Note: Descriptions are shown in the official language in which they were submitted.
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MODULATION OF IMMUNE-RESPONSE BY RIBAVIRIN
Field Of The Invention
The field of the invention is immunology.
Background Of The Invention
In addition to the commonly employed physiological and phenotypical diagnostic
parameters, diseases can sometimes be correlated with molecular markers such
as polidy,
mutations in specific genes, display of distinct cell surface markers and so
forth. Many of
these markers act as disease-specific predictors or indicators, and can thus
be used as a
diagnostic tool for a clearly defined physiological condition.
In recent years, many attempts have been made to correlate relatively complex
diseases such as autoimmunity, asthma, cancer etc. with specific molecular
markers. For
several studies have found a direct or indirect involvement of the
costimulatory molecules
B7-1 and B7-2 in modulating the immune system in diseases. However, despite
many
detailed insights into the various expression levels B7-1 and B7-2 in diseases
obtained
through such studies, a comprehensive and unified picture has not be
elaborated.
(Hepatology 25, No.S, 1997 p1108-1114: Expression of costimulatory molecules
B7-1 and
B7-2 and human hepatocellular carcinoma; J. Cancer Res. Clin. Oncol. 124,
No.7, 1998
p383-388: Expression of costimulatory molecules B7-1 and B7-2 on human gastric
carcinoma; J. Neuroimmunol. 84, No.2, 1998 p179-187: Costimulatory CD80 (B7-1)
and
CD86 (B7-2) on cerebrospinal fluid cells in multiple sclerosis; J Neuroimmunol
91, Nol-2,
1998, p198-203: B7-1 (CD80), B7-2 (CD86), interleukin-12 and transforming
growth
factor-beta mRNA expression in CSF and peripheral blood mononuclear cells from
multiple
sclerosis patients).
In many instances, apparently inconsistent correlations have been observed
between
B7-1, B7-2 and specific diseases. See Figure 1. In some types of cancer, for
example, B7-1
is present in relatively high amounts and B7-2 is present in relatively low
amounts. In other
types of cancers, B7-1 and B7-2 have exactly the opposite correlation. (J.
Cancer Res. Clin.
Oncol. 124, No.7 1998 p383-388: Expression of costimulatory molecules B7-1 and
B7-2
on human gastric carcinoma; Br. J. Haematol 102, No.S, 1998 p1257-1262: The
expression
of costimulatory molecules and their relationship to the prognosis of human
acute myeloid
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leukemia: poor prognosis of B7-2-positive leukemia; Int. J. Mol. Med. 2, No.2,
1998 p167-
171: Lack of B7-1 and B7-2 on head and neck cancer cells and possible
significance for
gene therapy).
B7-l and B7-2 expression also show only inconsistent correlation with known
cytokine patterns. See Figure 2. For example, enhanced expression of B7-1 has
been
correlated with both up- and down- regulation of Type 1 response, and B7-2 has
also been
correlated with both up- and down- regulation of Type 1 response. The same can
be said
for correlation with B7-l and B7-2 with Type 2 response. (see Figure 1) (Am.
J. Respir.
Cell. Mol. Biol. 17, No.2, 1997 p235-242: Differential regulation of human,
antigen-
specific Type 1 and Type 2 responses by the B-7 homologues CD80 and CD86; J.
Immunol. 156, No.B, 1996 p2387-2391: Costimulation of IL-4 production by
marine B7-1
and B7-2 molecules.).
Still further, it is not clear which drugs or even drug categories would be
effective in
modulating B7-1 or B7-2 activity, and even if such drugs were identified, and
it remains
unclear how to beneficially make use of these costimulatory molecules to
modulate the
immune system. Taking together all of these unknowns, there is still a
considerable need to
provide methods and compositions for modulating one or more of the B7 markers,
especially as a means of affecting the response of an immune system to a given
challenge.
Brief Description Of The Drawings
Figure 1 is a table correlating specific diseases and their correlation with
B7-1 and
B7-2 expression.
Figure 2 is a table correlating various types of diseases with Type l, Type 2,
B7-1,
and B7-2 expression.
Summary Of The Invention
This invention provides methods and compositions by which the response of an
immune system to a challenge is modified. In general, the response is modified
by
presenting the system with a nucleoside in a concentration selected to have an
effect on a
B7 marker that is inverse from the effect of the challenge.
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In one aspect of preferred embodiments; the challenges are selected from the
groups
consisting of allergens, neoplasm, virus, bacteria, infestation, and
autoimmune reaction.
Molecular markers of particular interest are B7-l and B7-2. In another aspect
of preferred
embodiments the nucleoside is a Ribavirin analogs, and in especially preferred
embodiments the nucleoside is Ribavirin. In yet another aspect of preferred
embodiments
sufficient nucleoside is provided to achieve a concentration range between
about 0.2 :M and
about 5 :M, respectively, in a fluid containing cells expressing the B7
marker.
In still another aspect of preferred embodiments, the challenge is correlated
with an
increase in Type 2 response, and application of the nucleoside is correlated
with a decrease
in Type 2 response.
Detailed Description Of Specific Embodiments
The present inventor has discovered that there is a surprising link between
certain
nucleosides, especially Ribavirin and its analogues, and expression of one or
more of the B7
markers. Further discoveries revealed another unexpected link -- that
application of such
nucleosides can be used to favorably affect the outcome of a disease or other
challenge. In
particular, a method of modulating a response of an immune system to a
challenge has been
discovered comprising: (a) correlating the challenge with an effect on a B7
marker; (b)
correlating application of a nucleoside within a concentration range with
modulation of the
B7 molecular marker that is inverse to the effect; and (c) presenting the
immune system
with the nucleoside within the concentration range.
As used herein, the term "nucleoside" refers to a compound composed of any
pentose or modified pentose moiety attached to a specific position of a
heterocycle or to the
natural position of a purine (9-position) or pyrimidine (1-position) or to the
equivalent
position in an analog, including especially both D- and L- forms of
nitrogenous bicyclic and
monocyclic heterocycles. The term "D-nucleosides" refers to nucleoside
compounds that
have a D-ribose sugar moiety (e.g., Adenosine). The term "L-nucleosides"
refers to
nucleoside compounds that have an L-ribose sugar moiety. The term "nucleotide"
means a
nucleosides in which phosphate esters substituted on the 5' position of a
nucleoside.
The term "pharmaceutically acceptable salts" refers to any salt derived from
inorganic and organic acids or bases.
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The term "neoplasm" refers broadly to any sort of autonomous morbid growth of
tissue that may or maf not become malignant, including all manner of tumors
and cancers.
The terms "treating" or "treatment" of a disease refer to executing a
protocol, which
may include administering one or more drugs to a patient, in an effort to
alleviate signs or
symptoms of the disease. Thus, "treating" or "treatment" do not require
complete
alleviation of signs or symptoms, do not require a cure, and specifically
include protocols
which have only marginal effect (such as placebo effect) on the patient.
As used herein, the term "immune system" means any collection of immuno-
competent cells that collectively identify and attack foreign entities, and
that dynamically
responds to new pathogens or other challenges. Examples of immune systems are
human or
other mammalian immune systems that include a spleen, thymus B-lymphocytes, T-
lymphocytes and antibodies. An immune system as defined herein must have a
cellular
component, but may or may not have a humoral component. Where a humoral
component
is included in the immune system, the humoral component may include soluble
molecules
secreted from immunocompetent cells, including antibodies or interleukins.
Examples for
soluble molecules are IgG, IgM, IgE or IL2, IL4, IL 10.
Under this definition, whole blood, as well as blood depleted of fibrinogen,
platelets
and erythrocytes is considered to comprise an immune system, since it contains
immuno-
competent cells that are capable of dynamically responding to new pathogens.
Other
immune systems are cell culture mediums containing immunocompetent cells. In
contrast, a
buffered solution of antibodies is not considered an immune system, since it
does not
contain a plurality of immunocompetent cells. In still other embodiments,
human or other
animals all contain immune systems as defined herein.
The term "challenge" is used herein to mean any component or event that
provokes
a response by the immune system. Challenges may be grouped in three
categories: self,
non-self and altered self challenges. Self type challenges include cells or
molecules,
wherein the immune system and the challenge are from the same organism, self
proteins or
autologous proteins and fragments thereof. Examples include human blood cells,
undifferentiated cells, antibodies or coagulation factors from the same human.
Non-self
type challenges include cells, viruses or molecules, wherein the immune system
and the
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challenge are from different organisms, or the challenge is xenogenic.
Examples include
organs or cells from anon-identical donor, bacteria, viruses, or any type of
molecules
typical for other species, including endotoxins, enzymes or structural
proteins. Altered self
type challenges include cells or molecules wherein the immune system and the
challenge
are from the same organism, but wherein the challenge is subject to
modifications,
degradative or neoplastic changes. Examples of such modifications include
modifying the
profile of a B7 marker on antigen presenting cells. Examples of degradative
changes include
cells committed to apoptosis or necrotic tissue. Examples of neoplastic
changes induction
of cancer.
The terms "immune system response" and "immune response" are used herein to
mean any response of an immune system to a challenge. Of particular interest
in this
application are immune responses that include modulation of a B7 marker. Such
modulation may comprise any combination of increase or decrease in B7-l and B7-
2
expression. 'Thus, all of the responses tabulated in the tables of Figures 1
and 2 are
examples of contemplated immune system responses.
Other contemplated immune system responses include engagement of cellular
components in cell specific interactions or changes in genetic activity. Cell
specific
interactions may be cell-cell interactions or cell-challenge interactions.
Examples for cell-
cell interactions are T-cells contacting T-helper cells or T-helper cells
contacting
macrophages. Examples for cell-challenge interactions are antigen presenting
cells
incorporating the challenge, processing the challenge and displaying the
processed
challenge on the cell surface, or B-cells displaying challenge specific
antibodies on their
cell surface and binding the challenge with the antibody. Changes in genetic
activity may be
rearrangements in genomic DNA, or selective activation of genes. Examples for
rearrangements in genomic DNA are splicing events leading to affinity
maturation of
antibodies against the challenge or splicing events leading to a class switch
between
different classes of antibodies. Examples for selective activation of genes
are increase or
decrease of transcription or translation of genes coding for interleukins or
B7-1 or B7-2.
As used herein, producing a B7 effect that is 'inverse" to the pattern
associated with
the challenge means that the B7 effect produced by the nucleoside alone is at
least
marginally in an opposite direction to that associated with the challenge
alone. Thus, if the
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challenge is associated with reduced B7-1 expression, an inverse B7 effect
would be one in
which B7-1 is at least marginally elevated. Similarly, if the challenge is
associated with an
increased B7-2 expression, an inverse B7 effect would be one in which B7-2 is
at least
marginally reduced.
As used herein the term "presenting the immune system with a nucleoside" means
that the nucleoside sufficiently contacts some component of the immune system
to produce
an immune system response. In preferred embodiments this means adding the
nucleoside to
a body. In other embodiments this means adding the nucleoside to a vessel, or
other
container of the immune system.
It should be appreciated that the definition of term "presenting the immune
system
with a nucleoside" is sufficiently broad to include any combination of in-
vivo, in-vitro, or
ex-vivo contact. In-vivo may include injection, ingestion, transdermal
delivery or inhalation.
Examples for various injection are intramuscular, intravenous, or subcutaneous
injection.
Examples for various forms of ingestion are tablets, syrups, or powders.
Occlusive
dressings, ointments or electrophoretic methods may achieve transdermal
delivery.
Inhalation may be encompass methods of vaporizing or spraying.
In-vitro contacting may be achieved by either dispensing a nucleoside
containing
solution to the immune system in a suitable vessel, or by dissolving the
nucleoside in a
solution that may or may not be part of the immune system. Examples for
dispensing
include automated or manual pipetting, dripping, pouring or injecting a
nucleoside
containing solution to the immune system. Alternatively, a nucleoside may also
be
dissolved in a fluid by stirring, mixing or pouring Ribavirin in the fluid.
This fluid may
comprise the immune system or may be a carrier solution including buffer,
isotonic
solutions, blood. This carrier may then be dispensed to the immune system.
Ex-vivo contacting may be achieved in several steps comprising ( 1 )
collecting part
of the immune system from a source, (2) administering the nucleoside to the
immune
system and (3) returning the immune system at least in part to the source.
Collecting part of
the immune system may be done by retrieving part of the immune system from an
in-vivo or
in-vitro source. Examples of in-vivo sources are vertebrate animals, including
humans, and
invertebrate animals. Retrieving may be done by venipuncture, eye bleeds. or
pinpricks.
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Examples of in-vitro sources are cell cultures containing the immune system,
treated or
stored blood. The retrieving may be done by any means of fluid transfer, for
example
automated or manual pipetting, aspiration, dripping and so on. Returning the
immune
system to the source may be done by any means of fluid transfer. This may be
in the case of
an in-vitro source automated or manual pipetting, aspiration, dripping or in
the case of an
in-vivo source injecting intravenously.
Contemplated nucleosides are Ribavirin (1-(3-D-Ribofuranosyl-1,2,4-Triazole-3-
Carboxamide), and analogs thereof. To clarify matters, Ribavirin analogs means
any
derivatized Ribavirin in which ( 1 ) one or more of the hydroxyl groups is
substituted by a
non-hydroxyl moiety having less than 25 atoms, including H, lower alkyl, lower
aryl, lower
aralkyl, lower alkyl alkenyl, halogen, and so forth, and independently one or
more of the
hydrogens is substituted by a non-hydrogen moiety having less than 25 atoms,
including
OH, lower alkyl, lower aryl, lower aralkyl, lower alkyl alkenyl, halogen, and
so forth.
The ribavirin, ribavirin analog, or other nucleoside is preferably formulated
in a
buffered aqueous solution. In alternative embodiments, however, the nucleoside
may be
formulated in many other liquid or solid forms. Liquid forms may be solutions
comprising
pure solvents including water, DMSO or ethanol. Liquid forms may also comprise
solutions
having mixtures of solvent with other solvents or dissolved solids including
water-ethanol
mixtures, water-DMSO mixtures, buffers. Furthermore, liquid forms of
nucleosides may be
mixed for example with consistency-modifying substances to form gels, creams
or
ointments. Examples are amphiphilic molecules, waxes or gelatin. Solid forms
may
comprise solids that may or may not be active ingredients. Examples for active
ingredients
are buffers, ion-exchange resins including MOPS, phosphates or citrates.
Examples of
inactive ingredients include starch, cellulose or silica. Furthermore, solid
forms may be in
various preparations, including tablets, capsules, powder etc.
In preferred embodiments, sufficient nucleoside is provided to achieve a
concentration range between about .2 :M and about 5 :M, respectively, in a
fluid containing
cells expressing the B7 marker. Less preferred embodiments contemplate other
concentrations within the range of 0.1 ~M to about 10 gM.
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In another aspect of preferred embodiments, the challenge is correlated with
an
increase in Type 2 response, and application of the nucleoside is correlated
with a decrease
in Type 2 response. Type 2 response can be understood as follows.
Mammalian immune systems contain two major classes of lymphocytes: B lympho-
cytes (B cells), which originate in the bone marrow; and T lymphocytes (T
cells) which
originate in the thymus. B cells are largely responsible for humoral immunity
(i.e., antibody
production), while T cells are largely responsible for cell-mediated immunity.
T cells are
generally considered to fall into two subclasses, helper T cells and cytotoxic
T cells. Helper
T cells activate other lymphocytes, including B cells and cytotoxic T cells,
and
macrophages, by releasing soluble protein mediators called cytokines that are
involved in
cell-mediated immunity. As used herein, lymphokines are a subset of cytokines.
Helper T cells are also generally considered to fall into two subclasses, Type
1 and
Type 2. Type 1 cells (also known as Thl cells) produce interleukin 2 (IL-2),
tumor necrosis
factor (TNFd) and interferon gamma (IFNU, and are responsible primarily for
cell-
mediated immunity such as delayed type hypersensitivity and antiviral
immunity. In
contrast, Type 2 cells (also known as Th2 cells) produce interleukins, IL4, IL-
5, IL-6, IL-9,
IL-10 and IL-13, and are primarily involved in assisting humoral immune
responses such as
those seen in response to allergens, e.g. IgE and lgG4 antibody isotype
switching
(Mosmann, 1989, Annu Rev Immunol, 7:145-173).
As used herein, the terms Type 1 and Type 2 "responses" are means to include
the
entire range of effects resulting from induction of Type 1 and Type 2
lymphocytes,
respectively. Among other things, such responses include variation in
production of the
corresponding cytokines through transcription, translation, secretion and
possibly other
mechanisms, increased proliferation of the corresponding lymphocytes, and
other effects
associated with increased production of cytokines, including motility effects.
As described in US Patent no. 5767097 to Tam (June 1998), the disclosure of
which
is incorporated herein by reference, either of Type 1 and Type 2 responses can
be
selectively suppressed while the other is either induced or left relatively
unaffected, and
either of Type 1 or Type 2 responses can be selectively induced while the
other is either
suppressed or left relatively unaffected. Also, as set forth in co-pending PCT
application
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no. PCT/LJS98/00634, the disclosure of which is incorporated herein by
reference, certain
nucleosides such as ribavirin are effective in selectively modulating Type 1
and Type 2
responses relative to one another. Determination of which nucleosides are
effective in
reducing Type 2 response is readily determined by experimentation.
It is contemplated that the methods described herein may be used to treat a
wide
variety of diseases, , and in fact any disease which responds favorably to
such treatment.
Among other things it is specifically contemplated that such combinations may
be used to
treat an allergen (allergy), a neoplasm (cancer), a virus (viral infection), a
bacterium
(bacterial infection), an infestation, or an autoimmune disease.
Infections contemplated to be treated with the nucleosides of the present
invention
include respiratory syncytial virus (RSV), hepatitis B virus (HBV), hepatitis
C virus (HCV),
herpes simplex type l and 2, herpes genitalis, herpes keratitis, herpes
encephalitis, herpes
zoster, human immunodeficiency virus (HIV), influenza A virus, hantann virus
(hemorrhagic fever), human papilloma virus (HPV), measles and fungus. It is
especially
contemplated that combinations claimed herein will be useful in treating
chronic viral and
bacterial infections, including HIV, Tuberculosis, leprosy and so forth.
Infestations contemplated to be treated with the nucleosides of the present
invention
include intracellular protozoan infestations, as well as helminth and other
parasitic
infestations. Again, it is especially contemplated that combinations claimed
herein will be
useful in treating chronic infestations.
Neoplasms contemplated to be treated include those caused by a virus, and the
effect
may involve inhibiting the transformation of virus-infected cells to a
neoplastic state,
inhibiting the spread of viruses from transformed cells to other normal cells
and/or arresting
the growth of virus-transformed cells.
Allergies contemplated to be treated include all IgE and IgG allergies, hyper
IgE
syndrome, and dermatic conditions such as atopic dermatitis. It is also
contemplated that
the claimed methods can be used to treat transplant rejection, (graft vs. host
disease) and
implant reactions.
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Autoimmune diseases can be classified as either non-organ-specific or
organ-specific. Non-organ-specific autoimmune diseases include rheumatoid
arthritis, gout
and gouty arthritis, Systemic Lupus Erythematosus (SLE), Sjogren syndrome,
scleroderma,
polymyositis and dermomyositis, ankylosing spondylitis, and rheumatic fever.
Organ-specific autoimmune diseases are known for virtually every organ,
including
insulin-dependent diabetes, thyroid diseases (Graves disease and Hashimoto
thyroiditis),
Addison disease, and some kidney and lung diseases including allergy and
asthma, multiple
sclerosis, myasthenia gravis, uveitis, psoriasis, forms of hepatitis and
cirrhosis, celiac
disease, inflammatory bowel disease, and some types of male and female
infertility.
Autoimmune processes may also be stimulated by viral infections including the
HIV virus,
may result from rejection of transplantation, and may accompany certain
tumors, or be
precipitated by exposure to some chemicals.
Synthesis
Synthesis of ribavirin is well known, and synthesis of ribavirin analogs is
contemplated to follow from the teachings of PCT application PCT/US97/18387
and
PCT/US97/00600, the disclosures for both of which are incorporated herein by
reference.
Administration
It is contemplated that nucleosides according to the present invention will be
administered in any appropriate pharmaceutical formulation, and under any
appropriate
protocol. Preferred dosages and protocols are contemplated to be best
established through
experimentation with particular patients. Such experimentation need not be
extensive, and it
is contemplated that nucleosides will be administered in humans at between
about 100
mg/day and about 5,000 mg/day. In humans and other systems, the ribavirin or
other
nucleoside is especially contemplated to be provided under parameters that
produce a
concentration of the nucleoside in a fluid containing cells expressing a B7
between about .2
:M and about 5 :M, respectively,.
Of course, where treatment of a disease is concerned, one of ordinary skill in
the art
will recognize that a therapeutically effective amount will vary with the
infection or
condition to be treated, its severity, the treatment regimen to be employed,
the
pharmacokinetics of the agent used, as well as the patient (animal or human)
treated. Thus,
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effective dosages may range from 1 mg/kg of body weight, or less, to 25 mg/kg
of body
weight or more. In general a therapeutically effective amount of the "second"
drug is
contemplated to range from slightly less than about 1 mg./kg. to about 25
mg./kg. of the
patient, depending upon the nucleoside used, the condition or infection
treated and the route
of administration. This dosage range generally produces effective blood level
concentrations
of active nucleoside ranging from about 0.04 to about 100 micrograms/cc of
blood in the
patient. It is contemplated, however, that appropriate patient-specific
regimens will be
developed by administering a small amount, and then increasing the amount
until either the
side effects become unduly adverse, or the intended effect is achieved.
Administration of nucleosides according to the present invention may take
place
orally, parenterally (including subcutaneous injections, intravenous,
intramuscularly, by
intrasternal injection or infusion techniques), by inhalation spray, or
rectally, topically and
so forth, and in dosage unit formulations containing conventional non-toxic
pharmaceutically acceptable carriers, adjuvants and vehicles.
It is contemplated that nucleosides according to the present invention can be
formulated in admixture with a pharmaceutically acceptable carrier. For
example, the
nucleosides of the present invention can be administered orally as
pharmacologically
acceptable salts. Because the nucleosides of the present invention are mostly
water soluble,
they can be administered intravenously in physiological saline solution (e.g.,
buffered to a
pH of about 7.2 to 7.5). Conventional buffers such as phosphates, bicarbonates
or citrates
can be used for this purpose. Of course, one of ordinary skill in the art may
modify the
formulations within the teachings of the specification to provide numerous
formulations for
a particular route of administration without rendersng the compositions of the
present
invention unstable or compromising their therapeutic activity. In particular,
the
modification of the present nucleosides to render them more soluble in water
or other
vehicle, for example, may be easily accomplished by minor modifications (salt
formulation,
esterification, etc. ) which are well within the ordinary skill in the art. It
is also well within
the ordinary skill of the art to modify the route of administration and dosage
regimen of a
particular nucleosides in order to manage the pharmacokinetics of the
contemplated
nucleosides for maximum beneficial effect in patients.
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In certain pharmaceutical dosage forms, the pro-drug form of administered
nucleosides, especially including acylated (acetylated or other) derivatives,
pyridine esters
and various salt forms of the present nucleosides are preferred. One of
ordinary skill in the
art will recognize how to readily modify the present nucleosides to pro-drug
forms to
facilitate delivery of active nucleosides to a target site within the host
organism or patient.
One of ordinary skill in the art will also take advantage of favorable
pharmacokinetic
parameters of the pro-drug forms, where applicable, in delivering the
contemplated
nucleosides to a targeted site within the host organism or patient to maximize
the intended
effect of the nucleoside.
In addition, contemplated nucleosides may be administered separately or
together,
and when administered separately this may occur in any order. The amounts of
the active
ingredients) and pharmaceutically active agents) and the relative timings of
administration
will be selected in order to achieve a desired combined therapeutic effect.
Administration routes of contemplated nucleosides may range from continuous
(intravenous drip) to several oral administrations per day (for example,
Q.LD.) and may
include oral, topical, parenteral, intramuscular, intravenous, sub-cutaneous,
transdermal
(which may include a penetration enhancement agent), buccal and suppository
administration, among other routes of administration.
In treatments according to the present invention, a therapeutically effective
amount
of a nucleoside is preferably intimately admixed with a pharmaceutically
acceptable Garner
according to conventional pharmaceutical compounding techniques to produce a
dose. A
carrier may take a wide variety of forms depending on the form of preparation
desired for
administration, e.g., oral or parenteral. In preparing pharmaceutical
compositions in oral
dosage form, any of the usual pharmaceutical media may be used. Thus, for
liquid oral
preparations such as suspensions, elixirs and solutions, suitable carriers and
additives
including water, glycols, oils, alcohols, flavoring agents, preservatives,
coloring agents and
the like may be used. For solid oral preparations such as powders, tablets,
capsules, and for
solid preparations such as suppositories, suitable carriers and additives
including starches,
sugar carrier, such as dextrose, mannitol, lactose and related carriers,
diluents, granulating
agents, lubricants, binders, disintegrating agents and the like may be used.
If desired, the
tablets or capsules may be enteric-coated or sustained release by standard
techniques.
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For parenteral formulations, the Garner will usually comprise sterile water or
aqueous sodium chloride solution, though other ingredients including those
that aid
dispersion may be included. Of course, where sterile water is to be used and
maintained as
sterile, the compositions and carriers must also be sterilized. Injectable
suspensions may
also be prepared, in which case appropriate liquid carriers, suspending agents
and the like
may be employed.
It will also be appreciated that in general, the most preferred uses according
to the
present invention are those in which the active nucleosides are relatively
less cytotoxic to
the non-target host cells and relatively more active against the target. In
this respect, it may
also be advantageous that L-nucleosides may have increased stability over D-
nucleosides,
which could lead to better pharmacokinetics. This result may attain because L-
nucleosides
may not be recognized by enzymes, and therefore may have longer half lives.
Thus, methods have been disclosed that employ ribavirin or other nucleosides
to
advantageously modulate a B7 molecular marker.. While specific embodiments
have been
disclosed herein, the scope of the invention is not be limited except through
interpretation of
the appended claims.
13
SUBSTITUTE SHEET (RULE 26)
