowing the
immune system to target the diseased tissue. The method and
composition should be safe and easy to administer and should
be effective in a short period of time after administration with
negligible, if any, side effects over a period of time.
Summary of the Invention
The present invention refers to the use of
neuraminidase for the preparation of a pharmaceutical
composition for alleviating the symptoms of disease states
associated with herpes virus and related disorders. The present
invention comprises the use of neuraminidase for the preparation
of a pharmaceutical composition for the administration to the
human or animal with the herpes related disorder of an effective
dose of neuraminidase or a fraction or active derivative thereof.
The effective dose is extremely low and does not cause side
effects such as an immune response to the neuraminidase
protein.
It has been found that the administration of
extremely low amounts of neuraminidase to a human or
animal which has been infected with a herpes-type virus causes
the elimination of the symptoms of the herpes—mediated
disorder, presumably through modulation of the immune
function.
In practice, the present invention comprises the
administration of a dose of neuraminidase between l0'8 and 10’2 mg
per dosage unit to a human or animal that has been infected with a
herpes-type virus. A preferred dose of neuraminidase is between
approximately 103 mg and 107 mg. The most preferred dose
of neuraminidase is approximately lO'4 mg. Preferably, the
total periodic daily dosage does not exceed about lO'2 mg per
subject, and still more preferably does not exceed from about
x 103 to 104 mg.
In practice, the present invention comprises the use
of neuraminidase for the preparation of a pharmaceutical
composition for the partitional administration of an amount not
to exceed lO'2 mg, although, in certain cases, the total
amount of neuraminidase administered in any one day may
exceed the preferred limit. The neuraminidase can be
administered as a liquid or it can be administered as a solid
wherein the neuraminidase is embedded or admixed in a
biodegradable or bioerodable matrix. The matrix can be a
time release matrix. These matrices are well known to those
of ordinary skill in the art and are not critical to the present
invention. The neuraminidase can be administered by injection
or by sublingual route. In one embodiment, the vehicle is an
aqueous solution that is contained within an inert container. In
another variation, the composition is in the form of a
suppository. The liquid form of the composition can be
injected subcutaneously, intramuscularly or intravenously. In
addition, the composition can be administered through the
muscosal membranes such as nasal membranes.
Accordingly, it is an object of the present
invention to provide a method for treating diseases that are
associated with herpes-type virus infections.
It is yet another object of the present invention to
provide a method and composition for the treatment of
chronic fatigue syndrome.
It is yet another object of the present invention to
provide a method and composition for the treatment of cold
sores.
It is yet another object of the present invention to
provide a method and composition for the treatment of
nasopharyngeal carcinoma.
It is yet another object of the present invention to
provide a method and composition for the treatment of HIV
infection.
It is yet another object of the present invention to
provide a method and composition for the treatment of
shingles.
It is yet another object of the present invention to
provide a method and composition for the treatment of
Burkitt’s lymphoma.
It is yet another object of the present invention to
provide a method and composition for the treatment of fever
blisters.
It is yet another object of the present invention to
provide a method and composition for the treatment of
mononucleosis.
These and other objects, features, and advantages
will become apparent after a review of the following detailed
description of the disclosed embodiments and the appended
claims. ‘
Detailed Description
The present invention refers to the use of
neuraminidase for the preparation of a pharmaceutical
composition for alleviating the symptoms of disease states
associated with herpes virus and related disorders. The present
invention comprises administration to the human or animal
with the herpes related disorder of an effective dose of
neuraminidase or a fraction or derivative thereof. The
effective dose is extremely low and does not cause an immune
response to the neuraminidase-type protein.
In accordance with the invention, there is provided
the use of neuraminidase for the preparation of a
pharmaceutical composition for stimulating the appropriate
metabolic and cellular regulatory systems (immune, CNS,
endocrine or cellular physiological events), which retard the
progress of the symptoms of HSV—l and HSV—2 and related
disease states. The present invention presumably results in
triggering control processes that correct the body’s immune
response such that it can properly target the herpes infected
tissue, and/or reversing the viral expression in the infected
cells through secondary cell control metabolites.
The alleviation of herpes symptoms observed
following parenterally administered neuraminidase, as
described herein, reflects stimulation of appropriate metabolic
regulatory systems in the herpes infected patients such that
viral expression, immune dysfunction and/or synthesis of
controlling metabolites reverse the symptoms of the herpes
infection.’ This reprogramming to establish proper homeostasis
results in clinical improvement of treated herpes patients.
When a cellular parasite (such as a virus) initially
infects a cell in the body, unique antigens are derived which
are displayed on the infected cell surface (see A. Nahmias and
B. Roizman, New Eng. J. Med. 289, pp. 667-674 (1973)).
These novel antigens, in tum, during the first exposure to the
body, are recognized by receptors on various circulating
T cell lymphocytes. This cell-mediated response provides for
one of the major components in the body’s defenses against
infectious agents (immune response). Cells which are involved
in this immune response are cytotoxic T cells or natural killer
cells (NK). These cells lyse the infected cells or helper T cells
(HT). The HT cells apparently assist in T-cell mediated
antibody—antigen interactions. Another T cell, the suppressor
T cell, which is also important in immune responses, can
suppress the reaction of B cell mediated antibody-antigen
interaction or HT and NK immune response.
Transport of many viruses and bacteria through
cell mucin on the cell surface into the cell appears to be
facilitated by the reaction of neuraminidase on its cell surface.
The reaction by neuraminidase on the cell surface cleaves the
sialic acid component, which also destroys a hemagglutinin
receptor site on the host cell (see J.N. Varghese, W.G. Laver,
and P.M. Colman, Nature (London) 303, pp. 35-40 (1983)).
When the sialic acid component is present on the cell surface,
it can stabilize certain cells through an increase in cellular
adhesiveness (see L. Berwick and D.R. Coman, Cancer Res.
22, pp. 982-986) or other cells through facilitation of cellular
mobilization (see M.M. Yamell and E.J. Ambrose, Eura. J.
Cancer 5, pp. 265-269 (1969)).
The neuraminidase (Acyl-neuraminyl hydrolase:
EC3.2.l.l8) that can be used in practicing the present
invention can be from any source including, but not limited to,
Arthrobacter ureafaciens, Vibrio cholerae, Clostridium
perfringens, or from mammalian sources.
Typically, a pharmaceutical dosage unit of the
present invention for the delivery of neuraminidase in a low
concentration comprises a liquid or solid pharrnaceutically
acceptable carrier and an effective amount of neuraminidase.
The aforesaid effective amount is preferably from between
approximately 102 to about 10'3 mg, and still more
preferably about 104 mg neuraminidase in the dosage unit in
association with pharrnaceutically acceptable excipients. The
preferred carrier is 0.1% phenol in 0.9% sodium chloride
(USP).
It should be noted here that although there have
been reports of treating other viral infections such as
rhinovirus and influenza infections with neuraminidase type
proteins, these reports used extremely high doses of
neuraminidase. For example, European Patent No. 0 004 214
discloses the administration of between 300 U and 5000 U of
neuraminidase for the treatment of the aforementioned
viruses. This is equivalent to approximately 15 mg to 250 mg
of neuraminidase per dose. In the present invention, the dose
range of neuraminidase is between 0.0001 mg to 0.01 mg.
Thus, the minimum dose disclosed in the ‘Z14 patent is
150,000 times the minimum dose that is effective in the
present invention and is 1,500 times more than the maximum
dose according to the present invention. Administration of
neuraminidase at the high concentrations taught by the ‘Z14
patent may result in a wide variety of side effects including
allergic reactions, cross-reactivity with cell surface proteins,
and the potential for anaphylactic reactions with subsequent
administration of the protein. At the concentrations taught by
the ‘Z14 patent, the therapeutic effects of the method are not
observed for any herpes-related disorder.
The neuraminidase can be administered through
standard methods, including intravenous, intramuscular, and
subcutaneous routes. The neuraminidase can also be
administered by sublingual and intranasal routes. Because the
effective amount of neuraminidase in a dose is so low, the
composition according to the present invention can also be
administered transdennally, anally or orally. The dosage units
can be either liquid or solid. Typically, the dosage unit may be
administered up to a maximum of about l5 times per day.
In contrast to experiments cited earlier, the novel
low dose application is preferably not administered directly to
infected cells at lesion sites, but is preferably administered
systemically, so as to elicit the body’s own defense systems to
reverse the disease state. It is believed that the systemic
administration of the low dose neuraminidase is not acting
directly on the herpes infected cells. When neuraminidase is
applied directly to tissue culture, where its action is on the
HSV infected cells, it is at a much higher concentration of
neuraminidase than is used in the present invention. For
example, neuraminidase used in the cell culture research is as
high as 0.03 mg of neuraminidase protein/1,000-10,000 rabbit
corneal cells when employed to discover the extent to which
immune complement functions (see H. Hatano and J.O. Oh,
Current Eye Res. 6, pp. 53-57 (1987)), and 3 mg
neuraminidase protein/100,000 cultured human cells when
applied to discover lysis enhancement (see W.A.F. Tompkins,
et al., J. Immunol. 116, pp. 489-495 (1976)). This 0.03 pg
concentration per cell in the in vitro studies is approximately
ten thousand billion fold higher concentration of
neuraminidase than the therapeutic dose used per body cell of
the instant invention.
Although not wanting to be bound by the
following explanation, it is believed for the mechanism of this
invention is that the small amount of this protein administered
is sufficient to trigger a negative feedback mechanism to the
body such that the body’s immune system or various
metabolites can effectively suppress or target the infected cells.
Under this theory, the low level of neuraminidase, or an active
derivative thereof, gives a signal to the body to correct the
abnormal synthesis/degradation process. The body’s sensors
are then adjusted to produce the necessary immune
components or messenger metabolites to allow proper
recognition of the herpes infected or expressing cells,
alleviating the abnormal processing. The immune system, as
well as the endocrine and CNS control systems, probably play
an integral regulatory role in response to the low dose
therapy, with the neuraminidase functioning through
mechanisms that reverse the herpes disease symptoms.
The invention is further illustrated by the following
examples.
Example I
A 40 year old female subject was treated with the
therapeutic agent for oral herpes infection. The patient
received a sublingual dose of 104 mg neuraminidase (Sigma
Chemical Company, St. Louis, Mo.) in a 50 microliter dosage
of 0.1% phenol in 0.9% NaCl at fifteen minute intervals for
two and one half hours, by which time the lesion pain fully
disappeared. The following morning, lesion pain returned so
the treatment is reinitiated. After a two hour treatment period,
the lesion pain again disappeared. The herpes lesions healed
within a few days and did not reoccur as frequently (monthly)
as they had during the previous twenty years.
Example II
A 37 year old male subject had shingles with
severe associated pain for about one month prior to initiation
of treatment with the therapeutic agent. The pain subsided
dramatically after twelve hourly sublingual 50 microliter
dosings of 10‘4 mg neuraminidase in 0.1% phenol in 0.9%
NaCl. The patient was pain-free for three days following the
first treatment phase. Slight pain was experienced on the
fourth day at which time he started sublingual administration
every fifteen minutes for two hours. After this treatment, pain
subsided. He was placed on a maintenance treatment regime of
one dose per day for three weeks. He has remained completely
free of shingles associated symptoms during the seventeen
months of follow-up observation.
Example III
A 33 year old patient had a 10 year history of
oral herpes with a reoccurrence rate of several episodes a
month. Lesions were severe and would often make the patient
nauseated from the severity of the outbreak. According to past
history, if the patient took nothing for the outbreak of lesions,
the infectious (feverish, throbbing) period would normally last
three to five days, then it would be two weeks before the
condition was completely healed.
Since initiating therapy with the therapeutic agent,
when the patient first noticed the lesions, she would begin
taking the dosage unit of 104 mg neuraminidase per 50
microliters of 0.9% NaCl with 0.1% NaCl every fifteen
minutes for one hour thereafter, until the burning sensation
disappeared. If the lesions were discovered in the very early
stages, i.e., when an itching sensation developed, before the
lesions were readily apparent, the lesion would never fully
develop and the progression would be halted before the full
blisters developed.
The patient reported that this had not been
possible with other medications taken for her oral herpes. If
the patient did not apply the treatment early enough or if the
lesions developed overnight while the patient slept, the blisters
would be painful, making her nauseous. Within a few
sublingual administrations of the dosage, relief would be
experienced in the form of a decrease in the infection and pain
level, as well as an elimination of the nausea resulting
therefrom. Subsequently, the frequency of outbreaks has also
decreased dramatically.
Example IV
A 21 year old female, diagnosed with genital
herpes, had a three year history of frequent HSV-2 infections.
After initiation of sublingual treatment with lO'4 mg
therapeutic agent per 50 microliters, four times per day
following the first signs of discomfort, the HSV symptoms
were blocked and reversed without further progression to the
full blown disease state. Prophylactic treatment was continued
for two days after the HSV symptoms were no longer evident.
The patient has remained herpes symptom-free to date (one
year).
Example V
A 40 year old female, with a large, painful lesion
under the tongue, was treated with 104 mg of the therapeutic
agent per 200 microliters, administered by subcutaneous
injections. The pain was dramatically reduced within six hours
of treatment initiation and had completely disappeared by the
next morning. Prophylactic subcutaneous treatments were
continued for another three days. The lesion was fully healed
within five days of initial treatment.
Example VI
Three patients, ages 45, 53 and 67, were treated
for chronic fatigue syndrome, a disease associated with the
Epstein-Barr virus. Neuraminidase was administered at a dose
of 10'4 mg sublingually 3 times a day for 3 days. All three
patients showed marked improvement with this regimen.
Example VII
A patient with nasopharyngeal carcinoma which is
associated with Epstein-Barr virus, underwent surgery with
subsequent radiation and chemotherapy. The treatments failed
to halt the spread and growth of the tumor. Administration of
neuraminidase (4 doses daily) was begun followed one week
later by cyclophosphamide therapy. After 3 weeks of
neuraminidase treatment, there were indications that symptoms
of severe peripheral neuropathy, brought about by the
chemotherapy, were being reversed.
Claims (19)
1. Use of neuraminidase, or an active derivative or a fraction thereof, in a process for the preparation of a pharmaceutical composition comprising per dosis unit, between 10" and 10'? mg neuraminidase, or an active derivative or a fraction thereof, in a pharmaceutically acceptable carrier for treating _ disease states associated with herpes virus and related disorders.
2. Use of claim 1 wherein the dosis unit comprises between 10" and lo‘3 mg.
3. Use of claim 1 wherein the dosis unit comprises approxi- mately 10" mg.
4. Use of any of claims 1 to 3 wherein the pharmaceutically acceptable carrier is a liquid.
5. Use of claim 4 wherein the pharmaceutically acceptable carrier is 0.1 % phenol in 0.9 % sodium chloride.
6. Use of any of claims 1 to 3 wherein the pharmaceutically acceptable carrier is a solid.
7. Use of claim 6 wherein the pharmaceutically acceptable carrier is a time-release matrix.
8. Use of any of claims 1 to 6 wherein the pharmaceutical composition is for subcutaneous, intramuscular, intravenious, sublingual, intranasal, transdermal, anal or oral routes.
9. Use of any of claims 1 to 7 wherein the pharmaceutical composition is for a single administration. 18
10. Use of any of claims 1 to 7 wherein the pharmaceutical composition is for periodical administration, the total periodic daily dosage not to exceed 10'? mg.
11. Use of any of claims 1 to 10 wherein the disease state is chronic fatigue syndrome.
12. Use of any of claims 1 to 10 wherein the disease state is cold sores.
13. Use of any of claims 1 to 10 wherein the disease state is nasopharyngeal carcinoma.
14. Use of any of claims 1 to 10 wherein the disease state is a HIV infection.
15. Use of any of claims 1 to 10 wherein the disease state is shingles.
16. Use of any of claims 1 to 10 wherein the disease state is Burkitt's lymphoma.
17. Use of any of claims 1 to 10 wherein the disease state is fever blisters.
18. Use of any of claims 1 to 10 wherein the disease state is mononucleosis.
19. Use of any of claims 1 to 10 wherein the disease state is HSV—1 or HSV—2 related. F. R. KELLY & CO., AGENTS FOR THE APPLICANTS
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
USUNITEDSTATESOFAMERICA09/04/19916 | |||
US68207191A | 1991-04-09 | 1991-04-09 | |
US86054692A | 1992-04-03 | 1992-04-03 |
Publications (2)
Publication Number | Publication Date |
---|---|
IE83322B1 true IE83322B1 (en) | |
IE921141A1 IE921141A1 (en) | 1992-10-21 |
Family
ID=27102809
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE114192A IE921141A1 (en) | 1991-04-09 | 1992-04-09 | Method and composition for the treatment of herpes related¹disorders |
Country Status (15)
Country | Link |
---|---|
US (2) | US5558863A (en) |
EP (1) | EP0579765B1 (en) |
JP (1) | JP3266254B2 (en) |
AT (1) | ATE196424T1 (en) |
AU (1) | AU662152B2 (en) |
BR (1) | BR9205877A (en) |
CA (1) | CA2108135C (en) |
DE (1) | DE69231465T2 (en) |
DK (1) | DK0579765T3 (en) |
ES (1) | ES2151489T3 (en) |
GR (1) | GR3035004T3 (en) |
IE (1) | IE921141A1 (en) |
IL (1) | IL101540A (en) |
NO (1) | NO313489B1 (en) |
WO (1) | WO1992018158A1 (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL152130A0 (en) * | 2000-04-07 | 2003-05-29 | Ellis L Kline | Methods and compositions for treating neoplasms |
JP5414366B2 (en) * | 2009-05-29 | 2014-02-12 | 独立行政法人科学技術振興機構 | Pain treatment |
KR20150063079A (en) * | 2012-09-28 | 2015-06-08 | 엘리스 클라인 | Glycosidase regimen for treatment of infectious disease |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2905678A1 (en) * | 1978-02-16 | 1979-12-20 | Science Union & Cie | PHARMACEUTICAL PREPARATIONS BASED ON BACTERIAL ENZYMES |
JPS575916A (en) * | 1980-06-13 | 1982-01-12 | Teijin Ltd | Polyester fiber with soft touch and production of knitted and woven fabrics therefrom |
-
1992
- 1992-04-06 JP JP51137692A patent/JP3266254B2/en not_active Expired - Fee Related
- 1992-04-06 CA CA002108135A patent/CA2108135C/en not_active Expired - Fee Related
- 1992-04-06 EP EP92911249A patent/EP0579765B1/en not_active Expired - Lifetime
- 1992-04-06 ES ES92911249T patent/ES2151489T3/en not_active Expired - Lifetime
- 1992-04-06 DE DE69231465T patent/DE69231465T2/en not_active Expired - Lifetime
- 1992-04-06 WO PCT/US1992/002745 patent/WO1992018158A1/en active IP Right Grant
- 1992-04-06 AU AU19264/92A patent/AU662152B2/en not_active Ceased
- 1992-04-06 DK DK92911249T patent/DK0579765T3/en active
- 1992-04-06 AT AT92911249T patent/ATE196424T1/en active
- 1992-04-06 BR BR9205877A patent/BR9205877A/en not_active Application Discontinuation
- 1992-04-09 IE IE114192A patent/IE921141A1/en not_active IP Right Cessation
- 1992-04-09 IL IL10154092A patent/IL101540A/en not_active IP Right Cessation
-
1993
- 1993-10-08 NO NO19933628A patent/NO313489B1/en not_active IP Right Cessation
-
1995
- 1995-02-21 US US08/393,120 patent/US5558863A/en not_active Expired - Lifetime
-
1996
- 1996-09-19 US US08/716,053 patent/US5736133A/en not_active Expired - Lifetime
-
2000
- 2000-12-06 GR GR20000402695T patent/GR3035004T3/en unknown
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