U.S. patent application number 15/397395 was filed with the patent office on 2017-04-27 for therapeutic methods and pharmaceutical compositions for treating warts with tellurium compounds.
The applicant listed for this patent is BIOMAS LTD.. Invention is credited to Michael AIbeck, Benjamin Sredni.
Application Number | 20170112874 15/397395 |
Document ID | / |
Family ID | 34807203 |
Filed Date | 2017-04-27 |
United States Patent
Application |
20170112874 |
Kind Code |
A1 |
Sredni; Benjamin ; et
al. |
April 27, 2017 |
Therapeutic Methods And Pharmaceutical Compositions For Treating
Warts With Tellurium Compounds
Abstract
A novel method for treating skin and mucosal membrane ailments
caused by human papilloma viruses, which utilizes
tellurium-containing compounds, is disclosed. Also disclosed are
pharmaceutical compositions containing tellurium-containing
compounds for treating such ailments.
Inventors: |
Sredni; Benjamin;
(Kfar-Saba, IL) ; AIbeck; Michael; (Ramat-Gan,
IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BIOMAS LTD. |
JERUSALEM |
|
IL |
|
|
Family ID: |
34807203 |
Appl. No.: |
15/397395 |
Filed: |
January 3, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14691000 |
Apr 20, 2015 |
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15397395 |
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10586746 |
Sep 2, 2010 |
9011933 |
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PCT/IL2005/000084 |
Jan 23, 2005 |
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14691000 |
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60538635 |
Jan 22, 2004 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 17/00 20180101;
A61P 31/20 20180101; A61P 39/06 20180101; A61P 31/12 20180101; A61P
25/24 20180101; A61K 47/20 20130101; A61P 35/00 20180101; A61P
31/10 20180101; A61P 31/00 20180101; A61K 31/095 20130101; A61K
9/0014 20130101; A61K 31/555 20130101; A61P 17/10 20180101; A61P
17/12 20180101; A61P 29/00 20180101; A61P 33/02 20180101; A61K
33/04 20130101; A61K 47/06 20130101; A61K 45/06 20130101 |
International
Class: |
A61K 33/04 20060101
A61K033/04; A61K 9/00 20060101 A61K009/00; A61K 45/06 20060101
A61K045/06; A61K 31/555 20060101 A61K031/555 |
Claims
1. A method of treating a skin or mucosal membrane ailment caused
by a human papilloma virus (HPV) in a subject in need thereof, the
method comprising administering to the subject a therapeutically
effective amount of at least one tellurium-containing compound.
2. The method of claim 1, wherein said at least one
tellurium-containing compound is selected from the group consisting
of tellurium dioxide (TeO.sub.2), a complex of TeO.sub.2, a
compound having general Formula I: ##STR00015## a compound having
general Formula II: ##STR00016## a compound having general Formula
III: ##STR00017## and a compound having general Formula IV:
##STR00018## wherein: each of t, u and v is independently 0 or 1;
each of m and n is independently an integer from 0 to 3; Y is
selected from the group consisting of ammonium, phsophonium,
potassium, sodium and lithium; X is a halogen atom; and each of
R.sub.1-R.sub.22 is independently selected from the group
consisting of hydrogen, hydroxyalkyl, hydroxy, thiohydroxy, alkyl,
alkenyl, alkynyl, alkoxy, thioalkoxy, halogen, haloalkyl, carboxy,
carbonyl, alkylcarbonylalkyl, carboxyalkyl, acyl, amido, cyano,
N-monoalkylamidoalkyl, N,N-dialkylamidoalkyl, cyanoalkyl,
alkoxyalkyl, carbamyl, cycloalkyl, heteroalicyclic, sulfonyl,
sulfinyl, sulfate, amine, aryl, heteroaryl, phosphate, phosphonate
and sulfoneamido.
3. The method of claim 2, wherein said tellurium-containing
compound is selected from the group consisting of a compound having
said general Formula I and a compound having said general Formula
II.
4. The method of claim 3, wherein t, u and v are each 0.
5. The method of claim 4, wherein each of R.sub.1, R.sub.8,
R.sub.9, and R.sub.10 is hydrogen.
6. The method of claim 5, wherein X is a halogen atom.
7. The method of claim 6, wherein X is chloro.
8. The method of claim 7, wherein Y is ammonium.
9. The method of claim 7, wherein Y is phsophonium.
10. The method of claim 2, wherein said tellurium-containing
compound has said general Formula III.
11. The method of claim 10, wherein each of R.sub.11-R.sub.14 is
hydrogen.
12. The method of claim 2, wherein said tellurium-containing
compound has said general Formula IV.
13. The method of claim 12, wherein n and m are each 0.
14. The method of claim 13, wherein each of R.sub.15, R.sub.18,
R.sub.19 and R.sub.22 is hydrogen.
15. The method of claim 2, wherein said complex of TeO.sub.2 is
TeO.sub.2.HOCH.sub.2CH.sub.2OH.NH.sub.4Cl.
16. The method of claim 1, wherein said administering is effected
systemically.
17. The method of claim 16, wherein said therapeutically effective
amount ranges from about 0.01 mg/m.sup.2/day to about 10.0
mg/m.sup.2/day.
18. The method of claim 16, wherein said administering is effected
topically.
19. The method of claim 18, wherein said administering is effected
by applying said therapeutically effective amount of said at least
one tellurium-containing compound onto a treated skin or mucosal
membrane area.
20. The method of claim 1, wherein said skin or mucosal membrane
ailment is selected from the group consisting of verruca vulgaris,
plantar warts, palmar warts, periungal warts, planar warts, mosaic
warts, genital warts, venereal warts (condylomata acuminata),
butcher's warts, malignant epidermodyspasia verruciformis, advanced
intraepithelial dysplasia, cervical cancer, mepidermodysplasia
verruciformis, cutnaeous warts in immunosuppressed patients,
laryngeal papillomas and oral papilloma.
21. The method of claim 1, further comprising administering to the
subject an additional active agent.
22. The method of claim 21, wherein said additional active agent is
selected from the group consisting of an antibiotic agent, an
antimicrobial agent, an anti-acne agent, an antibacterial agent, an
antifungal agent, an antiviral agent, a steroidal anti-inflammatory
agent, a non-steroidal anti-inflammatory agent, an anesthetic
agent, an antipruriginous agent, an antiprotozoal agent, an
anti-oxidant, a chemotherapeutic agent, an antidepressant, an anti
histamine, a vitamin, a hormone, a keratolytic agent and an
antidandruff agent.
23. The method of claim 1, further comprising administering to the
subject at least one additional active agent being capable of
treating said skin or mucosal membrane ailment caused by HPV.
24. The method of claim 1, wherein said at least one
tellurium-containing compound forms a part of a pharmaceutical
composition, said pharmaceutical composition further comprising a
pharmaceutically acceptable carrier.
25. The method of claim 24, wherein a concentration of said at
least one tellurium-containing compound ranges from about 0.01
weight percent to about 50 weight percents of the total weight of
said composition.
26. The method of claim 25, wherein a concentration of said at
least one tellurium-containing compound ranges from about 5 weight
percents to about 25 weight percents of the total weight of said
composition.
27. The method of claim 24, wherein said administering is effected
topically and said pharmaceutical composition is being in a form
selected from the group consisting of a cream, an ointment, a
paste, a gel, a lotion, a milk, a suspension, a solution, an
aerosol, a spray, a foam, a shampoo, a mousse, a serum, a swab, a
pledget, a pad, a tincture, a patch and a soap.
28. The method of claim 24, wherein said pharmaceutical composition
further comprises at least one additional active agent.
29. The method of claim 28, wherein said additional active agent is
selected from the group consisting of an antibiotic agent, an
antimicrobial agent, an anti-acne agent, an antibacterial agent, an
antifungal agent, an antiviral agent, a steroidal anti-inflammatory
agent, a non-steroidal anti-inflammatory agent, an anesthetic
agent, an antipruriginous agent, an antiprotozoal agent, an
anti-oxidant, a chemotherapeutic agent, an antidepressant, an anti
histamine, a vitamin, a hormone, a keratolytic agent and an
antidandruff agent.
30. The method of claim 24, wherein said pharmaceutical composition
further comprises at additional active agent being capable of
treating said skin or mucosal membrane ailment caused by HPV.
31. The method of claim 24, wherein said pharmaceutical composition
further comprises at least one ingredient selected from the group
consisting of a humectant, a deodorant agent, an antiperspirant, a
sun screening agent, a sunless tanning agent, a hair conditioning
agent, a pH adjusting agent, a chelating agent, a preservative, an
emulsifier, an occlusive agent, an emollient, a thickener, a
solubilizing agent, a penetration enhancer, an anti-irritant, a
colorant, a propellant and a surfactant.
32. The method of claim 24, wherein said pharmaceutical composition
has a pH that ranges from 4 to 7.
33. The method of claim 32, wherein said pharmaceutical composition
has a pH that ranges from 4 to 6.
34. A pharmaceutical composition identified for use in the
treatment of a skin or mucosal membrane ailment caused by a human
papilloma virus (HPV), comprising at least one tellurium-containing
compound and a pharmaceutically acceptable carrier.
35. The pharmaceutical composition of claim 34, wherein said at
least one tellurium-containing compound is selected from the group
consisting of tellurium dioxide (TeO.sub.2), a complex of
TeO.sub.2, a compound having general Formula I: ##STR00019## a
compound having general Formula II: ##STR00020## a compound having
general Formula III: ##STR00021## and a compound having general
Formula IV: ##STR00022## wherein: each of t, u and v is
independently 0 or 1; each of m and n is independently an integer
from 0 to 3; X is a halogen atom; Y is selected from the group
consisting of ammonium, phsophonium, potassium, sodium and lithium;
and each of R.sub.1-R.sub.22 is independently selected from the
group consisting of hydrogen, hydroxyalkyl, hydroxy, thiohydroxy,
alkyl, alkenyl, alkynyl, alkoxy, thioalkoxy, halogen, haloalkyl,
carboxy, carbonyl, alkylcarbonylalkyl, alkoxy, carboxyalkyl, acyl,
amido, cyano, N-monoalkylamidoalkyl, N,N-dialkylamidoalkyl,
cyanoalkyl, alkoxyalkyl, carbamyl, cycloalkyl, heteroalicyclic,
sulfonyl, sulfanyl, amine, aryl, heteroaryl, phosphate, phosphonate
and sulfoneamido.
36. The pharmaceutical composition of claim 35, wherein said
tellurium-containing compound is selected from the group consisting
of a compound having said general Formula I and a compound having
said general Formula II.
37. The pharmaceutical composition of claim 36, wherein t, u and v
are each 0.
38. The pharmaceutical composition of claim 37, wherein each of
R.sub.1, R.sub.8, R.sub.9 and R.sub.10 is hydrogen.
39. The pharmaceutical composition of claim 38, wherein X is
halogen.
40. The pharmaceutical composition of claim 39, wherein X is
chloride.
41. The pharmaceutical composition of claim 39, wherein Y is
ammonium.
42. The pharmaceutical composition of claim 39, wherein Y is
phosphonium.
43. The pharmaceutical composition of claim 35, wherein said
tellurium-containing compound has said general Formula III.
44. The pharmaceutical composition of claim 43, wherein each of
R.sub.11-R.sub.14 is hydrogen.
45. The pharmaceutical composition of claim 35, wherein said
tellurium-containing compound has said general Formula IV.
46. The pharmaceutical composition of claim 45, wherein n and m are
each 0.
47. The pharmaceutical composition of claim 46, wherein each of
R.sub.15, R.sub.18, R.sub.19 and R.sub.22 is hydrogen.
48. The pharmaceutical composition of claim 35, wherein said
complex of TeO.sub.2 is
TeO.sub.2.HOCH.sub.2CH.sub.2OH.NH.sub.4Cl.
49. The pharmaceutical composition of claim 34, being formulated
for systemic administration.
50. The pharmaceutical composition of claim 34, being formulated
for topical administration.
51. The pharmaceutical composition of claim 50, wherein a
concentration of said at least one tellurium-containing compound
ranges from about 0.01 weight percent to about 50 weight percents
of the total weight of the composition.
52. The pharmaceutical composition of claim 51, wherein a
concentration of said at least one tellurium-containing compound
ranges from about 5 weight percents to about 25 weight percents of
the total weight of the composition.
53. The pharmaceutical composition of claim 50, being in a form
selected from the group consisting of a cream, an ointment, a
paste, a gel, a lotion, a milk, a suspension, a solution, an
aerosol, a spray, a foam, a shampoo, a mousse, a serum, a swab, a
pledget, a pad, a tincture, a patch and a soap.
54. The pharmaceutical composition of claim 34, further comprising
at least one additional active agent.
55. The pharmaceutical composition of claim 54, wherein said
additional active agent is selected from the group consisting of an
antibiotic agent, an antimicrobial agent, an anti-acne agent, an
antibacterial agent, an antifungal agent, an antiviral agent, a
steroidal anti-inflammatory agent, a non-steroidal
anti-inflammatory agent, an anesthetic agent, an antipruriginous
agent, an antiprotozoal agent, an anti-oxidant, a chemotherapeutic
agent, an antidepressant, an anti histamine, a vitamin, a hormone,
a keratolytic agent and an antidandruff agent.
56. The pharmaceutical composition of claim 34, further comprising
at least one additional active agent being capable of treating said
skin or mucosal membrane ailment caused by HPV.
57. The pharmaceutical composition of claim 34, further comprising
at least one ingredient selected from the group consisting of a
humectant, a deodorant agent, an antiperspirant, a sun screening
agent, a sunless tanning agent, a hair conditioning agent, a pH
adjusting agent, a chelating agent, a preservative, an emulsifier,
an occlusive agent, an emollient, a thickener, a solubilizing
agent, a penetration enhancer, an anti-irritant, a colorant, a
propellant and a surfactant.
58. The pharmaceutical composition of claim 34, having a pH that
ranges from 4 to 7.
59. The pharmaceutical composition of claim 58, having a pH that
ranges from 4 to 6.
60. The pharmaceutical composition of claim 34, wherein said skin
or mucosal membrane ailment is selected from the group consisting
of verruca vulgaris, plantar warts, palmar warts, periungal warts,
planar warts, mosaic warts, genital warts, venereal warts
(condylomata acuminata), butcher's warts, malignant
epidermodyspasia verruciformis, advanced intraepithelial dysplasia,
cervical cancer, mepidermodysplasia verruciformis, cutnacous warts
in immunosuppressed patients, laryngeal papillomas and oral
papilloma.
61. The pharmaceutical composition of claim 34, being packaged in a
packaging material and identified in print, in or on said packaging
material, for use in the treatment of said skin or mucosal membrane
ailment.
Description
FIELD AND BACKGROUND OF THE INVENTION
[0001] The present invention relates to novel therapeutic methods
and pharmaceutical compositions for treating warts. More
particularly, the present invention relates to novel therapeutic
methods and pharmaceutical compositions for treating ailments
caused by human papilloma viruses.
[0002] Human papilloma virus (HPV) infections are common infections
of the outer layer of the skin, which affect most persons sometime
during their lifetime. To date, over seventy distinct types of HPVs
have been already identified. These viruses target the squamous
epithelia of the skin and mucosal membranes. Based on this
trophism, the different types of HPV have been subdivided into two
large categories: cutaneous and mucosal. A third category is
sometimes used to designate types of HPV specifically found in
people with epidermodysplasia verruciformis (EV).
[0003] HPV infections typically emerge as skin warts. However, by
being spread by auto-innoculation, warts may also occur at any
other location in the body. Subjects afflicted with warts may in
some cases experience complete regression after several months with
or without treatment with recurrence at the same or at different
locations.
[0004] Skin warts include, for example, common warts (e.g., verruca
vulgaris, plantar, palmar and periungal); planar warts (verruca
plana); mosaic warts; genital and venereal warts (e.g., condylomata
acuminata); butcher's warts; malignant epidermodyspasia
verruciformis; advanced intraepithelial dysplasia,
mepidermodysplasia verruciformis; cutnaeous warts in
immunosuppressed patients; laryngeal papillomas; and oral
papilloma. However, clinical manifestations sometimes further
include serious infections of the genital mucous membranes, (e.g.,
advanced intracpithelial dysplasia), which may progress to cervical
cancer.
[0005] Skin warts resulting from HPVs are unsightly and irritating,
and although the majority of such infections are benign and
self-limited, there are subtypes of papilloma virus that are
considered pre-malignant in certain clinical settings. Therefore,
the removal of emerged skin warts is highly recommended.
[0006] Throughout the years a number of therapies have been
developed for treating these coetaneous infections. However, most
of the presently known methods of treating warts are painful,
expensive, requiring long treatment periods and/or are ineffective.
Most of these methods are initially successful but involve a
longer-term treatment failure, exhibited by recurrence, as well as
side effects [see, for example, Goldfarbet al., Dermatol Clin,
1991; 9(2):287-96; Hettich, Dermatologica, 1984; 168 Supple
1:36-42; Bunney, M. H., Viral warts: their biology and treatment.
New York, N.Y.: Oxford University Press Inc., 1982; Belisario,
Australas J Dermatol, 1951; 1:20-30; and Beutneret al. Lancet,
1989; 1831-834].
[0007] The presently used methods of treating HPV infections
typically include the use of locally destructive chemicals or
agents, such as salicylic acid, lactic acid, trichloracetic acid,
dichloroacetic acid, nitric acid and glacial acetic acid;
surgically destructive methods such as excision, electrocautery,
electrodesiccation, curettage, blunt dissection and laser
vaporization or coagulation; blister-producing methods such as
liquid nitrogen cryotherapy, carbon dioxide cryotherapy and
cantharidin; cellular inhibition, which uses agents such as
podophyllin and podophyllotoxin, 5-fluorouracil, bleomycin,
colchicine, interferon local injections and radiation; altering the
cutaneous environment, which includes agents or techniques such as
retinoids, formalin, glutaraldehyde, aluminum chloride and heat
therapy; and immune stimulation methods of treatment, which include
dinitrochlorobenzene (DNCB), imiquimod (also known by the trade
name Aldara.TM.), interferon systemic injections and vaccination,
either autologous or intralesional.
[0008] Hence, the presently most common methods of warts treatment
can be divided into chemical, surgical and physical methods. The
physical methods typically include destruction of the infected
keratinocytes by cooling (e.g., liquid nitrogen) or heating (e.g.,
electrocautery, CO.sub.2 laser), and often lead to injury of
surrounding tissues, secondary infections and other undesired
consequences.
[0009] Surgical treatments are typically associated with
discomfort, prolonged healing and the formation of scars and/or
keloids, is addition to an inherent risk.
[0010] The chemical methods commonly use locally destructive
chemicals and typically include caustic chemicals that act through
nonspecific destructive mechanisms to cause cell death, killing the
infected keratinocytes. The keratinocytes are subsequently
desquamated from the skin surface. This non-specific form of
destructive therapy often causes side effects such as pain,
secondary infection, permanent scarring and is oftentimes
associated with recurrence of disease.
[0011] The chemical methods typically involve topical application
of the chemical agents as solutions, tinctures, creams, ointments,
patches, etc. One of the presently most used chemical agents for
treating warts is salicylic acid, which is typically administered
as a patch or a gel. A typical salicylic acid patch contains an
amount of salicylic acid in a sticky base or a rubber base.
However, the use of salicylic acid in the treatment of HPV requires
repeated administration of the composition for a prolonged period
of about 4-6 weeks, and is oftentimes unsuccessful.
[0012] Hence, most of the currently available methods focus on the
destruction of visible lesions rather than the underlying cause of
disease, namely the HPV. For example, removal of warts with
destructive chemical agents or with physical ablative means do not
affect viral particles that may be lurking in normal-appearing
areas surrounding the wart. This is one of the reasons of the high
rate of disease recurrence.
[0013] The inefficiency of the presently known methods of treating
warts have been widely studied and reported in the art. Thus, it
was found that using a liquid nitrogen, initial cure is seen in
52-83% of patients [Berth-Jones and Hutchinson, Br J Dermatol,
1992; 127(3):262-5; Erkens et al., J. A., Ned Tijdschr Geneeskd,
1991; 135(5):171-4]; Keefe and Dick. Clin Exp Dermatol, 1990;
15(4):260-3], however, only 57% of the patients remain clear of
warts after a median of 19 months [Keefe and Dick. Clin Exp
Dermatol, 1990; 15(4):260-3].
[0014] When using a histofreezer technique the success rate falls
to 28% [Erkens et al., J. A., Ned Tijdschr Geneeskd, 1991;
135(5):171-4] and is comparable with placebo or the success rates
achieved through direct in hypnotic suggestion (27-55%) [Ewin, D.
M., Am J Clin Hypn, 1992; 35(1):1-10]. Recently, however,
individual byproanalytic techniques were shown to cure 80% of
patients who have failed hypnosis [Robson et al., J Am Acad
Dermatol, 2000; 43(2 Pt 1):275-80].
[0015] Since 1970 intralesional bleomycine therapy success rate has
remained in the 70% range [see, for example, Sobh et al., Acta Derm
Venereol Stockh, 1991; 71(1):63-6; Shelley and Shelley, Arch
Dermatol, 1991; 127(2):234-6; Hayes and O'Keefe, J Am Acad
Dermatol, 1986; 15:1002-1006; Mishima and Matunaka, Acta Derm
Venereol (Stockh), 1971; 52:211-215; and Bennett and Reich, Ann
Intern Med, 1979; 90:945-948]. However, it was found that not all
warts are suitable for intralesional bleomycine, the treatment
exhibit significant systemic drug exposure and significant local
adverse and side effects. In addition, multiple treatments are
required to achieve substantial success.
[0016] Summarizing various published reports indicates that topical
standard salicylic acid treatment results, at best, in 40% cure
rate after 4 weeks compared to 8% cure in the placebo group.
Treatment with trichloro acetic acid typically results in 64-81%
cure rate, whereby treatment with 5-fluorouracil typically results
in even lower cure rates ranging from 10 to 50%. Carbon dioxide
laser evaporation for recalcitrant warts results in 31-86% cure
rate. This treatment, however, may result in significant
morbidity.
[0017] Using superpulsed mode to overcome these limitations was
found to convey only a slight advantage. Comparable results were
obtained with infrared coagulation. Early studies with pulsed dye
lasers showed promising results, which have not been confirmed yet
by later studies.
[0018] Since recalcitrant and recurrent warts are more common in
patients with a cell-mediated immune deficiency state, it is
suggested that spontaneous regression or successful treatment
depend on either naturally or iatrogenically related stimulation of
immunity [Robson et al. J Am Acad Dermatol, 2000; 43(2 Pt
1):275-80]. Thus, several systemic and topical immunotherapies for
warts have been reported, including squalic acid dibutylester,
levamizole, and interferons beta and gamma. The efficacy of these
therapies, however, was not definite.
[0019] The presently known methods for treating warts therefore
suffer major disadvantages, in terms of both efficacy and adverse
side effects associated therewith.
[0020] There is thus a widely recognized need for, and it would be
highly advantageous to have novel methods of treating warts, devoid
of the above limitations.
[0021] Various tellurium compounds have been described in the art
as having immunomodulating properties. These compounds are taught,
for example, in U.S. Pat. Nos. 4,752,614; 4,761,490; 4,764,461 and
4,929,739, and in a recently filed U.S. Provisional Patent
Application No. 60/610,660, which are all incorporated by reference
as if fully set forth herein. U.S. Pat. No. 4,752,614, which is
also incorporated by reference as if fully set forth herein,
teaches the use of certain tellurium compounds in the treatment of
certain tumors, autoimmune diseases, immune diseases and infectious
diseases. An anti-viral activity of these compounds was
demonstrated in this patent in plants and animals, whereby the
virus that is exemplified is West Nile Virus, which affects the
central nervous system.
[0022] The use of tellurium compounds to treat HPV and hence warts
has never been suggested nor practiced hitherto.
SUMMARY OF THE INVENTION
[0023] According to one aspect of the present invention there is
provided a method of treating a skin or mucosal membrane ailment
caused by a human papilloma virus (HPV) in a subject in need
thereof. The method comprises administering to the subject a
therapeutically effective amount of at least one
tellurium-containing compound.
[0024] According to further features in preferred embodiments of
the invention described below, the tellurium-containing compound is
selected from the group consisting of tellurium dioxide
(TeO.sub.2), a complex of TeO.sub.2, a compound having general
Formula I:
##STR00001##
a compound having general Formula II:
##STR00002##
a compound having general Formula III:
##STR00003##
a compound having general Formula IV:
##STR00004##
wherein: [0025] each oft, u and v is independently 0 or 1; [0026]
each of m and n is independently an integer from 0 to 3; [0027] X
is a halogen atom; [0028] Y is selected from the group consisting
of ammonium, phsophonium, potassium, sodium and lithium; and each
of R.sub.1-R.sub.22 is independently selected from the group
consisting of hydrogen, hydroxyalkyl, hydroxy, thiohydroxy, alkyl,
alkenyl, alkynyl, alkoxy, thioalkoxy, halogen, haloalkyl, carboxy,
carbonyl, alkylcarbonylalkyl, alkoxy, carboxyalkyl, acyl, amido,
cyano, N-monoalkylamidoalkyl, N,N-dialkylamidoalkyl, cyanoalkyl,
alkoxyalkyl, carbamyl, cycloalkyl, heteroalicyclic, sulfonyl,
sulfinyl, sulfate, amine, aryl, heteroaryl, phosphate, phosphonate
and sulfoneamido.
[0029] Preferred tellurium-containing compounds are those having
general Formula I above and those having general Formula II
above.
[0030] More preferred compounds are those having one or more of the
following features: [0031] t, u and v are each 0; [0032] each of
R.sub.1, R.sub.8, R.sub.9 and R.sub.10 is hydrogen; [0033] X is a
halogen atom, preferably chloro; and [0034] Y is ammonium or
phosphonium, preferably ammonium.
[0035] Additional preferred compounds are those having general
Formula III above, wherein, preferably, each of R.sub.11-R.sub.14
is hydrogen.
[0036] Additional preferred compounds are those having general
Formula IV above.
[0037] More preferred compounds in this category are those having
one or more of the following features: [0038] n and m are each 0;
and [0039] each of R.sub.15, R.sub.18, R.sub.19 and R.sub.22 is
hydrogen.
[0040] According to further features in preferred embodiments of
the invention described below, the administering is effected
systemically.
[0041] According to still further features in the described
preferred embodiments the therapeutically effective amount ranges
from about 0.01 mg/m.sup.2/day to about 10.0 mg/m.sup.2/day.
[0042] According to further features in preferred embodiments of
the invention described below, the administering is effected
topically.
[0043] According to still further features in the described
preferred embodiments topically administering the compound is
effected by applying onto a treated skin or mucosal membrane area a
therapeutically effective amount of the at least one
tellurium-containing compound described above.
[0044] According to still further features in the described
preferred embodiments the skin or mucosal membrane ailment is
selected from the group consisting of verruca vulgaris, plantar
warts, palmar warts, periungal warts, planar warts, mosaic warts,
genital warts, venereal warts (condylomata acuminata), butcher's
warts, malignant epidermodyspasia verruciformis, advanced
intraepithelial dysplasia, cervical cancer, mepidermodysplasia
verruciformis, cutnaeous warts in immunosuppressed patients,
laryngeal papillomas and oral papilloma.
[0045] According to still further features in the described
preferred embodiments the method further comprises administering to
the subject an additional active agent.
[0046] The additional active agent can be, for example, an
antibiotic agent, an antimicrobial agent, an anti-acne agent, an
antibacterial agent, an antifungal agent, an antiviral agent, a
steroidal anti-inflammatory agent, a non-steroidal
anti-inflammatory agent, an anesthetic agent, an antipruriginous
agent, an antiprotozoal agent, an anti-oxidant, a chemotherapeutic
agent, an antidepressant, an anti histamine, a vitamin, a hormone,
a keratolytic agent and an antidandruff agent.
[0047] According to still further features in the described
preferred embodiments the method further comprises administering to
the subject an additional active agent that is capable of treating
the skin or mucosal membrane ailment caused by the HPV.
[0048] According to still further features in the described
preferred embodiments the tellurium-containing compound forms a
part of a pharmaceutical composition, which further comprises a
pharmaceutically acceptable carrier.
[0049] Hence, according to another aspect of the present invention
there is provided a pharmaceutical composition identified for use
in the treatment of a skin or mucosal membrane ailment caused by a
human papilloma virus (HPV), comprising at least one
tellurium-containing compound as described hereinabove and a
pharmaceutically acceptable carrier.
[0050] According to further features in preferred embodiments of
the invention described below, a concentration of the at least one
tellurium-containing compound ranges from about 0.01 weight percent
to about 50 weight percents of the total weight of the
composition.
[0051] According to still further features in the described
preferred embodiments the concentration of the at least one
tellurium-containing compound ranges from about 5 weight percents
to about 25 weight percents of the total weight of the
composition.
[0052] According to still further features in the described
preferred embodiments, when used for topical application, the
pharmaceutical composition is being in a form selected from the
group consisting of a cream, an ointment, a paste, a gel, a lotion,
a milk, a suspension, a solution, an aerosol, a spray, a foam, a
shampoo, a mousse, a serum, a swab, a pledget, a pad, a tincture, a
patch and a soap.
[0053] According to still further features in the described
preferred embodiments the pharmaceutical composition further
comprises at least one additional active agent, as described
hereinabove.
[0054] According to still further features in the described
preferred embodiments the pharmaceutical composition further
comprises at least one ingredient such as, but not limited to, a
humectant, a deodorant agent, an antiperspirant, a sun screening
agent, a sunless tanning agent, a hair conditioning agent, a pH
adjusting agent, a chelating agent, a preservative, an emulsifier,
an occlusive agent, an emollient, a thickener, a solubilizing
agent, a penetration enhancer, an anti-irritant, a colorant, a
propellant and a surfactant.
[0055] According to still further features in the described
preferred embodiments the pharmaceutical composition has a pH that
ranges from 4 to 7.
[0056] According to still further features in the described
preferred embodiments the pharmaceutical composition has a pH that
ranges from 4 to 6.
[0057] The present invention successfully addresses the
shortcomings of the presently known configurations by providing
novel compositions and methods utilizing same for treating warts
and related ailments caused by HPVs, which are highly efficient,
and induce minimal or no adverse side effects.
[0058] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. Although
methods and materials similar or equivalent to those described
herein can be used in the practice or testing of the present
invention, suitable methods and materials are described below. In
case of conflict, the patent specification, including definitions,
will control. In addition, the materials, methods, and examples are
illustrative only and not intended to be limiting.
[0059] As used herein, the term "treating" includes abrogating,
substantially inhibiting, slowing or reversing the progression of a
condition, substantially ameliorating clinical or aesthetical
symptoms of a condition or substantially preventing the appearance
of clinical or aesthetical symptoms of a condition.
[0060] The term "comprising" means that other steps and ingredients
that do not affect the final result can be added. This term
encompasses the terms "consisting of" and "consisting essentially
of".
[0061] The phrase "consisting essentially of" means that the
composition or method may include additional ingredients and/or
steps, but only if the additional ingredients and/or steps do not
materially alter the basic and novel characteristics of the claimed
composition or method.
[0062] The term "method" refers to manners, means, techniques and
procedures for accomplishing a given task including, but not
limited to, those manners, means, techniques and procedures either
known to, or readily developed from known manners, means,
techniques and procedures by practitioners of the chemical,
pharmacological, biological, biochemical and medical arts.
[0063] The term "active ingredient" refers to a pharmaceutical
agent including any natural or synthetic chemical substance that
subsequent to its application has, at the very least, at least one
desired pharmaceutical or therapeutic effect.
[0064] The term "therapeutically effective amount" or
"pharmaceutically effective amount" denotes that dose of an active
ingredient or a composition comprising the active ingredient that
will provide the therapeutic effect for which the active ingredient
is indicated, herein, treating an HPV-caused ailment.
[0065] As used herein, the singular form "a," "an," and "the"
include plural references unless the context clearly dictates
otherwise. For example, the term "a compound" or "at least one
compound" may include a plurality of compounds, including mixtures
thereof.
[0066] Throughout this disclosure, various aspects of this
invention can be presented in a range format. It should be
understood that the description in range format is merely for
convenience and brevity and should not be construed as an
inflexible limitation on the scope of the invention. Accordingly,
the description of a range should be considered to have
specifically disclosed all the possible subranges as well as
individual numerical values within that range. For example,
description of a range such as from 1 to 6 should be considered to
have specifically disclosed subranges such as from 1 to 3, from 1
to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as
well as individual numbers within that range, for example, 1, 2, 3,
4, 5, and 6. This applies regardless of the breadth of the
range.
[0067] Whenever a numerical range is indicated herein, it is meant
to include any cited numeral (fractional or integral) within the
indicated range. The phrases "ranging/ranges between" a first
indicate number and a second indicate number and "ranging/ranges
from" a first indicate number "to" a second indicate number are
used herein interchangeably and are meant to include the first and
second indicated numbers and all the fractional and integral
numerals therebetween.
BRIEF DESCRIPTION OF THE DRAWINGS
[0068] The patent or application file contains at least one drawing
executed in color. Copies of this patent or patent application
publication with color drawings will be provided by the Office upon
request and payment of the necessary fee.
[0069] The invention is herein described, by way of example only,
with reference to the accompanying drawings. With specific
reference now to the drawings in detail, it is stressed that the
particulars shown are by way of example and for purposes of
illustrative discussion of the preferred embodiments of the present
invention only, and are presented in the cause of providing what is
believed to be the most useful and readily understood description
of the principles and conceptual aspects of the invention. In this
regard, no attempt is made to show structural details of the
invention in more detail than is necessary for a fundamental
understanding of the invention, the description taken with the
drawings making apparent to those skilled in the art how the
several forms of the invention may be embodied in practice.
[0070] In the drawings:
[0071] FIG. 1 is a photograph of the perianal area of a patient
afflicted with condyloma warts, as described in Example 2, before
treatment;
[0072] FIG. 2 is a photograph of the perianal area of a patient
afflicted with condyloma warts, as described in Example 2,
following about two weeks of treatment with an exemplary
composition according to the present invention;
[0073] FIG. 3 is a photograph of the perianal area of a patient
afflicted with condyloma warts, as described in Example 2,
following about four weeks of treatment with an exemplary
composition according to the present invention;
[0074] FIG. 4 is a photograph of the perianal area of a patient
afflicted with condyloma warts, as described in Example 2,
following about six weeks of treatment with an exemplary
composition according to the present invention;
[0075] FIG. 5 is a photograph of the perianal area of a patient
afflicted with condyloma warts, as described in Example 2,
following about eight weeks of treatment with an exemplary
composition according to the present invention;
[0076] FIG. 6 is a photograph of a patient afflicted with verrucca
lesion on the hand, as described in Example 3, before
treatment;
[0077] FIG. 7 is a photograph of a patient afflicted with verrucca
lesion on the hand, as described in Example 3, following about four
weeks of treatment with an exemplary composition according to the
present invention;
[0078] FIG. 8 is a photograph of a patient afflicted with verrucca
lesion on the hand, as described in Example 3, following about ten
weeks of treatment with an exemplary composition according to the
present invention;
[0079] FIG. 9 is a photograph of a patient afflicted with verrucca
lesions on the hand, as described in Example 4, before
treatment;
[0080] FIG. 10 is a photograph of a patient afflicted with verrucca
lesions on the hand, as described in Example 4, following about two
weeks of treatment with an exemplary composition according to the
present invention;
[0081] FIG. 11 is a photograph of a patient afflicted with verrucca
lesions on the hand, as described in Example 4, following about
four weeks of treatment with an exemplary composition according to
the present invention;
[0082] FIGS. 12a-c are photographs of the genital area of a patient
afflicted with condyloma warts, as described in Example 4, before
treatment;
[0083] FIGS. 13a-b are photographs of a patient afflicted with
condyloma warts, as described in Example 5, following about two
weeks of treatment with an exemplary cream composition according to
the present invention;
[0084] FIGS. 14a-b are photographs of the genital area of a patient
afflicted with condyloma warts, as described in Example 5,
following about four weeks of treatment with an exemplary cream
composition according to the present invention;
[0085] FIGS. 15a-b are photographs of the genital area of a patient
afflicted with condyloma warts, as described in Example 6, before
treatment;
[0086] FIGS. 16a-c are photographs of the genital area of a patient
afflicted with condyloma warts, as described in Example 6,
following about two weeks of treatment with an exemplary cream
composition according to the present invention;
[0087] FIG. 17 is a photograph of the genital area of a patient
afflicted with condyloma warts, as described in Example 6,
following about four weeks of treatment with an exemplary cream
composition according to the present invention;
[0088] FIG. 18 is a photograph of the genital area of a patient
afflicted with condyloma warts, as described in Example 7, before
treatment;
[0089] FIG. 19 is a photograph of the genital area of a patient
afflicted with condyloma warts, as described in Example 7,
following about two weeks of treatment with an exemplary cream
composition according to the present invention;
[0090] FIG. 20 is a photograph of a patient afflicted with
condyloma warts in the anus, as described in Example 8, before
treatment;
[0091] FIG. 21 is a photograph of a patient afflicted with
condyloma warts in the anus, as described in Example 8, following
two days of treatment with an exemplary cream composition according
to the present invention;
[0092] FIG. 22 is a photograph of a patient afflicted with
condyloma warts in the anus, as described in Example 8, following
about 5 weeks of treatment with an exemplary cream composition
according to the present invention;
[0093] FIG. 23 is a photograph of a patient afflicted with
condyloma warts in the anus, as described in Example 8, following
about 8 weeks of treatment with an exemplary cream composition
according to the present invention;
[0094] FIGS. 24a-b are photographs of a patient afflicted with
verruca vulgaris in both hands, as described in Example 9, before
treatment;
[0095] FIGS. 25a-b are photographs of a patient afflicted with
verruca vulgaris in both hands, as described in Example 9,
following about 3 weeks of treatment with an exemplary cream
composition according to the present invention;
[0096] FIGS. 26a-b are photographs of a patient afflicted with
verruca vulgaris in both hands, as described in Example 9,
following about 6 weeks of treatment with an exemplary cream
composition according to the present invention.
[0097] FIGS. 27a-d are photographs of the genital area of a patient
afflicted with condyloma warts, as described in Example 10, before
treatment (FIG. 27a) and following about 4 weeks (FIG. 27b), about
6 weeks (FIG. 27c) and about 8 weeks (FIG. 27d) treatment with an
exemplary cream composition according to the present invention;
[0098] FIGS. 28a-d are photographs of the genital area of a patient
afflicted with condyloma warts, as described in Example 11, before
treatment (FIG. 28a) and following about 2 weeks (FIG. 28b), about
4 weeks (FIG. 28c) and about 7 weeks (FIG. 28d) treatment with an
exemplary cream composition according to the present invention;
[0099] FIGS. 29a-e are photographs of the anus of a patient
afflicted with condyloma warts, as described in Example 12, before
treatment (FIG. 29a) and following about 2 weeks (FIG. 29b), about
5 weeks (FIG. 28c), about 8 weeks (FIG. 29d) and about 10 weeks
(FIG. 29e) treatment with an exemplary cream composition according
the present invention; and
[0100] FIGS. 30a-d are photographs of the anus of a patient
afflicted with condyloma warts, as described in Example 13, before
treatment (FIG. 30a) and following about 5 weeks (FIG. 30b), about
7 weeks (FIG. 30c) and about 9 weeks (FIG. 30d) treatment with an
exemplary cream composition according to the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0101] The present invention is of novel compositions of
tellurium-containing compounds which can be efficiently used for
treating skin and mucosal membrane ailments caused by HPVs. The
present invention is therefore further of methods of treating such
ailments, using tellurium-containing compounds. Specifically, the
methods and compositions of the present invention can be used to
treat any clinical manifestation of HPVs, such as, for example,
common warts (e.g., verruca vulgaris), genital and venereal warts
(e.g., condylomata acuminata), butcher's warts, malignant
epidermodyspasia verruciformis, cervical cancer, mepidermodysplasia
verruciformis, cutnaeous warts in immunosuppressed patients,
laryngeal papillomas and oral papilloma.
[0102] The principles and operation of the compositions and methods
according to the present invention may be better understood with
reference to the drawings and accompanying descriptions.
[0103] Before explaining at least one embodiment of the invention
in detail, it is to be understood that the invention is not limited
in its application to the details set forth in the following
description or exemplified by the Examples. The invention is
capable of other embodiments or of being practiced or carried out
in various ways. Also, it is to be understood that the phraseology
and terminology employed herein is for the purpose of description
and should not be regarded as limiting.
[0104] As mentioned in the Background section hereinabove,
tellurium-containing compounds have been described in the art as
immunomodulators. A particularly effective family of
tellurium-containing compounds is described, for example, in U.S.
Pat. Nos. 4,752,614; 4,761,490; 4,764,461 and 4,929,739. The
immunomodulating properties of this family of tellurium-containing
compounds is described, for example, in U.S. Pat. Nos. 4,962,207,
5,093,135, 5,102,908 and 5,213,899, which are all incorporated by
reference as if fully set forth herein.
[0105] One of the most promising compounds described in these
patents is ammonium trichloro(dioxyethylene-O,O')tellurate, which
is also referred to herein and in the art as AS101. As is widely
described in the art, AS101, as a representative example of the
family of tellurium-containing compound discussed hereinabove,
exhibits potent antiviral ["Antibabesial effect of the
immunomodulator AS101 in mice: role of increased production of
nitric oxide". Parasite Immunol 1996 June; "The antitumoral effect
of the immunomodulator AS101 and paclitaxel (Taxol) in a murine
model of lung adenocarcinoma". J Immunol 1996 February; "The
protective role of the immunomodulator AS101 against
chemotherapy-induced alopecia studies on human and animal models".
Int J Cancer 1996 January; and "Mechanism of radioprotection
conferred by the immunomodulator AS101". Exp Hematol 1993 January],
tumoricidal ["Effect of the immunomodulator AS101 on
chemotherapy-induced multilineage myelosuppression,
thrombocytopenia, and anemia in mice". Exp Hematol 1995 December;
and "Restoration of murine cytomegalovirus (MCMV) induced
myelosuppression by AS101". Immunol Lett 1994 December] and
adjuvant activity.
[0106] It has been suggested that AS101, as well as other
tellurium-containing immunomodulators, stimulate the innate and
acquired arm of the immune response. It is a potent inducer of
interferon (IFN) in mice ["Delay in the onset of systemic lupus
erythematosus following treatment with the immunomodulator AS101:
association with IL-10 inhibition and increase in TNF-alpha
levels". J Immunol 1997 September; "The immunomodulator AS-101
inhibits IL-10 release and augments TNF alpha and IL-1 alpha
release by mouse and human mononuclear phagocytes". Cell Immunol
1997 March; "The antitumoral effect of the immunomodulator AS101
and paclitaxel (Taxol) in a murine model of lung adenocarcinoma". J
Immunol 1996 February] and humans ["Effect of the immunomodulator
AS101 on chemotherapy-induced multilineage myelosuppression,
thrombocytopenia, and anemia in mice". Exp Hematol 1995
December].
[0107] AS101, as well as other tellurium-containing
immunomodulators, have also been shown to induce the secretion of a
spectrum of cytokines, such as IL-1, IL-6 and TNF-.alpha.. The
macrophages have been characterized as the main target for AS101
["Up-regulation by ammonium trichloro(dioxoethylene-0,0') tellurate
(AS101) of Fas/Apo-1 expression on B16 melanoma cells: implications
for the antitumor effects of AS101". J Immunol 1998 October] and it
found to inhibit IL-10 at the m-RNA level while increasing at the
same time the IL-12.
[0108] Other publications describing the immunomodulation
properties of AS101 include, for example, "The immunomodulator
AS101 restores T(H1) type of response suppressed by Babesia
rodhaini in BALB/c mice". Cell Immunol 1998 February; "Predominance
of THI response in tumor-bearing mice and cancer patients treated
with AS101". J Natl Cancer Inst 1996 September; "AS-101: a
modulator of in vitro T-cell proliferation". Anticancer Drugs 1993
June; "The immunomodulator AS101 administered orally as a
chemoprotective and radioprotective agent". Int J Immunopharmacol
1992 May; "Inhibition of the reverse transcriptase activity and
replication of human immunodeficiency virus type 1 by AS101 in
vitro". AIDS Res Hum Retroviruses 1992 May; "Immunomodulatory
effects of AS101 on interleukin-2 production and T-lymphocyte
function of lymphocytes treated with psoralens and ultraviolet A".
Photodermatol Photoimmunol Photomed 1992 February; "Use and
mechanism of action of AS101 in protecting bone marrow colony
forming units-granulocyte-macrophage following purging with ASTA-Z
7557". Cancer Res 1991 October 15; "The effect of the
immunomodulator agent AS101 on interleukin-2 production in systemic
lupus erythematosus (SLE) induced in mice by a pathogenic anti-DNA
antibody". Clin Exp Immunol 1990 March; "Toxicity study in rats of
a tellurium based immunomodulating drug, AS-101: a potential drug
for AIDS and cancer patients". Arch Toxicol 1989; "The biological
activity and immunotherapeutic properties of AS-101, a synthetic
organotellurium compound". Nat Immun Cell Growth Regul 1988; and "A
new immunomodulating compound (AS-101) with potential therapeutic
application". Nature 1987 November.
[0109] AS101, as well as other tellurium-containing
immunomodulators, are therefore capable of skewing the immune
response towards a Th1 phenotype. This type of response is crucial
against intracellular pathogens such as viruses.
[0110] Furthermore, toxicity tests have showed that LD50 values in
rats following intravenous and intramuscular dosage of AS101 are
500-1000 folds higher than the immunology effective dose. These
tellurium-containing compounds are therefore further characterized
as substantially non-toxic.
[0111] Based on these findings, while conceiving the present
invention, it was envisioned that since AS101 is a potent modulator
of the immune response from Th2 to Th1 response, and is further
characterized as a substantially non-toxic agent, this
tellurium-containing compound, as well as other tellurium compounds
of this family, could serve as potent therapeutic agents against
infections caused by HPV, devoid of the disadvantages associated
with the presently known agents for treating HPV infections
described hereinabove.
[0112] It should be noted in this respect that although AS101 has
been shown to exert an anti-viral activity, in studies conducted
heretofore, its efficacy as an anti-viral agent against human
viruses was found to be insufficient.
[0113] As is further mentioned hereinabove, another class of
tellurium-containing compounds has been recently disclosed in U.S.
Provisional Patent Application No. 60/610,660. As taught in this
patent application, this class of tellurium compounds was also
shown to exert immunomodulating properties and therefore, it was
further envisioned that these compounds could also serve as potent
therapeutic agents against infections caused by HPV.
[0114] As is demonstrated in the Examples section that follows,
while reducing the present invention to practice, it was indeed
found that treating human patients afflicted with various HPV
infections with a tellurium-containing compound such as AS101 was
highly efficient, resulting in high treatment responsiveness and
minimized side effects.
[0115] Hence, according to one aspect of the present invention
there is provided a method of treating a skin or mucosal membrane
ailment caused by HPV, which is effected by administering to a
subject in need thereof a therapeutically effective amount of one
or more tellurium-containing compounds.
[0116] As used herein, the phrase "tellurium-containing compound"
encompasses any compound that includes one or more tellurium atoms
and exhibits immunomodulating properties.
[0117] The phrase "immunomodulating properties" includes any effect
of the compound on the immune response of a subject. Exemplary
immunomodulating properties can be manifested, for example, by an
effect on cytokines secretion, interleukins production, lymphocytes
function, and the like.
[0118] The compound can be, for example, an inorganic
tellurium-containing compound such as, for example, tellurium
dioxide (TeO.sub.2), halogenated tellurium, sulfonated tellurium,
phsophorylated tellurium, as well as salts thereof (e.g., ammonium
salts, alkaline salts, phosphonium salts and the like) and any
complexes thereof.
[0119] The compound can alternatively be an organic
tellurium-containing compound which includes one or more tellurium
atoms and one or more organic moieties that are attached
thereto.
[0120] Representative examples of inorganic tellurium-containing
compounds that were shown to exert immunomodulating properties and
hence are particularly useful in the context of the present
invention include, for example, TeO.sub.2 and TeX.sub.4, wherein X
is halogen.
[0121] As used herein, the term "halogen", which is also referred
to herein interchangeably as "a halogen atom" or "halo", includes
chloro (Cl), bromo (Br), iodo (I) and fluoro (F).
[0122] Also included are compounds that form TeO.sub.2 in aqueous
solutions, preferably in the form of a complex such as, for
example, a TeO.sub.2 complex with citric acid or ethylene glycol. A
representative example of the latter is the complex
TeO.sub.2.HOCH.sub.2CH.sub.2OH.NH.sub.4Cl.
[0123] Organic tellurium-containing compounds that were shown to
exert immunomodulating properties and hence are particularly useful
in the context of the present invention include, for example,
ammonium salts, or any other salts, of halogenated
tellurium-containing compounds having a bidentate cyclic moiety
attached to the tellurium atom. The bidentate cyclic moiety is
preferably a di-oxo moiety having two oxygen atoms attached to the
tellurium atom. Alternatively, the bidentate cyclic moiety can be a
di-thio moiety, in which two sulfur atoms are attached to the
tellurium atom.
[0124] Preferred compounds in this category are collectively
represented by the general Formula I:
##STR00005##
[0125] In the general Formula I above, each oft, u and v is
independently 0 or 1, such that the compound may include a
five-membered ring, a six-membered ring, a seven-membered ring or
an eight-membered ring. Preferably, each of t, u and v is 0, such
that the compound includes a five-membered ring. [0126] X is a
halogen atom, as described hereinabove, and is preferably chloro.
[0127] Y is selected from the group consisting of ammonium,
phsophonium, potassium, sodium and lithium, and is preferably
ammonium. [0128] each of R.sub.1-R.sub.10 is independently selected
from the group consisting of hydrogen, hydroxyalkyl, hydroxy,
thiohydroxy, alkyl, alkenyl, alkynyl, alkoxy, thioalkoxy, halogen,
haloalkyl, carboxy, carbonyl, alkylcarbonylalkyl, alkoxy,
carboxyalkyl, acyl, amido, cyano, N-monoalkylamidoalkyl,
N,N-dialkylamidoalkyl, cyanoalkyl, alkoxyalkyl, carbamyl,
cycloalkyl, heteroalicyclic, sulfonyl, sulfinyl, sulfate, amine,
aryl, heteroaryl, phosphate, phosphonate and sulfoneamido.
[0129] As used herein, the term "alkyl" refers to a saturated
aliphatic hydrocarbon including straight chain and branched chain
groups. Preferably, the alkyl group has 1 to 20 carbon atoms.
Whenever a numerical range; e.g., "1-20", is stated herein, it
implies that the group, in this case the alkyl group, may contain 1
carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and
including 20 carbon atoms. More preferably, the alkyl is a medium
size alkyl having 1 to 10 carbon atoms. Most preferably, unless
otherwise indicated, the alkyl is a lower alkyl having 1 to 5
carbon atoms. The alkyl group may be substituted or unsubstituted.
When substituted, the substituent group can be, for example,
hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl,
heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy,
thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, sulfate,
cyano, nitro, sulfonamide, phosphonyl, phosphinyl, carbonyl,
thiocarbonyl, carboxy, thiocarboxy, carbamate, thiocarbamate,
amido, sulfonamido, and amino, as these terms are defined
herein.
[0130] As used herein, the term "hydroxyalkyl" refers to an alkyl,
as this term is defined herein, substituted by a hydroxy group, as
defined herein, and includes, for example, hydroxymethyl,
hydroxyethyl, hydroxypropyl and hydroxy-n-butyl.
[0131] The term "haloalkyl" refers to an alkyl, as this term is
defined herein, substituted by a halogen, as defined herein, and
includes, for example, chloromethyl, 2-iodoethyl, 4-bromo-n-butyl,
iodoethyl, 4-bromo-n-pentyl and the like.
[0132] The term "alkanoyloxy" refers to a carbonyl group, as define
herein and includes, for example, acetyl, propionyl, butanoyl and
the like.
[0133] The term "carboxyalkyl" refers to an alkyl, as this term is
defined herein, substituted by a carboxy group, as defined herein,
and includes, for example, carboxymethyl, carboxyethyl,
ethylenecarboxy and the like.
[0134] The term "alkylcarbonylalkyl" refers to an alkyl, as this
term is defined herein, substituted by a carbonyl group, as defined
herein, and includes, for example, methanoylmethyl, ethanoylethyl
and the like.
[0135] The term "amidoalkyl" refers to an alkyl, as this term is
defined herein, substituted by an amide group, as defined herein,
and includes, for example, --CH.sub.2CONH.sub.2;
--CH.sub.2CH.sub.2CONH.sub.2; --CH.sub.2CH.sub.2CH.sub.2CONH.sub.2
and the like.
[0136] The term "cyanoalkyl" refers to an alkyl, as this term is
defined herein, substituted by an cyano group, as defined herein,
and includes, for example, --CH.sub.2CN; --CH.sub.2CH.sub.2CN;
--CH.sub.2CH.sub.2CH.sub.2CN and the like.
[0137] The term "N-monoalkylamidoalkyl" refers to an alkyl, as this
term is defined herein, substituted by an amide group, as defined
herein, in which one of R' and R'' is an alkyl, and includes, for
example, --CH.sub.2CH.sub.2CONHCH.sub.3, and
--CH--.sub.2CONHCH.sub.2CH.sub.3.
[0138] The term N,N-dialkylamidoalkyl refers to an alkyl, as this
term is defined herein, substituted by an amide group, as defined
herein, in which both R' and R'' are alkyl, and includes, for
example, --CH.sub.2CON(CH.sub.3).sub.2;
CH.sub.2CH.sub.2CON(CH.sub.2--CH.sub.3).sub.2 and the like.
[0139] A "cycloalkyl" group refers to an all-carbon monocyclic or
fused ring (i.e., rings which share an adjacent pair of carbon
atoms) group wherein one of more of the rings does not have a
completely conjugated pi-electron system. Examples, without
limitation, of cycloalkyl groups are cyclopropane, cyclobutane,
cyclopentane, cyclopentene, cyclohexane, cyclohexadiene,
cycloheptane, cycloheptatriene, and adamantane. A cycloalkyl group
may be substituted or unsubstituted. When substituted, the
substituent group can be, for example, alkyl, hydroxyalkyl,
trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,
heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy,
thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, cyano, nitro,
phosphonyl, phosphinyl, carbonyl, thiocarbonyl, carboxy,
thiocarboxy, carbamate, thiocarbamate, amido, sulfonamido, and
amino, as these terms are defined herein.
[0140] An "alkenyl" group refers to an alkyl group which consists
of at least two carbon atoms and at least one carbon-carbon double
bond.
[0141] An "alkynyl" group refers to an alkyl group which consists
of at least two carbon atoms and at least one carbon-carbon triple
bond.
[0142] An "aryl" group refers to an all-carbon monocyclic or
fused-ring polycyclic (i.e., rings which share adjacent pairs of
carbon atoms) groups having a completely conjugated pi-electron
system. Examples, without limitation, of aryl groups are phenyl,
naphthalenyl and anthracenyl. The aryl group may be substituted or
unsubstituted. When substituted, the substituent group can be, for
example, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl,
alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy,
aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl,
sulfate, cyano, nitro, phosphonyl, phosphinyl, phosphonium,
carbonyl, thiocarbonyl, carboxy, thiocarboxy, carbamate,
thiocarbamate, amido, sulfonamido, and amino, as these terms are
defined herein.
[0143] A "heteroaryl" group refers to a monocyclic or fused ring
(i.e., rings which share an adjacent pair of atoms) group having in
the ring(s) one or more atoms, such as, for example, nitrogen,
oxygen and sulfur and, in addition, having a completely conjugated
pi-electron system. Examples, without limitation, of heteroaryl
groups include pyrrole, furan, thiophene, imidazole, oxazole,
thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline
and purine. The heteroaryl group may be substituted or
unsubstituted. When substituted, the substituent group can be, for
example, alkyl, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl,
alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy,
aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl,
sulfate, cyano, nitro, phosphonyl, phosphinyl, phosphonium,
carbonyl, thiocarbonyl, carboxy, thiocarboxy, carbamate,
thiocarbamate, amido, sulfonamido, and amino, as these terms are
defined herein.
[0144] A "heteroalicyclic" group refers to a monocyclic or fused
ring group having in the ring(s) one or more atoms such as
nitrogen, oxygen and sulfur. The rings may also have one or more
double bonds. However, the rings do not have a completely
conjugated pi-electron system. The heteroalicyclic may be
substituted or unsubstituted. When substituted, the substituted
group can be, for example, lone pair electrons, alkyl,
hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl,
heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy,
thiohydroxy, thioalkoxy, thioaryloxy, sulfinyl, sulfonyl, sulfate,
cyano, nitro, phosphonyl, phosphinyl, phosphonium, carbonyl,
thiocarbonyl, carboxy, thiocarboxy, carbamate, thiocarbamate,
amido, sulfonamido, and amino, as these terms are defined
herein.
[0145] Representative examples are piperidine, piperazine,
tetrahydro furane, tetrahydropyrane, morpholino and the like.
[0146] A "hydroxy" group refers to an --OH group.
[0147] An "alkoxy" group refers to both an --O-alkyl and an
--O-cycloalkyl group, as defined herein.
[0148] An "aryloxy" group refers to both an --O-aryl and an
--O-heteroaryl group, as defined herein.
[0149] A "thiohydroxy" group refers to a --SH group.
[0150] A "thioalkoxy" group refers to both an --S-alkyl group, and
an --S-cycloalkyl group, as defined herein.
[0151] A "thioaryloxy" group refers to both an --S-aryl and an
--S-heteroaryl group, as defined herein.
[0152] A "carbonyl" group refers to a --C(.dbd.O)--R' group, where
R' is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl
(bonded through a ring carbon) or heteroalicyclic (bonded through a
ring carbon) as defined herein.
[0153] A "thiocarbonyl" group refers to a --C(.dbd.S)--R' group,
where R' is as defined herein for R'.
[0154] A "carboxy" group refers to a --C(.dbd.O)--O--R' or a
--O--C(--O)--R' group, where R' is as defined herein.
[0155] A "sulfinyl" group refers to an --S(.dbd.O)--R' group, where
R' is as defined herein.
[0156] A "sulfonyl" group refers to an --S(.dbd.O).sub.2--R' group,
where R' is as defined herein.
[0157] A "sulfate" group refers to a --O--S(.dbd.--O).sub.2--OR'
group, where R' is as defined herein.
[0158] A "sulfonamido" group refers to a --S(--O).sub.2--NR'R''
group or a R'S(.dbd.O).sub.2--NR'', with R' is as defined herein
and R'' is as defined for R'.
[0159] A "carbamyl" or "carbamate" group refers to an
--OC(.dbd.O)--NR'R'' group or a R''OC(.dbd.O)--NR'-- group, where
R' and R'' are as defined herein.
[0160] A "thiocarbamyl" or "thiocarbamate" group refers to an
--OC(.dbd.S)--NR'R'' group or an R''OC(.dbd.S)NR'-- group, where R'
and R'' are as defined herein.
[0161] An "amino" group refers to an --NR'R'' group where R' and
R'' are as defined herein.
[0162] An "amido" group refers to a --C(.dbd.O)--NR'R'' group or a
R'C(.dbd.O)--NR'' group, where R' and R'' are as defined
herein.
[0163] A "nitro" group refers to an --NO.sub.2 group.
[0164] A "cyano" group refers to a --C.ident.N group.
[0165] The term "phosphonyl" describes a --O--P(.dbd.OX)(OR'XOR'')
group, with R' and R'' as defined hereinabove.
[0166] The term "phosphinyl" describes a --PR'R'' group, with R'
and R'' as defined hereinabove.
[0167] As cited hereinabove, the compounds in this category are
salts of organic tellurium-containing compounds. The salts can be,
for example, ammonium salts, phsophonium salts and alkaline salts
such as potassium salts, sodium salts, lithium salts and the
like.
[0168] Hence, Y in Formula I above can be a phosphonium group, as
defined herein, an ammonium group, as defined herein, potassium
(K.sup.+), sodium (Na.sup.+) or lithium (Li.sup.+).
[0169] As used herein, the term "phosphonium" describes a
--P.sup.+R'R''R''' group, with R' and R'' as defined herein and
R''' is as defined for R'. The term "phsophonium", as used herein,
further refers to a --P.sup.+R.sub.6 group, wherein each of the six
R substituents is independently as defined herein for R', R'' and
R'''.
[0170] The term "ammonium" describes a --N.sup.+R'R''R''' group,
with R', R'' and R''' as defined herein.
[0171] More preferred compounds in this category include compounds
having the general Formula I described above, in which Y is
ammonium or phosphonium, t, u and v are each 0, each of
R.sub.1-R.sub.9 is hydrogen and R.sub.10 is hydrogen or alkyl.
These compounds can be represented by the following structure:
##STR00006##
[0172] wherein R is hydrogen or alkyl, preferably methyl, and X is
halogen, preferably chloro.
[0173] The presently most preferred compound for use in the context
of the present invention has the following structure:
##STR00007##
[0174] This compound is ammonium
trichloro(dioxyethylene-O,O')tellurate, which is also referred to
herein and in the art as AS101.
[0175] An additional exemplary compound in this category is:
##STR00008##
[0176] Additional representative examples of organic
tellurium-containing compound that are suitable for use in the
context of the present invention include halogenated tellurium
having a bidentate cyclic moiety attached to the tellurium atom.
The bidentate cyclic moiety is preferably a di-oxo ligand having
two oxygen atoms attached to the tellurium atom. Alternatively, the
bidentate cyclic moiety can be a di-thio ligand, in which two
sulfur atoms are attached to the tellurium atom.
[0177] Preferred compounds in this category can be represented by
the general Formula II:
##STR00009##
wherein t, u, v, X and R.sub.1-R.sub.10 are as defined
hereinabove.
[0178] More preferred compounds are those in which t, u, and v are
each 0, and X is chloro, such as, but not limited to, the compound
having the following structure:
##STR00010##
[0179] The organic tellurium-containing compounds having Formulae I
and II can be readily prepared by reacting tetrahalotelluride such
as TeCl.sub.4 with a dihydroxy compound, as is described in detail
in U.S. Pat. Nos. 4,752,614, 4,761,490, 4,764,461 and
4,929,739.
[0180] Additional representative examples of organic
tellurium-containing compound that are suitable for use in the
context of the present invention include compounds in which two
bidentate cyclic moieties are attached to the tellurium atom.
Preferably, each of the cyclic moieties is a di-oxo moiety.
Alternatively, one or more of the cyclic moieties is a di-thio
moiety.
[0181] Preferred compounds in this category are collectively
represented by the general Formula III:
##STR00011##
[0182] wherein each of R.sub.11-R.sub.14 is independently selected
from the group consisting of hydrogen, hydroxyalkyl, hydroxy,
thiohydroxy, alkyl, alkenyl, alkynyl, alkoxy, thioalkoxy, halogen,
haloalkyl, carboxy, carbonyl, alkylcarbonylalkyl, alkoxy,
carboxyalkyl, acyl, amido, cyano, N-monoalkylamidoalkyl,
N,N-dialkylamidoalkyl, cyanoalkyl, alkoxyalkyl, carbamyl,
cycloalkyl, heteroalicyclic, sulfonyl, sulfinyl, sulfate, amine,
aryl, heteroaryl, phosphate, phosphonate and sulfoneamido, as these
terms are defined herein.
[0183] More preferred compounds in this category are those in which
each of R.sub.11-R.sub.14 is hydrogen.
[0184] Additional representative examples of organic
tellurium-containing compounds that are suitable for use in the
context of the present invention include the recently disclosed
bis-tellurium compounds having general Formula IV:
##STR00012##
[0185] wherein each of R.sub.15-R.sub.22 is independently selected
from the group consisting of hydrogen, hydroxyalkyl, hydroxy,
thiohydroxy, alkyl, alkenyl, alkynyl, alkoxy, thioalkoxy, halogen,
haloalkyl, carboxy, carbonyl, alkylcarbonylalkyl, alkoxy,
carboxyalkyl, acyl, amido, cyano, N-monoalkylamidoalkyl,
N,N-dialkylamidoalkyl, cyanoalkyl, alkoxyalkyl, carbamyl,
cycloalkyl, heteroalicyclic, sulfonyl, sulfinyl, sulfate, amine,
aryl, heteroaryl, phosphate, phosphonate and sulfoneamido, as these
terms are defined herein; and
[0186] m and n are each an integer from 0 to 3.
[0187] Preferred compounds in this category are those in which m
and n are each 0.
[0188] The presently most preferred compound in this family is a
compound in which R.sub.15, R.sub.18, R.sub.19 and R.sub.22 are all
hydrogen, and which has the following structure:
##STR00013##
[0189] Compounds having the general Formula IV can be readily
prepared by reacting substantially equimolar amounts of a tellurium
tetralkoxide and a polycarboxylic acid. These materials are
combined in the presence of a water free organic solvent such as
dried ethanol, dimethyl sulfoxide, i-propanol and the like.
Generally the reaction may take place at ambient conditions but if
desired higher or lower temperatures and higher or lower pressures
may be utilized.
[0190] Exemplary tellurium tetraalkoxide compounds that are usable
in the preparation of the compounds having general Formula IV above
include, without limitation, tetramethoxide, tetraethoxide,
tetrapropoxide, tetraisopropoxide, tetrabutoxide, and
tetrapentoxide tellerium compounds.
[0191] Useful polycarboxylic acids include also polyhydroxy
polycarboxylic and hydroxy polycarboxylic acids. Exemplary
polycarboxylic acids that are usable in the preparation of the
compounds having general Formula IV above include, without
limitation, tartaric acid, glutaric acid, succinic acid, malonic
acid, gluconic acid and the like.
[0192] Additional organic tellurium-containing compounds that are
suitable for use in the context of the present invention include
those having the general Formula V:
##STR00014##
[0193] wherein each of Ra, Rb, Rc and Rd is independently selected
from the group consisting of halogen alkyl, aryl, cycloalkyl,
alkoxy, aryloxy, thioalkoxy, thioaryloxy, carboxy, carbonyl,
thiocarboxy, thiocarbonyl, carbamyl, and thiocarbamyl, as these
terms are defined hereinabove, whereby at least one of Ra-Rd is not
halogen, namely, is selected from the group consisting of alkyl,
aryl, cycloalkyl, alkoxy, aryloxy, thioalkoxy, thioaryloxy,
carboxy, carbonyl, thiocarboxy, thiocarbonyl, carbamyl, and
thiocarbamyl.
[0194] Compounds in this category include those in which one of Ra,
Rb, Rc and Rd is halogen alkyl, aryl, cycloalkyl, alkoxy, aryloxy,
thioalkoxy, thioaryloxy, carboxy, carbonyl, thiocarboxy,
thiocarbonyl, carbamyl, or thiocarbamyl, whereby the others halogen
atoms, e.g., chloro.
[0195] Other compounds in this category include those in which two
or three of Ra, Rb, Rc and Rd are as described above and the others
are halogens e.g., chloro.
[0196] Other compounds in this category include those in which each
of Ra, Rb, Rc and Rd is as described hereinabove.
[0197] An exemplary compound in this category is PhTeCl.sub.3.
[0198] The compounds described above can be administered or
otherwise utilized in this and other aspects of the present
invention, either as is or as a pharmaceutically acceptable salt
thereof.
[0199] The phrase "pharmaceutically acceptable salt" refers to a
charged species of the parent compound and its counter ion, which
is typically used to modify the solubility characteristics of the
parent compound and/or to reduce any significant irritation to an
organism by the parent compound, while not abrogating the
biological activity and properties of the administered
compound.
[0200] As is demonstrated in the Examples section that follows,
AS101, a representative example of a tellurium-containing compound
according to the present invention, was found to be highly
efficient in treating various ailments caused by various HPVs,
including verruca vulgaris and genital and anus condylomata
acuminata. The treatment was accompanied with minimal or no adverse
side effects and the ailments (e.g., warts) were substantially
completely removed.
[0201] The high efficiency of the treatment according to the
present invention, as compared with the presently known methods of
treating HPV-caused ailments, is attributed to the immunomodulating
and anti-viral activity of the tellurium-containing compounds
described above. As such, treatment with the tellurium-containing
compounds described above, affects not only the manifested visible
lesions but rather suppress the cause of the ailment--the virus
itself. As a result, viral particles that may be lurking in
normal-appearing areas surrounding the warts, are also destroyed.
This effect of the tellurium-containing compounds described herein
is clearly demonstrated in, for example, FIGS. 13a and 13b, where
it can be seen that the area affected by the treatment (seen as
black spots) is larger that the visible lesion area before
treatment (see, FIGS. 12a-c).
[0202] The method according to this aspect of the present invention
can therefore be efficiently utilized for treating skin and mucosal
membrane ailments caused by a HPV.
[0203] As used herein, the phrase "a skin or mucosal membrane
ailment caused by a HPV", which also referred to herein
interchangeable as "HPV-caused ailment", encompasses any ailment
that is associated, either directly or indirectly, with any type of
HPV As is discussed hereinabove, to date, there are more than
seventy identified distinct types of HPVs. These different types
have been subdivided into two large categories: cutaneous and
mucosal. Since, as is further discussed hereinabove, some
HPV-caused ailments may develop into cervical cancer, these
different virus types have been further categorized in this respect
by their risk grade and therefore include low-risk HPV types,
moderate-risk HPV types and high-risk HPV types.
[0204] According to an embodiment this aspect of the present
invention, the method described above is therefore further directed
at treating moderate-risk and high-risk FPV types and thus at
treating and preferably preventing the development of cancer.
[0205] Exemplary skin and mucosal membrane ailments that are
treatable by the method of this aspect of the present invention
therefore include verruca vulgaris, plantar warts, palmar warts,
periungal warts, planar warts, mosaic warts, genital warts,
venereal warts (condylomata acuminata), butcher's warts, malignant
epidermodyspasia verruciformis, advanced intraepithelial dysplasia,
cervical cancer, mepidermodysplasia verruciformis, cutnaeous warts
in immunosuppressed patients, laryngeal papillomas and oral
papilloma.
[0206] The various ailments caused by HPVs are typically manifested
in various skin areas and mucosal membranes, including, for
example, hands, face, forearms, elbows, legs, nails and anus, and
genital areas such as the perianal area, perineum, vulva, penis,
vagina, and in rare severe cases the cervix. Although rare,
HPV-caused ailments can be also manifested on the oral mucosa,
conjunctivae and larynx.
[0207] The compounds described above can be administered to a
subject afflicted by an HPV-caused ailment by any of various
systemic routes.
[0208] Suitable routes of systemic administration may, for example,
include the inhalation, oral, buccal, rectal, transmucosal,
transdermal, intradermal, transnasal, intestinal and/or parenteral
routes; the intramuscular, subcutaneous and/or intramedullary
injection routes; the intrathecal, direct intraventricular,
intravenous, intraperitoneal, intranasal, and/or intraocular
injection routes; and/or the route of direct injection into a
tissue region of a subject of the present invention.
[0209] When administering systemically, a therapeutically effective
amount of the tellurium-containing compounds described herein may
range, for example, from about 0.01 mg/m.sup.2/day to about 10.0
mg/m.sup.2/day and thus can be for example, 0.01 mg/m.sup.2/day,
0.02 mg/m.sup.2/day, 0.03 mg/m.sup.2/day, 0.04 mg/m.sup.2/day, 0.05
mg/m.sup.2/day, 0.06 mg/m.sup.2/day, 0.07 mg/m.sup.2/day, 0.08
mg/m.sup.2/day, 0.09 mg/m.sup.2/day and 0.1 mg/m.sup.2/day.
Preferably, when administered parenterally, the therapeutically
effective amount is 0.1 mg/m.sup.2/day and higher and thus can be,
for example, 0.2 mg/m.sup.2/day, 0.3 mg/m.sup.2/day, 0.4
mg/m.sup.2/day, 0.5 mg/m.sup.2/day, 0.6 mg/m.sup.2/day, 0.7
mg/m.sup.2/day, 0.8 mg/m.sup.2/day, 0.9 mg/m.sup.2/day, 1.0
mg/m.sup.2/day, 2.0 mg/m.sup.2/day, 3.0 mg/m.sup.2/day, 4.0
mg/m.sup.2/day, 5.0 mg/m.sup.2/day, and up to 10.0 mg/m.sup.2/day.
When administered orally, a daily dose typically ranges between 10
mg and 150 mg.
[0210] As used herein, the term "about" refers to .+-.10%.
[0211] Optionally and preferably, the compounds described above can
be administered to a subject afflicted by an HPV ailment by local
routes, and more preferably, the compounds are administered
topically.
[0212] Topical application of the tellurium-containing compounds
described herein is preferably effected by applying onto a treated
skin or mucosal membrane area a therapeutically effective amount
the compound.
[0213] The treated area can be, for example, hands, face, forearms,
elbows, legs, nails, anus, and genital areas such as the perianal
area, perineum, vulva, penis, vagina, and if needed, the
cervix.
[0214] Herein, the phrase "treated area" encompasses the affected
area (e.g., the wart(s)) as well as the tissues surrounding the
indicated area. The topical application is effected on and around
the clinical manifestation (e.g., the wart(s)).
[0215] The method according to this aspect of the present invention
can further comprise, in addition to administering the
tellurium-containing compounds described above, co-administration
of an additional active agent. The co-administration can be
effected prior to, concomitant with or subsequent to the
administration of the tellurium-containing compound. The additional
active agent is used for providing an additive beneficial effect in
terms of the ailment being treated, conditions associated with the
ailment being treated or other parameters such as psychological
effects and prophylactic effects.
[0216] Hence, exemplary additional active agents according to this
embodiment of present invention include, without limitation, one or
more, or any combination of an antibiotic agent, an antimicrobial
agent, an anti-acne agent, an antibacterial agent, an antifungal
agent, an antiviral agent, a steroidal anti-inflammatory agent, a
non-steroidal anti-inflammatory agent, an anesthetic agent, an
antipruriginous agent, an antiprotozoal agent, an anti-oxidant, a
chemotherapeutic agent, an antidepressant, an anti histamine, a
vitamin, a hormone and an anti-dandruff agent.
[0217] Suitable anti-acne agents for use in this context of the
present invention include, without limitation, keratolytics such as
salicylic acid, sulfur, glycolic, pyruvic acid, resorcinol, and
N-acetylcysteine and retinoids such as retinoic acid and its
derivatives (e.g., cis and trans, esters).
[0218] Suitable antibiotics for use in this context of the present
invention include, without limitation, benzoyl peroxide, octopirox,
erythromycin, zinc, tetracyclin, triclosan, azelaic acid and its
derivatives, phenoxy ethanol and phenoxy proponol, ethylacetate,
clindamycin and meclocycline; sebostats such as flavinoids; alpha
and beta hydroxy acids; and bile salts such as scymnol sulfate and
its derivatives, deoxycholate and cholate.
[0219] Representative examples of non-steroidal anti-inflammatory
agents that are usable in this context of the present invention
include, without limitation, oxicams, such as piroxicam, isoxicam,
tenoxicam, sudoxicam, and CP-14,304; salicylates, such as aspirin,
disalcid, benorylate, trilisate, safapryn, solprin, diflunisal, and
fendosal; acetic acid derivatives, such as diclofenac, fenclofenac,
indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac,
zidometacin, acematacin, fentiazac, zomepirac, clindanac, oxepinac,
felbinac, and ketorolac; fenamates, such as mefenamic,
meclofenamic, flufenamic, niflumic, and tolfenamic acids; propionic
acid derivatives, such as ibuprofen, naproxen, benoxaprofen,
flurbiprofen, ketoprofen, fenoprofen, fenbufen, indopropfen,
pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen,
tioxaprofen, suprofen, alminoprofen, and tiaprofenic; pyrazoles,
such as phenylbutazone, oxyphenbutazone, feprazone, azapropazone,
and trimethazone. Mixtures of these non-steroidal anti-inflammatory
agents may also be employed, as well as the dermatologically
acceptable salts and esters of these agents. For example,
etofenamate, a flufenamic acid derivative, is particularly useful
for topical application.
[0220] Representative examples of steroidal anti-inflammatory drugs
include, without limitation, corticosteroids such as
hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone,
dexamethasone-phosphate, beclomethasone dipropionates, clobetasol
valerate, desonide, desoxymethasone, desoxycorticosterone acetate,
dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone
valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone,
flumethasone pivalate, fluosinolone acetonide, fluocinonide,
flucortine butylesters, fluocortolone, fluprednidene
(fluprednylidene) acetate, flurandrenolone, halcinonide,
hydrocortisone acetate, hydrocortisone butyrate,
methylprednisolone, triamcinolone acetonide, cortisone,
cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate,
fluradrenolone, fludrocortisone, diflurosone diacetate,
fluradrenolone acetonide, medrysone, amcinafel, amcinafide,
betamethasone and the balance of its esters, chloroprednisone,
chlorprednisone acetate, clocortelone, clescinolone, dichlorisone,
diflurprednate, flucloronide, flunisolide, fluoromethalone,
fluperolone, fluprednisolone, hydrocortisone valerate,
hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone,
paramethasone, prednisolone, prednisone, beclomethasone
dipropionate, triamcinolone, and mixtures thereof.
[0221] Suitable antipruritic agents include, without limitation,
pharmaceutically acceptable salts of methdilazine and
trimeprazine.
[0222] Non-limiting examples of anesthetic drugs that are suitable
for use in context of the present invention include
pharmaceutically acceptable salts of lidocaine, bupivacaine,
chlorprocaine, dibucaine, etidocaine, mepivacaine, tetracaine,
dyclonine, hexylcaine, procaine, cocaine, ketamine, pramoxine and
phenol.
[0223] Suitable antimicrobial agents, including antibacterial,
antifungal, antiprotozoal and antiviral agents, for use in context
of the present invention include, without limitation, beta-lactam
drugs, quinolone drugs, ciprofloxacin, norfloxacin, tetracycline,
erythromycin, amikacin, triclosan, doxycycline, capreomycin,
chlorhexidine, chlortetracycline, oxytetracycline, clindamycin,
ethambutol, metronidazole, pentamidine, gentamicin, kanamycin,
lineomycin, methacycline, methenamine, minocycline, neomycin,
netilmicin, streptomycin, tobramycin, and miconazole. Also included
are tetracycline hydrochloride, farnesol, erythromycin estolate,
erythromycin stearate (salt), amikacin sulfate, doxycycline
hydrochloride, chlorhexidine gluconate, chlorhexidine
hydrochloride, chlortetracycline hydrochloride, oxytetracycline
hydrochloride, clindamycin hydrochloride, ethambutol hydrochloride,
metronidazole hydrochloride, pentamidine hydrochloride, gentamicin
sulfate, kanamycin sulfate, lineomycin hydrochloride, methacycline
hydrochloride, methenamine hippurate, methenamine mandelate,
minocycline hydrochloride, neomycin sulfate, netilmicin sulfate,
paromomycin sulfate, streptomycin sulfate, tobramycin sulfate,
miconazole hydrochloride, amanfadine hydrochloride, amanfadine
sulfate, triclosan, octopirox, parachlorometa xylenol, nystatin,
tolnaftate and clotrimazole and mixtures thereof.
[0224] Non-limiting examples of anti-oxidants that are usable in
the context of the present invention include ascorbic acid (vitamin
C) and its salts, ascorbyl esters of fatty acids, ascorbic acid
derivatives (e.g., magnesium ascorbyl phosphate, sodium ascorbyl
phosphate, ascorbyl sorbate), tocopherol (vitamin E), tocopherol
sorbate, tocopherol acetate, other esters of tocopherol, butylated
hydroxy benzoic acids and their salts,
6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid
(commercially available under the trade name Trolox.RTM.), gallic
acid and its alkyl esters, especially propyl gallate, uric acid and
its salts and alkyl esters, sorbic acid and its salts, lipoic acid,
amines (e.g., N,N-diethylhydroxylamine, amino-guanidine),
sulfhydryl compounds (e.g., glutathione), dihydroxy fumaric acid
and its salts, lycine pidolate, arginine pilolate,
nordihydroguaiaretic acid, bioflavonoids, curcumin, lysine,
methionine, proline, superoxide dismutase, silymarin, tea extracts,
grape skin/seed extracts, melanin, and rosemary extracts.
[0225] Non-limiting examples of chemotherapeutic agents usable in
context of the present invention include daunorubicin, doxorubicin,
idarubicin, amrubicin, pirarubicin, epirubicin, mitoxantrone,
etoposide, teniposide, vinblastine, vincristine, mitomycin C, 5-FU,
paclitaxel, docetaxel, actinomycin D, colchicine, topotecan,
irinotecan, gemcitabine cyclosporin, verapamil, valspodor,
probenecid, MK571, GF120918, LY335979, biricodar, terfenadine,
quinidine, pervilleine A and XR9576.
[0226] Non-limiting examples of antidepressants usable in context
of the present invention include norepinephrine-reuptake inhibitors
("NRIs"), selective-serotonin-reuptake inhibitors (SSRIs),
monoamine-oxidase inhibitors (MAOIs),
serotonin-and-noradrenaline-reuptake inhibitors ("SNFIs),
corticotropin-releasing factor (CRF) antagonists,
.alpha.-adrenoreceptor antagonists, NK1-receptor antagonists,
5-HT.sub.1A-receptor agonist, antagonists, and partial agonists and
atypical antidepressants, as well as norepinephrine-reuptake
inhibitors such as, but are not limited to amitriptyline,
desmethylamitriptyline, clomipramine, doxepin, imipramine,
imipramine-oxide, trimipramine; adinazolam, amiltriptylinoxide,
amoxapine, desipramine, maprotiline, nortriptyline, protriptyline,
amineptine, butriptyline, demexiptiline, dibenzepin, dimetacrine,
dothiepin, fluacizine, iprindole, lofepramine, melitracen,
metapramine, norclolipramine, noxiptilin, opipramol, perlapine,
pizotyline, propizepine, quinupramine, reboxetine, tianeptine, and
serotonin-reuptake inhibitors such as, but are not limited to,
binedaline, m-chloropiperzine, citalopram, duloxetine, etoperidone,
femoxetine, fluoxetine, fluvoxamine, indalpine, indeloxazine,
milnacipran, nefazodone, oxaflazone, paroxetine, prolintane,
ritanserin, sertraline, tandospirone, venlafaxine and
zimeldine.
[0227] Exemplary anti-dandruff ingredients usable in context of the
present invention include, without limitation, zinc pyrithione,
shale oil and derivatives thereof such as sulfonated shale oil,
selenium sulfide, sulfur; salicylic acid, coal tar,
povidone-iodine, imidazoles such as ketoconazole, dichlorophenyl
imidazolodioxalan, clotrimazole, itraconazole, miconazole,
climbazole, tioconazole, sulconazole, butoconazole, fluconazole,
miconazolenitrite and any possible stereo isomers and derivatives
thereof such as anthralin, piroctone olamine (Octopirox), selenium
sulfide, and ciclopirox olamine, and mixtures thereof.
[0228] Non-limiting examples of vitamins usable in context of the
present invention include vitamin A and its analogs and
derivatives: retinol, retinal, retinyl palmitate, retinoic acid,
tretinoin, iso-tretinoin (known collectively as retinoids), vitamin
E (tocopherol and its derivatives), vitamin C (L-ascorbic acid and
its esters and other derivatives), vitamin B.sub.3 (niacinamide and
its derivatives), alpha hydroxy acids (such as glycolic acid,
lactic acid, tartaric acid, malic acid, citric acid, etc.) and beta
hydroxy acids (such as salicylic acid and the like).
[0229] Non-limiting examples of dermatological active ingredients
usable in context of the present invention include jojoba oil and
aromatic oils such as methyl salicylate, wintergreen, peppermint
oil, bay oil, eucalyptus oil and citrus oils, as well as ammonium
phenolsulfonate, bismuth subgallate, zinc phenolsulfonate and zinc
salicylate. Non-limiting examples of antifungal agents include
miconazole, clotrimazole, butoconazole, fenticonasole, tioconazole,
terconazole, sulconazole, fluconazole, haloprogin, ketonazole,
ketoconazole, oxinazole, econazole, itraconazole, terbinafine,
nystatin and griseofulvin.
[0230] Non-limiting examples of antihistamines usable in context of
the present invention include chlorpheniramine, brompheniramine,
dexchlorpheniramine, tripolidine, clemastine, diphenhydramine,
promethazine, piperazines, piperidines, astemizole, loratadine and
terfenadine.
Suitable hormones for use in the context of the present invention
include, for example, androgenic compounds and progestin
compounds.
[0231] Representative examples of androgenic compounds include,
without limitation, methyltestosterone, androsterone, androsterone
acetate, androsterone propionate, androsterone benzoate,
androsteronediol, androsteronediol-3-acetate,
androsteronediol-17-acetate, androsteronediol 3-17-diacetate,
androsteronediol-17-benzoate, androsteronedione, androstenedione,
androstenediol, dehydroepiandrosterone, sodium
dehydroepiandrosterone sulfate, dromostanolone, dromostanolone
propionate, ethylestrenol, fluoxymesterone, nandrolone
phenpropionate, nandrolone decanoate, nandrolone furylpropionate,
nandrolone cyclohexane-propionate, nandrolone benzoate, nandrolone
cyclohexanecarboxylate, androsteronediol-3-acetate-1-7-benzoate,
oxandrolone, oxymetholone, stanozolol, testosterone, testosterone
decanoate, 4-dihydrotestosterone, 5.alpha.-dihydrotestosterone,
testolactone, 17.alpha.-methyl-19-nortestosterone and
pharmaceutically acceptable esters and salts thereof, and
combinations of any of the foregoing.
[0232] Representative examples of progestin compounds include,
without limitation, desogestrel, dydrogesterone, ethynodiol
diacetate, medroxyprogesterone, levonorgestrel, medroxyprogesterone
acetate, hydroxyprogesterone caproate, norethindrone, norethindrone
acetate, norethynodrel, allylestrenol, 19-nortestosterone,
lynoestrenol, quingestanol acetate, medrogestone, norgestrienone,
dimethisterone, ethisterone, cyproterone acetate, chlormadinone
acetate, megestrol acetate, norgestimate, norgestrel, desogrestrel,
trimegestone, gestodene, nomegestrol acetate, progesterone,
5.alpha.-pregnan-30,20.alpha.-diol sulfate,
5.alpha.-pregnan-3.beta.,20.beta.-diol sulfate,
5.alpha.-pregnan-3.beta.-ol-20-one,
16,5.alpha.-pregnen-3.beta.-ol-20-one,
4-pregnen-20.beta.-ol-3-one-20-sulfate, acetoxypregnenolone,
anagestone acetate, cyproterone, dihydrogesterone, flurogestone
acetate, gestadene, hydroxyprogesterone acetate,
hydroxymethylprogesterone, hydroxymethyl progesterone acetate,
3-ketodesogestrel, megestrol, melengestrol acetate, norethisterone
and mixtures thereof.
[0233] In addition to the above, the treatment of an HPV-caused
ailment according to the present invention may be combined with
other treatment methods known in the art (i.e., combination
therapy). Thus, the method according to this aspect of the present
invention may further involve additional treatment by any of the
methods described above for treating HPV infections. The
tellurium-containing compounds described above can thus be, for
example, co-administered (simultaneously or separately) with
additional agents for treating HPVs infections such as, for
example, salicylic acid, 5-fluoruracil and the like. Alternatively,
the method described above can be accompanied by any of the
physical treatment methods described above (e.g., laser therapy, NO
therapy and the like).
[0234] In any of the different embodiments of the method according
to this aspect of the present invention, the tellurium-containing
compounds described herein can be provided to a subject either per
se, or as part of a pharmaceutical composition where it is mixed
with a pharmaceutically acceptable carrier.
[0235] Hence, according to another aspect of the present invention
there is provided a pharmaceutical composition, which comprises a
tellurium-containing compound as described herein and a
pharmaceutically acceptable carrier.
[0236] As used herein a "pharmaceutical composition" refers to a
preparation of one or more of the active ingredients described
herein with other chemical components such as physiologically
suitable carriers and excipients. The purpose of a pharmaceutical
composition is to facilitate administration of a compound to the
subject treated.
[0237] Hereinafter, the phrases "physiologically acceptable
carrier" and "pharmaceutically acceptable carrier" which may be
interchangeably used refer to a carrier or a diluent that does not
cause significant irritation to the subject and does not abrogate
the biological activity and properties of the administered
compound.
[0238] Herein the term "excipient" refers to an inert substance
added to a pharmaceutical composition to further facilitate
administration of an active ingredient. Examples, without
limitation, of excipients include calcium carbonate, calcium
phosphate, various sugars and types of starch, cellulose
derivatives, gelatin, vegetable oils and polyethylene glycols.
[0239] Techniques for formulation and administration of drugs may
be found in "Remington's Pharmaceutical Sciences," Mack Publishing
Co., Easton, Pa., latest edition, which is incorporated herein by
reference.
[0240] As described above, suitable routes of systemic
administration may, for example, include oral, rectal,
transmucosal, transnasal, intestinal or parenteral delivery,
including intramuscular, subcutaneous and intramedullary injections
as well as intrathecal, direct intraventricular, intravenous,
inrtaperitoneal, intranasal, or intraocular injections.
[0241] Alternately, one may administer a preparation in a local
rather than systemic manner, for example, via injection of the
preparation directly into a specific region of a patient's
body.
[0242] Pharmaceutical compositions of the present invention may be
manufactured by processes well known in the art, e.g., by means of
conventional mixing, dissolving, granulating, dragee-making,
levigating, emulsifying, encapsulating, entrapping or lyophilizing
processes.
[0243] Pharmaceutical compositions for use in accordance with the
present invention may be formulated in conventional manner using
one or more physiologically acceptable carriers comprising
excipients and auxiliaries, which facilitate processing of the
active ingredients into preparations which, can be used
pharmaceutically. Proper formulation is dependent upon the route of
administration chosen.
[0244] For injection, the active ingredients of the invention may
be formulated in aqueous solutions, preferably in physiologically
compatible buffers such as Hank's solution, Ringer's solution, or
physiological salt buffer.
[0245] For transmucosal administration, penetrants appropriate to
the barrier to be permeated are used in the formulation. Such
penetrants are generally known in the art.
[0246] For oral administration, the compounds can be formulated
readily by combining the active compounds with pharmaceutically
acceptable carriers well known in the art. Such carriers enable the
compounds of the invention to be formulated as tablets, pills,
dragees, capsules, liquids, gels, syrups, slurries, suspensions,
and the like, for oral ingestion by a patient. Pharmacological
preparations for oral use can be made using a solid excipient,
optionally grinding the resulting mixture, and processing the
mixture of granules, after adding suitable auxiliaries if desired,
to obtain tablets or dragee cores. Suitable excipients are, in
particular, fillers such as sugars, including lactose, sucrose,
mannitol, or sorbitol; cellulose preparations such as, for example,
maize starch, wheat starch, rice starch, potato starch, gelatin,
gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose,
sodium carbomethylcellulose; and/or physiologically acceptable
polymers such as polyvinylpyrrolidone (PVP). If desired,
disintegrating agents may be added, such as cross-linked polyvinyl
pyrrolidone, agar, or alginic acid or a salt thereof such as sodium
alginate.
[0247] Dragee cores are provided with suitable coatings. For this
purpose, concentrated sugar solutions may be used which may
optionally contain gum arabic, talc, polyvinyl pyrrolidone,
carbopol gel, polyethylene glycol, titanium dioxide, lacquer
solutions and suitable organic solvents or solvent mixtures.
Dyestuffs or pigments may be added to the tablets or dragee
coatings for identification or to characterize different
combinations of active compound doses.
[0248] Pharmaceutical compositions, which can be used orally,
include push-fit capsules made of gelatin as well as soft, sealed
capsules made of gelatin and a plasticizer, such as glycerol or
sorbitol. The push-fit capsules may contain the active ingredients
in admixture with filler such as lactose, binders such as starches,
lubricants such as talc or magnesium stearate and, optionally,
stabilizers. In soft capsules, the active ingredients may be
dissolved or suspended in suitable liquids, such as fatty oils,
liquid paraffin, or liquid polyethylene glycols. In addition,
stabilizers may be added. All formulations for oral administration
should be in dosages suitable for the chosen route of
administration.
[0249] For buccal administration, the compositions may take the
form of tablets or lozenges formulated in conventional manner.
[0250] For administration by nasal inhalation, the active
ingredients for use according to the present invention are
conveniently delivered in the form of an aerosol spray presentation
from a pressurized pack or a nebulizer with the use of a suitable
propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,
dichloro-tetrafluoroethane or carbon dioxide. In the case of a
pressurized aerosol, the dosage unit may be determined by providing
a valve to deliver a metered amount. Capsules and cartridges of,
e.g., gelatin for use in a dispenser may be formulated containing a
powder mix of the compound and a suitable powder base such as
lactose or starch.
[0251] The preparations described herein may be formulated for
parenteral administration, e.g., by bolus injection or continuous
infusion. Formulations for injection may be presented in unit
dosage form, e.g., in ampoules or in multidose containers with
optionally, an added preservative. The compositions may be
suspensions, solutions or emulsions in oily or aqueous vehicles,
and may contain formulatory agents such as suspending, stabilizing
and/or dispersing agents.
[0252] Pharmaceutical compositions for parenteral administration
include aqueous solutions of the active preparation in
water-soluble form. Additionally, suspensions of the active
ingredients may be prepared as appropriate oily or water based
injection suspensions. Suitable lipophilic solvents or vehicles
include fatty oils such as sesame oil, or synthetic fatty acids
esters such as ethyl oleate, triglycerides or liposomes. Aqueous
injection suspensions may contain substances, which increase the
viscosity of the suspension, such as sodium carboxymethyl
cellulose, sorbitol or dextran. Optionally, the suspension may also
contain suitable stabilizers or agents which increase the
solubility of the active ingredients to allow for the preparation
of highly concentrated solutions.
[0253] Alternatively, the active ingredient may be in powder form
for constitution with a suitable vehicle, e.g., sterile,
pyrogen-free water based solution, before use.
[0254] The preparation of the present invention may also be
formulated in rectal compositions such as suppositories or
retention enemas, using, e.g., conventional suppository bases such
as cocoa butter or other glycerides.
[0255] Pharmaceutical compositions suitable for use in context of
the present invention include compositions wherein the active
ingredients are contained in an amount effective to achieve the
intended purpose. More specifically, a therapeutically effective
amount means an amount of active ingredients effective to prevent,
alleviate or ameliorate symptoms of disease or prolong the survival
of the subject being treated.
[0256] Determination of a therapeutically effective amount is well
within the capability of those skilled in the art.
[0257] For any preparation used in the methods of the invention,
the therapeutically effective amount or dose can be estimated
initially from in vitro assays. For example, a dose can be
formulated in animal models and such information can be used to
more accurately determine useful doses in humans.
[0258] Toxicity and therapeutic efficacy of the active ingredients
described herein can be determined by standard pharmaceutical
procedures in vitro, in cell cultures or experimental animals. The
data obtained from these in vitro and cell culture assays and
animal studies can be used in formulating a range of dosage for use
in human. The dosage may vary depending upon the dosage form
employed and the route of administration utilized. The exact
formulation, route of administration and dosage can be chosen by
the individual physician in view of the patient's condition. [See
e.g., Fingl, et al., (1975) "The Pharmacological Basis of
Therapeutics", Ch. 1 p.1].
[0259] Depending on the severity and responsiveness of the
condition to be treated, dosing can be of a single or a plurality
of administrations, with course of treatment lasting from several
days to several weeks or until cure is effected or diminution of
the disease state is achieved.
[0260] The amount of a composition to be administered will, of
course, be dependent on the subject being treated, the severity of
the affliction, the manner of administration, the judgment of the
prescribing physician, etc.
[0261] Compositions including the preparation of the present
invention formulated in a compatible pharmaceutical carrier may
also be prepared, placed in an appropriate container, and labeled
for treatment of an indicated condition.
[0262] Compositions of the present invention may, if desired, be
presented in a pack or dispenser device, such as an FDA approved
kit, which may contain one or more unit dosage forms containing the
active ingredient. The pack may, for example, comprise metal or
plastic foil, such as a blister pack. The pack or dispenser device
may be accompanied by instructions for administration. The pack or
dispenser may also be accommodated by a notice associated with the
container in a form prescribed by a governmental agency regulating
the manufacture, use or sale of pharmaceuticals, which notice is
reflective of approval by the agency of the form of the
compositions or human or veterinary administration. Such notice,
for example, may be of labeling approved by the U.S. Food and Drug
Administration for prescription drugs or of an approved product
insert.
[0263] As is further described above, a suitable route of
administering the tellurium-containing compounds of the present
invention include topical application.
[0264] Hence, in a preferred embodiment of the present invention,
the pharmaceutical composition is formulated in a form suitable for
topical application on the treated area.
[0265] As used herein, the phrase "topical application" describes
application onto a biological surface, whereby the biological
surface include, for example, a skin area (e.g., hands, forearms,
elbows, legs, face, nails, anus and genital areas as described
above) or a mucosal membrane.
[0266] By selecting the appropriate carrier and optionally other
ingredients that can be included in the composition, as is detailed
hereinbelow, the compositions of the present invention may be
formulated into any form typically employed for topical
application. Hence, the compositions of the present invention can
be, for example, in a form of a cream, an ointment, a paste, a gel,
a lotion, a milk, a suspension, an aerosol, a spray, a foam, a
shampoo, a hair conditioner, a serum, a swab, a pledget, a pad, a
patch and a soap.
[0267] Ointments are semisolid preparations, typically based on
petrolatum or petroleum derivatives. The specific ointment base to
be used is one that provides for optimum delivery for the active
agent chosen for a given formulation, and, preferably, provides for
other desired characteristics as well (e.g., emolliency). As with
other carriers or vehicles, an ointment base should be inert,
stable, nonirritating and nonsensitizing. As explained in
Remington: The Science and Practice of Pharmacy, 19th Ed., Easton,
Pa.: Mack Publishing Co. (1995), pp. 1399-1404, ointment bases may
be grouped in four classes: oleaginous bases; emulsifiable bases;
emulsion bases; and water-soluble bases. Oleaginous ointment bases
include, for example, vegetable oils, fats obtained from animals,
and semisolid hydrocarbons obtained from petroleum. Emulsifiable
ointment bases, also known as absorbent ointment bases, contain
little or no water and include, for example, hydroxystearin
sulfate, anhydrous lanolin and hydrophilic petrolatum. Emulsion
ointment bases are either water-in-oil (W/O) emulsions or
oil-in-water (O/W) emulsions, and include, for example, cetyl
alcohol, glyceryl monostearate, lanolin and stearic acid. Preferred
water-soluble ointment bases are prepared from polyethylene glycols
of varying molecular weight.
[0268] Lotions are preparations that are to be applied to the skin
surface without friction. Lotions are typically liquid or
semiliquid preparations in which solid particles, including the
active agent, are present in a water or alcohol base. Lotions are
typically preferred for treating large body areas, due to the ease
of applying a more fluid composition. Lotions are typically
suspensions of solids, and oftentimes comprise a liquid oily
emulsion of the oil-in-water type. It is generally necessary that
the insoluble matter in a lotion be finely divided. Lotions
typically contain suspending agents to produce better dispersions
as well as compounds useful for localizing and holding the active
agent in contact with the skin, such as methylcellulose, sodium
carboxymethyl-cellulose, and the like.
[0269] Creams are viscous liquids or semisolid emulsions, either
oil-in-water or water-in-oil. Cream bases are typically
water-washable, and contain an oil phase, an emulsifier and an
aqueous phase. The oil phase, also called the "internal" phase, is
generally comprised of petrolatum and/or a fatty alcohol such as
cetyl or stearyl alcohol. The aqueous phase typically, although not
necessarily, exceeds the oil phase in volume, and generally
contains a humectant. The emulsifier in a cream formulation is
generally a nonionic, anionic, cationic or amphoteric surfactant.
Reference may be made to Remington: The Science and Practice of
Pharmacy, supra, for further information.
[0270] Pastes are semisolid dosage forms in which the bioactive
agent is suspended in a suitable base. Depending on the nature of
the base, pastes are divided between fatty pastes or those made
from a single-phase aqueous gels. The base in a fatty paste is
generally petrolatum, hydrophilic petrolatum and the like. The
pastes made from single-phase aqueous gels generally incorporate
carboxymethylcellulose or the like as a base. Additional reference
may be made to Remington: The Science and Practice of Pharmacy, for
further information.
[0271] Gel formulations are semisolid, suspension-type systems.
Single-phase gels contain organic macromolecules distributed
substantially uniformly throughout the carrier liquid, which is
typically aqueous, but also, preferably, contain an alcohol and,
optionally, an oil. Preferred organic macromolecules, i.e., gelling
agents, are crosslinked acrylic acid polymers such as the family of
carbomer polymers, e.g., carboxypolyalkylenes that may be obtained
commercially under the trademark Carbopo.TM.. Other types of
preferred polymers in this context are hydrophilic polymers such as
polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers
and polyvinylalcohol; cellulosic polymers such as hydroxypropyl
cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose,
hydroxypropyl methylcellulose phthalate, and methyl cellulose; gums
such as tragacanth and xanthan gum; sodium alginate; and gelatin.
In order to prepare a uniform gel, dispersing agents such as
alcohol or glycerin can be added, or the gelling agent can be
dispersed by trituration, mechanical mixing or stirring, or
combinations thereof.
[0272] Sprays generally provide the active agent in an aqueous
and/or alcoholic solution which can be misted onto the skin for
delivery. Such sprays include those formulated to provide for
concentration of the active agent solution at the site of
administration following delivery, e.g., the spray solution can be
primarily composed of alcohol or other like volatile liquid in
which the active agent can be dissolved. Upon delivery to the skin,
the carrier evaporates, leaving concentrated active agent at the
site of administration.
[0273] Foam compositions are typically formulated in a single or
multiple phase liquid form and housed in a suitable container,
optionally together with a propellant which facilitates the
expulsion of the composition from the container, thus transforming
it into a foam upon application. Other foam forming techniques
include, for example the "Bag-in-a-can" formulation technique.
Compositions thus formulated typically contain a low-boiling
hydrocarbon, e.g., isopropane. Application and agitation of such a
composition at the body temperature cause the isopropane to
vaporize and generate the foam, in a manner similar to a
pressurized aerosol foaming system. Foams can be water-based or
hydroalcoholic, but are typically formulated with high alcohol
content which, upon application to the skin of a user, quickly
evaporates, driving the active ingredient through the upper skin
layers to the site of treatment.
[0274] Skin patches typically comprise a backing, to which a
reservoir containing the active agent is attached. The reservoir
can be, for example, a pad in which the active agent or composition
is dispersed or soaked, or a liquid reservoir. patches typically
further include a frontal water permeable adhesive, which adheres
and secures the device to the treated region. Silicone rubbers with
self-adhesiveness can alternatively be used. In both cases, a
protective permeable layer can be used to protect the adhesive side
of the patch prior to its use. Skin patches may further comprise a
removable cover, which serves for protecting it upon storage.
[0275] Examples of pharmaceutically acceptable carriers that are
suitable for pharmaceutical compositions for topical applications
include carrier materials that are well-known for use in the
cosmetic and medical arts as bases for e.g., emulsions, creams,
aqueous solutions, oils, ointments, pastes, gels, lotions, milks,
foams, suspensions, aerosols and the like, depending on the final
form of the composition.
[0276] Representative examples of suitable carriers according to
the present invention therefore include, without limitation, water,
liquid alcohols, liquid glycols, liquid polyalkylene glycols,
liquid esters, liquid amides, liquid protein hydrolysates, liquid
alkylated protein hydrolysates, liquid lanolin and lanolin
derivatives, and like materials commonly employed in cosmetic and
medicinal compositions.
[0277] Other suitable carriers according to the present invention
include, without limitation, alcohols, such as, for example,
monohydric and polyhydric alcohols, e.g., ethanol, isopropanol,
glycerol, sorbitol, 2-methoxyethanol, diethyleneglycol, ethylene
glycol, hexyleneglycol, mannitol, and propylene glycol; ethers such
as diethyl or dipropyl ether; polyethylene glycols and
methoxypolyoxyethylenes (carbowaxes having molecular weight ranging
from 200 to 20,000); polyoxyethylene glycerols, polyoxyethylene
sorbitols, stearoyl diacetin, and the like.
[0278] When the pharmaceutical composition according to the present
invention is formulated for topical application, the concentration
of the tellurium-containing compound preferably ranges from about
0.01 weight percent and about 50 weight percents from the total
weight of the composition.
[0279] Thus, depending on the condition being treated and the
composition form, the concentration of the tellurium-containing
compound can be, for example, 0.01 weight percent, 0.05 weight
percent, 0.1 weight percent, 0.5 weight percent, 1 weight percent,
2 weight percents, 3 weight percents, 4 weight percents or 5 weight
percents. Preferably, the concentration of the tellurium-containing
compound is 5 weight percents and higher and thus can be, for
example, 5 weight percents, 6 weight percents, 7 weight percents, 8
weight percents, 9 weight percents or 10 weight percents. 10 weight
percents and higher and therefore can be, for example, 11 weight
percents, 12 weight percents, 13 weight percents, 14 weight
percents, 15 weight percents, 16 weight percents, 17 weight
percents, 18 weight percents, 19 weight percents, 20 weight
percents, 21 weight percents, 22 weight percents, 23 weight
percents, 24 weight percents and up to 25 weight percents of the
total weight of the composition. Alternatively, the concentration
of the tellurium-containing compound is higher than 25 weight
percents and can be up to 50 weight percents of the total weight of
the composition.
[0280] Each of the pharmaceutical compositions described herein may
further comprise, according to an embodiment of the present
invention an additional active agent, as described hereinabove.
[0281] Each of the pharmaceutical compositions described herein can
optionally further comprise a variety of components that are
suitable for providing the compositions with additional usage
benefits. Such conventional optional components are well known to
those skilled in the art and are referred to herein as
"ingredients".
[0282] Some non-limiting representative examples of these
ingredients include humectants, deodorants, antiperspirants, sun
screening agents, sunless tanning agents, hair conditioning agents,
pH adjusting agents, chelating agents, preservatives, emulsifiers,
occlusive agents, emollients, thickeners, solubilizing agents,
penetration enhancers, anti-irritants, colorants, propellants (as
described above) and surfactants.
[0283] Thus, for example, the compositions of the present invention
can comprise humectants or moisturizing agents. Representative
examples of humectants that are usable in this context of the
present invention include, without limitation, guanidine, glycolic
acid and glycolate salts (e.g. ammonium slat and quaternary alkyl
ammonium salt), aloe vera in any of its variety of forms (e.g.,
aloe vera gel), allantoin, urazole, polyhydroxy alcohols such as
sorbitol, glycerol, hexanetriol, propylene glycol, butylene glycol,
hexylene glycol and the like, polyethylene glycols, sugars and
starches, sugar and starch derivatives (e.g., alkoxylated glucose),
hyaluronic acid, lactamide monoethanolamine, acetamide
monoethanolamine and any combination thereof.
[0284] The compositions of the present invention can further
comprise a pH adjusting agent. The addition of a pH adjusting agent
is particularly preferred when the compositions are applied
topically on the skin or in the genital areas. The pH of these
treated areas is typically lower than 6.0. Hence, it is preferable
for the compositions of the present invention to have a pH value of
between about 4 and about 7, preferably between about 4 and about
6, so as to avoid irritations to the skin or induction of imbalance
of the bacteria population if the genital areas. Suitable pH
adjusting agents include, for example, one or more of adipic acids,
glycines, citric acids, calcium hydroxides, magnesium
aluminometasilicates, buffers or any combinations thereof.
[0285] Representative examples of deodorant agents that are usable
in the context of the present invention include, without
limitation, quaternary ammonium compounds such as
cetyl-trimethylammonium bromide, cetyl pyridinium chloride,
benzethonium chloride, diisobutyl phenoxy ethoxy ethyl dimethyl
benzyl ammonium chloride, sodium N-lauryl sarcosine, sodium
N-palmIthyl sarcosine, lauroyl sarcosine, N-myristoyl glycine,
potassium N-lauryl sarcosine, stearyl, trimethyl ammonium chloride,
sodium aluminum chlorohydroxy lactate, tricetylmethyl ammonium
chloride, 2,4,4'-trichloro-2'-hydroxy diphenyl ether, diaminoalkyl
amides such as L-lysine hexadecyl amide, heavy metal salts of
citrate, salicylate, and piroctose, especially zinc salts, and
acids thereof, heavy metal salts of pyrithione, especially zinc
pyrithione and zinc phenolsulfate. Other deodorant agents include,
without limitation, odor absorbing materials such as carbonate and
bicarbonate salts, e.g. as the alkali metal carbonates and
bicarbonates, ammonium and tetraalkylammonium carbonates and
bicarbonates, especially the sodium and potassium salts, or any
combination of the above.
[0286] Antiperspirant agents can be incorporated in the
compositions of the present invention either in a solubilized or a
particulate form and include, for example, aluminum or zirconium
astringent salts or complexes.
[0287] Representative examples of sun screening agents usable in
context of the present invention include, without limitation,
p-aminobenzoic acid, salts and derivatives thereof (ethyl,
isobutyl, glyceryl esters; p-dimethylaminobenzoic acid);
anthranilates (i.e., o-amino-benzoates; methyl, menthyl, phenyl,
benzyl, phenylethyl, linalyl, terpinyl, and cyclohexenyl esters);
salicylates (amyl, phenyl, octyl, benzyl, menthyl, glyceryl, and
di-pro-pyleneglycol esters); cinnamic acid derivatives (menthyl and
benzyl esters, a-phenyl cinnamonitrile; butyl cinnamoyl pyruvate);
dihydroxycinnamic acid derivatives (umbelliferone,
methylumbelliferone, methylaceto-umbelliferone);
trihydroxy-cinnamic acid derivatives (esculetin, methylesculetin,
daphnetin, and the glucosides, esculin and daphnin); hydrocarbons
(diphenylbutadiene, stilbene); dibenzalacetone and
benzalacetophenone; naphtholsulfonates (sodium salts of
2-naphthol-3,6-disulfonic and of 2-naphthol-6,8-disulfonic acids);
di-hydroxynaphthoic acid and its salts; o- and
p-hydroxybiphenyldisulfonates; coumarin derivatives (7-hydroxy,
7-methyl, 3-phenyl); diazoles (2-acetyl-3-bromoindazole, phenyl
benzoxazole, methyl naphthoxazole, various aryl benzothiazoles);
quinine salts (bisulfate, sulfate, chloride, oleate, and tannate);
quinoline derivatives (8-hydroxyquinoline salts,
2-phenylquinoline); hydroxy- or methoxy-substituted benzophenones;
uric and violuric acids; tannic acid and its derivatives (e.g.,
hexaethylether); (butyl carbotol) (6-propyl piperonyl) ether,
hydroquinone; benzophenones (oxybenzene, sulisobenzone,
dioxybenzone, benzoresorcinol, 2,2',4,4'-tetrahydroxybenzophenone,
2,2'-dihydroxy-4,4'-dimethoxybenzophenone, octabenzone;
4-isopropyldibenzoylmethane; butylmethoxydibenzoylmethane;
etocrylene; octocrylene; [3-(4'-methylbcnzylidene bornan-2-one) and
4-isopropyl-di-benzoylmethane, and any combination thereof.
[0288] Representative examples of sunless tanning agents usable in
context of the present invention include, without limitation,
dihydroxyacetone, glyceraldehyde, indoles and their derivatives.
The sunless tanning agents can be used in combination with the
sunscreen agents.
[0289] The chelating agents are optionally added to the
compositions of the present invention so as to enhance the
preservative or preservative system. Preferred chelating agents are
mild agents, such as, for example, ethylenediaminetetraacetic acid
(EDTA), EDTA derivatives, or any combination thereof.
[0290] Suitable preservatives that can be used in the context of
the present composition include, without limitation, one or more
alkanols, disodium EDTA (ethylenediamine tetraacetate), EDTA salts,
EDTA fatty acid conjugates, isothiazolinone, parabens such as
methylparaben and propylparaben, propylene glycols, sorbates, urea
derivatives such as diazolindinyl urea, or any combinations
thereof.
[0291] Suitable emulsifiers that can be used in the context of the
present invention include, for example, one or more sorbitans,
alkoxylated fatty alcohols, alkylpolyglycosides, soaps, alkyl
sulfates, monoalkyl and dialkyl phosphates, alkyl sulphonates, acyl
isothionates, or any combinations thereof.
[0292] Suitable occlusive agents that can be used in the context of
the present invention include, for example, petrolatum, mineral
oil, beeswax, silicone oil, lanolin and oil-soluble lanolin
derivatives, saturated and unsaturated fatty alcohols such as
behenyl alcohol, hydrocarbons such as squalane, and various animal
and vegetable oils such as almond oil, peanut oil, wheat germ oil,
linseed oil, jojoba oil, oil of apricot pits, walnuts, palm nuts,
pistachio nuts, sesame seeds, rapeseed, cade oil, corn oil, peach
pit oil, poppyseed oil, pine oil, castor oil, soybean oil, avocado
oil, safflower oil, coconut oil, hazelnut oil, olive oil, grape
seed oil and sunflower seed oil.
[0293] Suitable emollients, that can be used in the context of the
present invention include, for example, dodecane, squalane,
cholesterol, isohexadecane, isononyl isononanoate, PPG Ethers,
petrolatum, lanolin, safflower oil, castor oil, coconut oil,
cottonseed oil, palm kernel oil, palm oil, peanut oil, soybean oil,
polyol carboxylic acid esters, derivatives thereof and mixtures
thereof.
[0294] Suitable thickeners that can be used in the context of the
present invention include, for example, non-ionic water-soluble
polymers such as hydroxyethylcellulose (commercially available
under the Trademark Natrosol.RTM. 250 or 350), cationic
water-soluble polymers such as Polyquat 37 (commercially available
under the Trademark Synthalen.RTM. CN), fatty alcohols, fatty acids
and their alkali salts and mixtures thereof.
[0295] Representative examples of solubilizing agents that are
usable in this context of the present invention include, without
limitation, complex-forming solubilizers such as citric acid,
ethylenediamine-tetraacetate, sodium meta-phosphate, succinic acid,
urea, cyclodextrin, polyvinylpyrrolidone,
diethylammonium-ortho-benzoate, and micelle-forming solubilizers
such as TWEENS and spans, e.g., TWEEN 80. Other solubilizers that
are usable for the compositions of the present invention are, for
example, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene
n-alkyl ethers, n-alkyl amine n-oxides, poloxamers, organic
solvents, phospholipids and cyclodextrines.
[0296] Suitable penetration enhancers usable in context of the
present invention include, but are not limited to,
dimethylsulfoxide (DMSO), dimethyl formamide (DMF), allantoin,
urazole, N,N-dimethylacetamide (DMA), decylmethylsulfoxide
(C.sub.10 MSO), polyethylene glycol monolaurate (PEGML), propylene
glycol (PG), propylene glycol monolaurate (PGML), glycerol
monolaurate (GML), lecithin, the 1-substituted
azacycloheptan-2-ones, particularly
1-n-dodecylcyclazacycloheptan-2-one (available under the trademark
Azone.RTM. from Whitby Research Incorporated, Richmond, Va.),
alcohols, and the like. The permeation enhancer may also be a
vegetable oil. Such oils include, for example, safflower oil,
cottonseed oil and corn oil.
[0297] Suitable anti-irritants that can be used in the context of
the present invention include, for example, steroidal and non
steroidal anti-inflammatory agents or other materials such as aloe
vera, chamomile, alpha-bisabolol, cola nitida extract, green tea
extract, tea tree oil, licoric extract, allantoin, caffeine or
other xanthines, glycyrrhizic acid and its derivatives.
[0298] The compositions of the present invention may be packed or
presented in any convenient way. For example, they may be packed in
a tube, a bottle, or a pressurized container, using techniques well
known to those skilled in the art and as set forth in reference
works such as Remington's Pharmaceutical Science 15.sup.th Ed. It
is preferred that the packaging is done in such a way so as to
minimize contact of the unused compositions with the environment,
in order to minimize contamination of the compositions before and
after the container is opened.
[0299] The compositions are preferably identified in print, in or
on the packaging material, for use in the treatment an ailment
caused by HPV, as described hereinabove.
[0300] Additional objects, advantages, and novel features of the
present invention will become apparent to one ordinarily skilled in
the art upon examination of the following examples, which are not
intended to be limiting. Additionally, each of the various
embodiments and aspects of the present invention as delineated
hereinabove and as claimed in the claims section below finds
experimental support in the following examples.
EXAMPLES
[0301] Reference is now made to the following examples, which
together with the above descriptions, illustrate the invention in a
non limiting fashion.
Example 1
Preparation of Compositions Containing Tellurium Compounds
[0302] Compositions for topical or systemic application, which
contain one or more of the tellurium compounds described herein and
optionally pharmaceutically acceptable carriers and excipients, are
formulated as creams, lotions, ointments, gels, solutions, foams,
mousses and the like (as is detailed hereinabove), using
conventional methods (see, for example, (see, for example, Harry's
Cosmeticology, Seventh Edition, Edited by J B Wilkinson and R J
Moore, Longmann Scientific & Technical, 1982, Chapter 13 "The
Manufacture of Cosmetics" pages 757-799; and "Remington's
Pharmaceutical Sciences," Mack Publishing Co., Easton, Pa., latest
edition).
[0303] Exemplary compositions for topical application according to
the present invention were prepared in the form of a cream as
follows:
Preparation of Composition 1
[0304] Forty (40) grams of a powdered ammonium
trichloro(dioxoethylene-O,O')tellurate (AS-101, manufactured under
GLP by IMI (TAMI) Institute for Research & Development Ltd.,
Israel) were dissolved in 100 ml dimethyl sulfoxide, so as to make
a 40% w/w solution. The solution was then combined with an equal
weight of petrolatum, U.S.P. (e.g., Intensive Vaseline cream) so as
to make a cream containing about 17%-20% by weight of the
tellurate.
Preparation of Composition 2
[0305] Composition 2 was prepared as described above for
Composition 1, with the addition of 6% by weight of salicylic
acid.
[0306] Another exemplary composition according to the present
invention was prepared in the form of a solution, which can be
administered as drops, as follows:
Preparation of Composition 3
[0307] 10 grams of ammonium trichloro(dioxoethylene-O,O')tellurate
(AS-101) were dissolved in 90 grams DMSO to thereby form a 10%
solution of AS-101.
Example 2
Treatment of Condyloma Acuminatum with a Tellurium Composition
[0308] A human patient with condyloma acuminatum in the perianal
region was treated with Composition 1 (described in Example 1
hereinabove) by topically applying the composition twice daily on
and around the affected area for a period of about 4 weeks.
[0309] Following a few days of treatment the lesion changed color
from pink to grey-black and following about 4 to 5 weeks, the
lesion substantially sloughed off without leaving any scarring.
FIGS. 1-5 present images of the treated area, which show the effect
of the therapy on the condyloma at bi-weekly intervals during the
period of treatment.
Example 3
Treatment of Verruca with a Tellurium Composition
[0310] A human patient with a verrucca lesion on the hand was
treated with Composition 3 described in Example 1 hereinabove. The
formulation was applied on and around the affected area twice daily
for a period of about 10 weeks. FIGS. 6-8 present images showing
the progress of treatment at bi-weekly intervals. As is shown in,
for example, FIG. 8, at the end of the period of treatment, the
wart substantially sloughed off, leaving no scar on the treated
area.
Example 4
Treatment of Verruca with a Tellurium Composition
[0311] A human patient with multiple verrucca lesions on the hand
was treated with Composition 3 described in Example 1 hereinabove.
The formulation was applied twice daily for a period of about 4
weeks. FIGS. 9-11 present images showing the progress of treatment
at biweekly intervals. As is shown in, for example, FIG. 11, at the
end of the period of treatment, the wart substantially sloughed
off, leaving no scar on the treated area.
Example 5
Treatment of Condyloma Acuminatum with a Tellurium Composition
[0312] A 26-years old female with condyloma acuminata in the
genital region was treated with Composition 1 (described in Example
1 hereinabove) by topically applying the composition twice daily on
and around the affected area for a period of about 4 weeks.
[0313] FIGS. 12-14 present images of the treated area,
demonstrating the effect of the therapy on the condyloma at
bi-weekly intervals during the period of treatment. As is shown in,
for example, FIGS. 14a-b, at the end of the period of treatment,
the wart substantially sloughed off, leaving no scar on the treated
area.
Example 6
Treatment of Condyloma Acuminatum with a Tellurium Composition
[0314] A 25-years old female with condyloma acuminata in the
genital region was treated with Composition 1 (described in Example
1 hereinabove) by topically applying the composition twice daily on
and around the affected area for a period of about 4 weeks.
[0315] FIGS. 15-17 present images of the treated area,
demonstrating the effect of the therapy on the condyloma at
bi-weekly intervals during the period of treatment. As is shown in,
for example, FIG. 17, at the end of the period of treatment, the
wart substantially sloughed off, leaving no scar on the treated
area.
Example 7
Treatment of Condyloma Acuminatum with a Tellurium Composition
[0316] A 28-years old female with condyloma acuminata in the
genital region was treated with Composition 1 (described in Example
1 hereinabove) by topically applying the composition twice daily on
and around the affected area for a period of about 2 weeks.
[0317] FIGS. 18-19 present images of the treated area, before (FIG.
18) and after (FIG. 19) treatment with a composition according to
the present invention, demonstrating the effect of the therapy on
the condyloma during the period of treatment. As is shown in FIG.
19, at the end of the period of treatment, the wart substantially
sloughed off, leaving no scar on the treated area.
Example 8
Treatment of Condyloma Acuminatum with a Tellurium Composition
[0318] A 29-years old male with condyloma acuminata in the anus was
treated with Composition 1 (described in Example 1 hereinabove) by
topically applying the composition twice daily on and around the
affected area for a period of about 8-9 weeks.
[0319] FIGS. 20-23 present images of the treated area,
demonstrating the effect of the therapy on the condyloma after two
days (FIG. 21) about 5 weeks (FIG. 22) and about 8 weeks of
therapy. As is shown in, for example, FIG. 23, at the end of the
period of treatment, the wart substantially sloughed off, leaving
no scar on the treated area.
Example 9
Treatment of Verruca Vulgaris with a Tellurium Composition
[0320] A 18-years old female with verruca vulgaris on both hands
was treated with Composition 2 (described in Example 1 hereinabove)
by topically applying the composition twice daily on and around the
affected area for a period of about 6-7 weeks.
[0321] FIGS. 24-26 present images of the treated area,
demonstrating the effect of the therapy on the verruca vulgaris
after about 3 weeks (FIGS. 25 a-b) and about 6 weeks (FIGS. 26 a-b)
of treatment.
Example 10
Treatment of Condyloma Acuminata with a Tellurium Composition
[0322] A 28-years old female with condyloma acuminata in the
genital was treated with Composition 1 (described in Example 1
hereinabove) by topically applying the composition twice daily on
and around the affected area for a period of about 8 weeks.
[0323] FIGS. 27a-d present images of the treated area, which show
the effect of the therapy on the condyloma acuminata at about
bi-weekly or tri-weekly intervals during the period of
treatment.
Example 11
Treatment of Condyloma Acuminata with a Tellurium Composition
[0324] A 35-years old female with condyloma acuminata in the
genital was treated with Composition 1 (described in Example 1
hereinabove) by topically applying the composition twice daily on
and around the affected area for a period of about 8-9 weeks.
[0325] FIGS. 28a-d present images of the treated area, which show
the effect of the therapy on the condyloma acuminata at about
bi-weekly or tri-weekly intervals during the period of
treatment.
Example 12
Treatment of Condyloma Acuminatum with a Tellurium Composition
[0326] A 27-years old male with condyloma acuminata in the anus was
treated with Composition 1 (described in Example 1 hereinabove) by
topically applying the composition twice daily on and around the
affected area for a period of about 10 weeks.
[0327] FIGS. 29a-e present images of the treated area,
demonstrating the effect of the therapy on the condyloma after at
about bi-weekly or tri-weekly intervals during the period of
treatment.
Example 13
Treatment of Condyloma Acuminatum with a Tellurium Composition
[0328] A 25-years old male with condyloma acuminata in the anus was
treated with Composition 1 (described in Example 1 hereinabove) by
topically applying the composition twice daily on and around the
affected area for a period of about 10 weeks.
[0329] FIGS. 30a-d present images of the treated area,
demonstrating the effect of the therapy on the condyloma after
about 4 weeks' intervals during the period of treatment.
Example 14
Treatment of Verruca Vulgaris with a Tellurium Composition
Open Use Pilot Study
[0330] Protocol:
[0331] Twenty-eight patients (19 men and 9 women) aged 17-72 years
(mean 26 years) were enrolled in an open use pilot study. All
patients had typical verruca vulgaris of the hands. Eleven of them
had relatively new lesions (of less than 6 months) which had not
been treated previously, while the other 17 had long-standing,
heavily pre-treated (including liquid nitrogen, laser, salicylic
acid, etc.) lesions.
[0332] Two patients were immunosuppressed (post recent heart and
bone marrow transplants). An additional patient had received
chemotherapy a few months previously for lung carcinoma (complete
remission during the protocol treatment period) and another patient
had surgery one month prior to the study for carcinoma of the
thyroid. [0333] 1. All patients were examined by the protocol
physicians, so as to evaluate the ability of AS101 to eradicate
verruca vulgaris and the safety of the topical application.
[0334] A 10% solution of ammonium trichloro (dioxoethylene-O,O')
tellurate (AS-101) in DMSO (Composition 3 in Example 1 hereinabove)
was applied on and around a single lesion twice daily, two drops in
the morning and two drops at night for three weeks. Patients were
examined once a week in the period of treatment and a bi-weekly
follow up was carried out for 3-12 weeks post treatment. In
patients with multiple warts, only one wart was selected for
treatment.
[0335] A complete response was defined as the total disappearance
of the wart; a major response was over 80% reduction in the size
and an overall response in those who had either a complete response
or a major response.
[0336] Results:
[0337] Twenty-three patients were available for evaluation at the
end of the study. Five patients stopped treatment for unclear
reasons. After three weeks of treatment, a complete response was
observed in 10 out of 23 (43%) of the patients and a lesser
response in 3 out of 23 (13%). Seven of the patients who had a
major response were treated for another three weeks. At the end of
the additional three weeks, one patient had a complete response
while another showed further improvement.
[0338] Overall response (complete or major) was observed in 20 out
of 23 patients (87%) after 3-6 weeks of treatment. The response
rate was unrelated to the previous treatment and was the same for
previously treated and untreated warts.
[0339] No side effects were observed besides the temporary (several
days duration) black discoloration around the wart, and sometimes
sublingually, which was reported by some of the patients in the
study. Some patients experienced slight pain for a few hours
following the application. This pain was significantly less than
the pain caused by the use of liquid nitrogen in the cryosurgical
removal of warts.
Example 15
Treatment of Condyloma Acuminata in Females with a Tellurium
Composition
Open Use Pilot Study
[0340] Protocol:
[0341] Female patients aged 18 years and up were enrolled in an
open use pilot study. All patients had diagnosed HPV genital
warts.
[0342] Patients were examined by the protocol physicians, so as to
evaluate the ability of AS101 to eradicate Condyloma acuminata and
the safety of the topical application.
[0343] A 20% cream composition (Composition 1 described in Example
1 above) was applied on and around the targeted area twice daily,
and was maintained for at least two hours before taking a shower.
Patients were examined every other week during treatment and every
two months for a six months post treatment period.
[0344] A complete response was defined as a reduction of 95-100% in
the size of the warts (averaged); a partial response was defined as
a reduction of 70-94% in the size of the warts (averaged); and no
response was defined as less than 70% reduction in the size of the
warts (averaged).
[0345] Results:
[0346] This study is still ongoing, and therefore conclusive data
has not been established yet. Preliminary results, however,
obtained regarding the 21 patients who completed the treatment
indicate a complete cure in 18 patients (85.7%), following a
treatment period ranging between a minimum period of 14 days and a
maximal period of 84 days (an average treatment period of 38 days),
and no response in 1 patient (4.7%). Two patients were dropped out
of the trial voluntarily.
[0347] Local, light to moderate anticipated side effects such as
erythrema, itching, slight burn and the like were observed in 9 of
the 21 patients (42.8%), whereby non-local adverse effects such as
allergic reaction or strong local burn were observed in 3 patients
(14.2%).
Example 16
Treatment of Condyloma Acuminata in Males with a Tellurium
Composition
Open Use Pilot Study
[0348] Protocol:
[0349] Male patients aged 18 years and up were enrolled in an open
use pilot study. All patients had diagnosed HPV in the anus.
[0350] All patients were examined by the protocol physicians so as
to evaluate the ability of AS101 to eradicate Condyloma Acuminata
and the safety of the topical application.
[0351] A 20% cream composition (Composition 1 described in Example
1 above) was applied on and around the targeted area twice daily.
Patients were examined on a bi-weekly basis during treatment and
every two months for a six months post treatment period.
[0352] A complete response was defined as a reduction of 95-100% in
the size of the warts (averaged); a partial response was defined as
a reduction of 70-94% in the size of the warts (averaged); and no
response was defined as less than 70% reduction in the size of the
warts (averaged).
[0353] Results:
[0354] Since the studies described above are still ongoing,
conclusive data has not been established yet. Preliminary results,
however, obtained regarding the 12 patients who completed the
treatment indicate a complete cure in 7 patients (53.8%), following
a treatment period ranging between a minimum period of 42 days and
a maximal period of 105 days (an average treatment period of 67
days), and no response in 3 patients (25%). One patient dropped out
of the trial voluntarily.
[0355] Local, light to moderate anticipated side effects such as
erythrema, itching, slight burn and the like were observed in 9 of
the 12 patients (75%), whereby non-local adverse effects such as
allergic reaction, or strong local burn were observed in 2 patients
(16.6%).
[0356] It is appreciated that certain features of the invention,
which are, for clarity, described in the context of separate
embodiments, may also be provided in combination in a single
embodiment. Conversely, various features of the invention, which
are, for brevity, described in the context of a single embodiment,
may also be provided separately or in any suitable
subcombination.
[0357] Although the invention has been described in conjunction
with specific embodiments thereof, it is evident that many
alternatives, modifications and variations will be apparent to
those skilled in the art. Accordingly, it is intended to embrace
all such alternatives, modifications and variations that fall
within the spirit and broad scope of the appended claims. All
publications, patents and patent applications mentioned in this
specification are herein incorporated in their entirety by
reference into the specification, to the same extent as if each
individual publication, patent or patent application was
specifically and individually indicated to be incorporated herein
by reference. In addition, citation or identification of any
reference in this application shall not be construed as an
admission that such reference is available as prior art to the
present invention.
* * * * *