Note: Descriptions are shown in the official language in which they were submitted.
M247:15990:WP~
HERPES SIMPLEX TREATMENT
Technical Field
This invention relates to treatment of Herpes
Simplex (Herpesvirus Hominis), a viral disease of
widespread occurrence. Herpes Simplex occurs in two
antigenic tyes, Herpes febrilis and Herpes genitalis,
referred as Type 1 and Type 2. Infection is usually
manifested by the appearance of vesicular eruptions,
oral herpetic lesions, commonly referred to as fever
blisters, or cold sores about the lips in the instance
of Herpes Simplex Type l, and vesicular lesions on
and about the male or female genitalia in the instance
of Herpes Simplex Type 2. Persons with Herpes Simplex
infections are likely to have recurrent periods of
- lesion development spaced by periods of remission.
2~ Management of the condition involves easing the
itching sensation which accompanies the lesion periods,
and speeding remission.
Background Art
While no cure is presently known for Herpes Simplex
in either form, certain substances have been advanced
for management of the disease. In U.S~P. 4,256,763 to
McHugh a method of treating inflammatory viral
infections such as Herpes Simplex and acne was
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1 dIsclosed involving the application of 3,3-bis
(p-hydroxyphenyl) phthalide, in amounts up to lO0
milligrams, preferably 15 to 30 milligrams initially
and repetitively at predetermined intervals.
Because 3,3-bis (p-hydroxyphenyl) phthalide is a
cathartic, there is an unpleasant side effect ~o its
use which suggests reduced usage concentratiorls, but
the patentee does not suggest any lower dosage will
be efEective in Herpes Simplex management.
Summary of the Invention
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It is an object of the present invention to
provide an effective Herpes Simplex treatment at much
reduced dosage levels to minimize side effects. It
is another object to provide a new ~se for phenol,
4,4'-(2-pyridinyl methylene) bis diacetate (ester).
It is a further object to provide for the rapid
amelioration of Herpes Simplex symptoms, itching,
lesion development and the like, by treatment with
quite low quantities of phenol, 4,4'-(2-pyridinyl
methylene) bis diacetate (ester), and to maintain the
patient in a remissive state with continued low dosage
treatment after remission. Still other objects
include provision of products comprising phenol, 4,4'-
(2-pyridinyl methylene) bis diacetate (ester), carriers
and therapeutic agents for coapplication with phenol,
~,4'-(2-pyridinyl methylene) bis diacetate (ester).
- These and other objects of the invention to become ``
apparent hereinafter, are realized in accordance with
the invention in the method of treatment of Herpes
Simplex infection condition which includes administering
an effective dosage of phenol, 4,4'-(2-pyridinyl
methylene) bis,- diacetate (ester) to a person having an
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1 Herpes Simplex condtion.
In particular embodiments, the method includes
administering such dosage orally, administering a
dosage of from about 0.1 to about 9.5 milligrams of
phenol, 4,4'-(2-pyridinyl methylene) bis diacetate
(ester), suspending the phenol, 4,4'-(2-pyridinyl
methylene) bis,- diacetate (ester) in a carrier for
administration, combining the phenol, 4,4'-(2-pyridinyl
methylene) bis,- diacetate (ester) with a second
therapeutic agent in an effective dosage for
administration therewith, e.g. by selecting an effective
dosage of one or more vitamins for coadministration
with the phenol, 4,4'-t2-PYridinYl methylene) bis
diacetate (ester), and carrier if any, and maintaining
the phenol, 4,4'-(2-pyridinyl methylene) bis,- diacetate
(ester) free of enteric coating for administration.
The invention further contemplates provision of
a product comprising a dosage of phenol, 4,4'-
~2-pyridinyl methylene) bis, diacetate (ester)
effective upon oral ingestion- for management of Herpes
Simplex, and less than is effective for catharsis of
the person receiving the dosage and combined with an
ingestible carrier. Typically, the product comprises
a dosage between 0.1 and 9.5 milligrams, and may
further comprise one or more vitamins in effective
dosage, preferably free of an enteric coating.
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l Preferred Modes
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Phenol, 4,4'-(2-pyridinyl methylene) bis diacetate
(ester~, commonly referred to as Bisacodyl, is a
diphenyl trimethane suitably prepared from 2-pyridine-
carboxaldehyde condensed with phenol in the presenceof sulfuric acid or other dehydrant, followed by
esterification with acetic anhydride and anhydrous
sodium acetate, as described in U.S.P. 2l764,590. It
is a white to off-white crystalline powder slightly
soluble in water but fairly soluble in common organic
solvents. It is known to be used as a contact laxative,
acting to increase peristalsis throughout the large
intestlne. A typical dose as a laxative is oral or
rectal not less than 10 milligrams and up to 30
milligrams and is administered in an enteric coating
to ensure passage to the larage intestine. It is
known to inhibit glucose absorption and intestinal
Na-K-ATPase activity.
The effectiveness of phenol, 4,4'-(2-pyridinyl
methylene) bis,- diacetate (ester) in treatment of Herpes
Simplex is not to be expected from a study of its
past usages or chemical structure, and is not
scientifically explainable at this time. It has been
found surprisingly effective in Herpes Simplex
management, causing nearly immediate remission and
suppressing recurrence, although administered at quite
moderate levels, less than those recommended for
laxative action, and far less than 3,3-bis (p-
hydroyphenyl) phthalide dosages recommended in U.S.P.
4,256,7~3. The use of phenol, 4,4'-(2-pyridinyl
methylene) bis,- diacetate (ester) as taught herein
thus enables Herpes Simplex management with reduced
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1 incidence of side effects than encountered with the
use of alternate methodologies.
The phenol, 4,4'-(2-pyridinyl methylene) bis,-
diacetate (s~ter) may be combined with other therap~utic
agents each for its own purpose e.g. to reli~ve
stress, or to enhance the ef~ectivenes~ of the phenol,
4,4'-(2-pyridinyl methylene) bis,- diacetate (ester~ when
administered. Such agents as vitamins A, D, E, C, Folic
acid, 3-1, B-2, Niacin, B-6, and B-12, among others
can be comblned with the phenol, 4,4'-~2-pyridinyl
methylene) bis diacetate (ester). Other agents for
combining with phenol, 4,4'-(2-pyridinyl methylcnc) bi~
diacetate (ester) include amino acids, such as lysine
and leucine; proteins such as gelatin and gliadin; or
carbohydrates, e.g. starch, lactose and the likc.
Whether administered orally, topically or intra-
venously, ~he phenol, 4,4'-(2-pyridinyl me~hylene)
bis,- diacetate ~ester) may be suitably dispersed in a
carrier, e.g. tablet or capsule carriers and components
such as cxcipients, bulking agents, lubricants,
disintegrants, dyes and the like as are known in
tablet ma~ing technology for the purposc of easing the
administration of the phenol, 4,4'-(2-pyridinyl methylene)
bis diacetate ~ester). The term carrier further
embraces vehicles used or useful in preparing injection
form o the phenol, 4,4'-(2-pyridinyl methylene) bis,-
diacetate (ester) prioducts of the invention, such as
sesame oil and the like.
It is convenient to provide capsules or tablets of
the composition according to the invention in sets or
groups, of a sufficient number and strength to constitute a
daily dosage of an appropriate amount. A typical total
daily dose is ~rom about 10 to about 13 mg, and it is
conveniently provided in 3-4 mg units ~capsules or tablets),
~5 one uni~ to be taken orally at intervals of 6-12 hours to
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provide the appropriate total daily dose.
EXAMPLE I
Capsules of phe'n,ol, 4,4'-(2-pyridinyl methylene)
bis,-diacetate (ester) were prepared by mixing per
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1 capsule 3.35 milligrams of phenol, 4,4'-(2-pyridinyl
methylene) bis,- diacetate ~ester) with 490 milligrams
of an aliquot of a mixture oE vitamins comprising:
Vitamin A2500 units
Vitamin D400 units
Vitamin E15 units
Vitamin C 60 mg.
Folic acid 0.3 mg.
Vitamin B-l 1.0 mg.
Vitamin B-2 1.2 mg.
Niacin 13.5 mg.
Vitamin B-6 1.0 mg.
Vitamin B-12 4.5 mg.
blended with 2 parts of cornstarch per part of vitamin
mix.
Adult males having a virulent recurrence of Herpes
Simplex Types 1 and 2 were given a series of EXAMPLE
I capsules prepared as above, or a like CONTROL I
capsule prepared with phenolphthalein 3,3-bis
(p-hydroxyphenyl phthalide) rather than phenol,
4,4'-(2-pyridinyl methylene) bis diacetate [ester),
or a CONTROL II as taught in U.S~P. 4,256,763. The
CONTROL II capsules comprised:
Phenolphthalein 30 mg.
Acetominophen325 mg.
Chlorpheniramine
Maleate2 mg. ``
; Caffein 33 mg.
Phenylephrine HCL 10 mg.
The effective dosage rate for the CONTROL I and II
treatments was 30 milligrams per 8 hours for the
first day, and a like amount at 12 hour intervals
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thereafter. The EXAMPLE I dosage rate was one capsule
(3.35 mg. per dosage) every six to eight hours on the
first day and thereafter at 8 to 12 hour intervals.
All subjects showed rapid remission. The EXAMPLE
I material was no less effective for being at the
reduced dosage rate, and incidence of diarrhea from the
laxative effect was less of a problem than with the
CONTROL I and II tests.
The inclusion of vitamins in the EXA.~PLE I
formulation adds stress relief factors to the formulation
to ameliorate the stress which often accompanies
onset of a Herpes condition.
EXA.~PLE II
A second capsule formula of the invention
composition ~as prepared from:
phenol, 4~4'-(2-pyridinyl methylene)
bis diacetate ~ester)3.5 mg.
phenacetin 350. mg.
chloropheniramine maleate3. mg.
caffein 38. mg.
phenylpropanolamine HCL9. mg.
by blending the ingredients eutectically.
EXAMPLE III
A tablet form of the invention dosage is prepared
by blending phenol, 4,4'-(2-pyridinyl methylene) bis
diacetate (ester), 3.5 mg., 100 mg. lactose, 100 mgO
starch, and 10 mg. taic as a lubricant. It will be
noted that this formulation can be packaged in
bapsule form with the omission of the talc and adjusting
~he lactose and starch concentration`accordingly.
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EXAMPLE IV
A protein containing capsule is prepared by blending
eutectlcally phenol, 4,4'--(2-pyridinyl methylene) bis
diacetate (ester), 3.5 mg., 200 mg. lactose, 100 mg.
gliadin or gelatin protein, and about 100 mg. of the
amino acid lysine.
EXAMPLE V
An intramuscular injectable formulation is
prepared by blending, per dosage, 5 cc. sesame oil, 250
units of Vitamin E, and 5 mg. of phenol, 4,4'-(2-pyridinyl
methylene) bls diacetate (ester).
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