US6485755B1

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(2)

United States Patent

Antelman

(006485755.

US 'S 6.485.755 Bl
Nov. 26, 2002

(10) Patent No.:
(45) Date of Patent:

G64)

(75)
(73)

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(21)
(22)

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(60)

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66)

METHODS OF USING ELECTRON ACTIVE
COMPOUNDS FOR MANAGING CANCER
Inventor: Marvin S. Antelman, Rehovot (IL)
Assignee: Marantech Holding, Providence, RI
(Ws)
Notice: Subject to any disclaimer, the term of this
patent is extended or adjusted under 35
US.C. 154(b) by 0 days.
Appl. No.: 09/692,488
Filed: Oct. 20, 2000
Related U.S. Application Data
Continuation-in-part of application No. 09/552,172, filed on
Apr. 18, 2000, now Pat. No. 6,258,385.
Provisional application No. 60/174,793, filed on Jan. 6,
2000, provisional application No. 60/184,053, filed on Feb.
22, 2000, and provisional application No. 60/214,503, filed
on Jun. 28, 2000.
Int. C1? oe A61K 33/38; A61K 33/00;
AGIK 47/00; A61K 47/30
. 424/618; 424/600; 424/617;
24/639; 424/646; 424/653; 424/630;
514/788.1
Field of Search .... 424/600, 617,
424/618, 630, 639, 646, 647, 648, 653,
635; 514/788.1
References Cited
U.S. PATENT DOCUMENTS
3,923,982 A 12/1975 Lamand et al. 424/140
4,447,254 A 5/1984 Hughes et al. 71/67
4,574,782 A * 3/1986 Borrelli et al. 600/10
4,735,796 A * 4/1988 Gordon ...... 424/932
4,828,832 A 5/1989 De Cuellar et al. 424/618
4,952,411 A 8/1990 Fox, Jt, et al. 424/618
5,017,295 A 5/1991 Antelman 210/764
$,073,382 A 12/1991 Antelman 424/604
5,078,902 A 1/1992 Antelman 210/764
$,089,275 A 2/1992 Antelman 424/602
5,098,582 A 3/1992 Antelman 210/759
5,211,855 A 5/1993 Antelman 210/758
5,223,149 A 6/1993 Antelman 210/764
5,320,906 A * 6/1994 Eley et al. ..
5,334,588 A 8/1994 Fox, Jr. et al. 514/171
5,336,416 A 8/1994 Antelman 210/764
5,336,499 A 8/1994 Antelman 424/405
5,571,520 A 11/1996 Antelman 424/405
5,612,019 A 3/1997 Gordon et al. 424/9.32
5,676,977 A 10/1997 Antelman 424/618

5,772,896 A
5,928,958 A *

FOREIGN PATENT DOCUMENTS
JP 2000060976, 2/2000
OTHER PUBLICATIONS

STN/CAS online, file CIN, Acc. No. 13(8):6866B, China
Dly. (North Am. Ed.), Jan. 30, 1984, p. 5), Abstract.*
Antelman, Marvin S.; “Silver (II,IM1) Disinfectants”; Soap/
Cosmetics/Chemical Specialties, Mar. 1994, pp. 52-59.
Antelman, Marvin S.; Abstracts of the American Chemical
Society; 1992(203),

Antelman, Marvin S.; “Anti—Pathogenic Multivalent Silver
Molecular Semiconductors”; Precious Metals; 1992(16); pp.
141-149.

Antelman, Marvin S.; “Multivalent Silver Bactericides”;
Precious Metals; 1992(16); pp. 151-163.

Fung, Man C. and Bowen, Debra L.; “Silver Products for
Medical Indications: Risk—Benefit Assessment”, Clinical
Toxicology, 1996, pp. 119-126.

Dorland et al., Dorland’s Ilustrated Medical Dictionary,
Philadelphia: W.B. Saunders Company, 1994, 28" Edition,
p. 351, 759, and 760.

Gennaro, A., Remington’s Pharmaceutical Sciences, Easton,
PA: Mack Publishing Company, 1985, 17” Edition, p.
1573-1575, 1585-1594, and 1601.

6/1998 Denkewicz, Jr. et al.
7/1999 Pilgrimm

210/754
- 436/526

* cited by examiner

Primary Examiner—lose' G. Dees
Assistant Examiner—rank Choi
(74) Attorney, Agent, or Firm—Pennie & Edmonds LLP

(57) ABSTRACT

The present invention provides methods for preventing,
treating, and/or managing one or more cancerous conditions
in a patient, such as a human. A multivalent metal oxide,
such as Ag(I,III), Cu(II), Pr(Il,IV), and Bi(IIL,V) oxides
or a pharmaceutically acceptable derivative thereof, may be
administered to the patient in an amount and for a period of
time which is therapeutically effective to prevent, treat,
and/or manage such condition(s). These cancerous condi-
tions include systemic and external cancers, and may also
include conditions and symptoms associated with cancer.
The present invention also provides a pharmaceutical com-
position suitable for treating such cancerous conditions. The
compositions of the invention may be adapted for at least
one of subcutaneous injection, intramuscular injection,
intravenous injection, infusion, transdermal, or topical appli-
cation.

31 Claims, No Drawings

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METHODS OF USING ELECTRON ACTIVE
COMPOUNDS FOR MANAGING CANCER

CROSS-REFERENCE TO RELATED
APPLICATION

This application is a continuation-in-part of application
Ser. No. 09/552,172, filed Apr. 18, 2000, now U.S. Pat. No.
6,258,385, and claims the benefit of Provisional Application
No. 60/174,793, filed Jan. 6, 2000, No. 60/184,053, filed
Feb. 22, 2000, and No. 60/214,503, filed Jun. 28, 2000.

FIELD OF THE INVENTION

The invention relates to pharmaceutical compositions
including at least one metal oxide, such as an electron active
metal oxide, and methods of using such compositions, for
the prevention, treatment, and management of cancer and
conditions or diseases related to the presence of cancer or a
predisposition to cancer.

BACKGROUND OF THE INVENTION

Cancers are a leading cause of death in animals and
humans. The exact cause of cancer is not known, but links
between certain factors, such as smoking or exposure to
carcinogens including tobacco smoke and chromium (VI),
exposure to radiation, such as from x-rays, radioisotopes,
and ultra-violet light, viruses, such as papaloma, Espstein
Barr, and Raus sarcoma virus and the incidence of certain
types of cancers and tumors has been shown by a number of
researchers. Genetic factors and genome defects such as
those found a chromosome 11 have also been linked to
cancer. Traditional methods of cancer therapy include treat-
ment with chemotherapeutic agents that inhibit cell division
or radiation therapy that disrupts DNA in dividing cells.
These treatments, however, may also adversely affect nor-
mal cells that happen to be dividing or synthesizing DNA at
the time of treatment. Dosage levels low enough to insure
survival of a cancer patient often are not sufficiently cyto-
toxic to tumor cells to retard continuing cell division after
treatment. Additionally, the mechanism for the action of
these chemotherapeutic agents is frequently unknown,
which complicates the safe and effective use of these agents.
Several different cancers and conditions associated with
cancer are discussed below as examples illustrating the
importance of combating cancer and associated conditions.

Breast carcinoma is the most common malignancy among,
women and shares with lung carcinoma the highest fatality
rate of all cancers affecting females. For example, approxi-
mately one of every 11 women in the U.S.A. will develop
breast cancer. For white women, the probability is about 1 in
10; for African American women, the rate is close to 1 in 14.
The annual mortality rate from 1930 to the present has
remained fairly constant at about 27 deaths per 1000,000
females, and is slightly higher for whites than African
Americans.

In women, breast carcinoma is rare before age 30 but the
incidence rises rapidly after menopause. Post-menopausal
breast masses are typically considered cancerous until
biopsy proves otherwise. Cystosarcoma phyllodes, which
are a non-cancerous tumor, are the most common tumor of
the breast; other malignancies are significantly more rare.
Breast cancer in men is rare and tends not to be recognized
until late with poor therapeutic results.

Most breast cancers, including those frequently desig-
nated as scirrhus, infiltrative, papillary, ductile, medullary,
and lobular, appear as a slowly growing, painless mass,

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though a vague discomfort may be present. Physical signs
typically include a retracted nipple, bleeding from the
nipple, a distorted areola or breast contour, skin dimpling
over the lesion, attachment of the mass to surrounding
tissue, including the underlying fascia and overlying skin,
edema of the skin of the breast with an orange peel
appearance, and axillary or supraclavicular lymph nodes. In
advanced cases, skin nodules with ultimate breakdown and
ulcer formation may be seen.

The presence of metastases should always be suspected as
the disease metastasizes by direct extension and via the
lymph system and the bloodstream. Among the most com-
mon sites are the lungs and pleura, the skeleton (especially
skull, spine, and pelvis), and the liver. Although the exact
causes of breast cancer are not known, a doctor from France
discovered a virus called mice breast tumor virus (vtmr) in
1985 that was later described as an oncomavirus with
particules type B. This virus caused breast cancer in mice
breast. It can be transmitted by breast milk or it can be
incorporated in the human genome. Current treatments for
breast cancer in general include surgery, radiotherapy, che-
motherapy and hormonal therapy.

Cervical cancer includes those cancer moieties which are
indigenous to the cervix. These cancer moieties are referred
to generally as cervical carcinomas of which 85-90% are
squamous cell carcinomas, and the balance are largely
adenocarcinomas. The severity of cervical cancers are
gauged by the clinical tests called PAP smears which indi-
cate whether the carcinoma cells are confined to the cervix
or have penetrated beyond it but not to the pelvic wall, or to
the pelvic wall itself and even beyond the pelvis. Cervical
cancers kill about 33% of their victims annually in the
United States.

Carcinoma of the uterine cervix, the second most com-
mon malignancy of the female reproductive tract, most
commonly affects women aged 40 to 56 years old. The
incidence is higher among women from lower socioeco-
nomic groups and among those with a history of early and
frequent coitus and multiple sexual partners. Recently, vene-
real transmission of human papilloma virus (hpy) and herpes
virus type 2 (nsv-2) have been implicated as important in the
etiology of cervical neoplasia.

The earliest histologic change in what is considered a
continuum from normal to invasive cancer is minimal cer-
vical dysplasia, in which abnormal cell proliferation occurs
in the lower third of the epithelium. Most of the minimal
dysplasias are self-limiting and regress to normal tissue.
Most severe dysplasias in the upper two-thirds of the epi-
thelium showing abnormal proliferation, however, progress
to carcinoma in situ, in which a full thickness of the
epithelium contains abnormal calls. When cancer cells pen-
etrate the basement membrane and invade the stroma
(invasive carcinoma) they can spread by direct extension to
adjacent pelvic organs or by lymphatic permeation and
dissemination.

Of cervical carcinomas, 85 to 90% are squamous cell
carcinoma. These vary from well-differentiated cells with
keratinization to the highly anaplastic spindle cells of cer-
vical tumors. Adenocarcinomas, observed in only 10 to 15%
of cases, are more rare.

Early cervical neoplasia can be detected pre-clinically by
cytologic examination of cervical smears obtained during
routine annual pelvic examinations. At this stage, the disease
is asymptomatic. The cervical smears (pap test) can detect
90% of early cervical neoplasias. Thus, the use of cervical
smears has reduced the death rate from cervical cancer by

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more than 50% through recognition and treatment of pre-
invasive neoplasia. Treatment of cervical cancer typically
involves conization, radiotherapy, surgical therapy, and che-
motherapy.

For diagnostic and prognostic purposes, the results of 5
cervical smear tests may be grouped into four categories:
class I characterized by the absence of observed abnormal
cells; class II characterized by the presence of atypical cells
and usually associated with inflammation; class III charac-
terized by the presence of cells representative of or suspi-
cious of carcinoma; and classes IV and V each characterized
by the presence of carcinoma cells.

Additionally, the clinical stage or progression of the
cervical carcinoma may be further characterized as follows.
Stage 0 is characterized by carcinoma in situ with intra
epithelial carcinoma. Stage I includes carcinomas strictly
confined to the cervix. Stage IA is characterized by micro
invasive carcinoma and stage IB is characterized by occult
cancer.

In stage II, the carcinoma extends beyond the cervix but
not onto the pelvic wall. Stage IIA exhibits no obvious
parametrial involvement while stage ITB exhibits obvious
parametrial involvement. In stage III, the carcinoma extends
onto the pelvic wall. Stage IIIA is characterized by the lack
of extension onto the pelvic wall and stage IIIB is charac-
terized by extension onto the pelvic wall.

In stage IV, the carcinoma has extended beyond the true
pelvis or has clinically involved the mucosa of the bladder.
Stage IVA is characterized by the spread of the growth to
adjacent organs. Stage IVB is characterized by the spread to
distant organs.

Skin cancer is a disease in which cancer (malignant) cells
are found in the layers of the skin. The skin has two main
layers and several kinds of cells: a top layer called the
epidermis, which contains three kinds of cells: flat, scaly
cells on the surface called squamous cells; round cells called
basal cells; and cells called melanocytes, which give the skin
its color. The dermis is the inner, second layer of the skin.

The skin is the most environmentally-stressed organ in
mammals, particularly in humans. The skin is subjected to
toxic chemicals and hostile environments, as well as being
the only organ directly exposed to ultraviolet (“UV”) light in
the presence of oxygen. Lengthy exposure of the skin to UV
light typically damages the skin, resulting, in sunburn,
photo-aging, carcinogenesis, and other related skin disor-
ders. “Skin cancer” is generally used to describe the three
major forms of skin cancer; basal cell and squamous carci-
noma together with melanoma. These carcinomas account
for about 97% of skin cancers. Melanoma, however,
accounts for over 87% of deaths due to said cancers.

Melanoma is a disease of the skin in which cancer
(malignant) cells are associated with the cells that color the
skin (melanocytes). Melanoma usually occurs in adults, but
it may occasionally be found in children and adolescents. s:
Melanoma is sometimes called cutaneous melanoma or
malignant melanoma. Melanoma can spread (metastasize)
quickly to other parts of the body through the lymph system
or through the blood.

About 80% of non-melanoma skin cancer will be basal 6c
cell carcinoma. It can occur at any location on the body
surface, but occurs more commonly on sun-exposed
surfaces, such as the face. The earliest sign may be a red flat
area, a small nodule, a small spot that bleeds on rubbing, a
small ulcer, or a scaly patch. About 20% of non-melanoma
skin cancer will be squamous cell carcinoma. The difference
between basal cell carcinoma and squamous cell carcinoma

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is often discernable only at the microscopic level, as the two
may look identical. Squamous cell carcinoma, however,
tends to grow more rapidly, and form an ulcer sooner.
Squamous cell carcinoma may afflict any skin surface, but is
common on the lips and ears.

Neurofibromatosis is a hereditary autosomal dominant
disorder that is accompanied by a predisposition to cancer.
Neurofibromatosis produces pigmented spots and tumors of
the skin and of peripheral, optic and acoustic nerves. Sub-
cutaneous and bony deformities may also be observed. One
third of the patients with neurofibromatosis are asymptom-
atic and the condition is discovered during routine exami-
nation. In one-third of patients, cosmetic problems are the
initial complaints. Characteristic skin lesions, apparent at
birth or in infancy in 90% of the patients, include medium
brown patches distributed most commonly over the trunk,
pelvis, and flexor creases of elbows and knees. For diag-
nostic purposes, the presence of six or more of these
freckle-like lesions with one larger than 1.5 cm is charac-
teristic of neurofibromatosis. Multiple cutaneous tumors,
flesh colored and of variable size and shape typically appear
in late childhood.

The above-mentioned discussion merely illustrates the
breadth and importance of cancer as an affliction of animals
and humans in particular. Those of ordinary skill in the art
will understand that various other types of cancers exist that
also require suitable prevention, treatment, and/or manage-
ment. In view of this discussion, there is a need for phar-
maceutical compositions that can be administered at dosage
levels low enough to insure survival of a cancer patient but
which are sufficiently cytotoxic to cancer cells or cells
associated with cancer to retard or eliminate continuing cell
division after treatment, i.c., management or treatment of the
cancer.

Metal oxides, such as electron active metal oxides com-
prising multivalent silver cations, have been disclosed for
various uses, as they are reported to be non-toxic to animals
and humans. M. Antelman, “Anti-Pathogenic Multivalent
Silver Molecular Semiconductors,” Precious Metals, vol.
16:141-149 (1992); M. Antelman, “Multivalent Silver
Bactericides,” Precious Metals, vol. 16:151-163 (1992). For
example, tetrasilver tetroxide activated with an oxidizing
agent is disclosed for use in bactericidal, fungicidal, and
algicidal use, such as in municipal and industrial water
treatment applications and for the treatment of AIDS.

A variety of sources also report the use of certain divalent
silver compounds for water treatment, as well as the use of
such compounds, typically in combination with certain
oxidizing agents, metals, or other compounds, as
disinfectants, bactericides, algicides, and fungicides. One
source also reports a single in vitro study of the use of such
compounds for the treatment of AIDS. These sources
include M. Antelman, “Silver (II, II) Disinfectants,” Soap/
Cosmetics/Chemical Specialties, pp. 52-59 (March, 1994),
and U.S. Pat. Nos. 5,017,295; 5,073,382; 5,078,902; 5,089,
275; 5,098,582, 5,211,855; 5,223,149; 5,336,416; and 5,772,
8906.

USS. Pat. No. 5,336,499 discloses tetrasilver tetroxide and
persulfate compositions having certain in vitro anti-
pathogenic properties, i.e., bactericidal, fungicidal, viricidal,
and algicidal, in certain concentrations as low as 0.3 ppm,
particularly in nutrient broth cultures. The persulfate is
disclosed to be an oxidizing agent that activates the tetroxide
crystals. Also disclosed are an in vitro study regarding the
inhibition of yeast growth in nutrient broth and the formu-
lation of a gynecological cream and douche based on these

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results, and a report of an in vitro AIDS test with the
compositions indicating total suppression of the virus at 18
ppm.

In vitro assays, such as those disclosed in Ahmed, S. A.,
Gogal Jr., R. M. and Walsh, J. E., a New Rapid and Simple
Non-radioactive Assay to Monitor and Determine the Pro-
liferation of Lymphocytes: an Alternative to [SH]-thymidine
Incorporation Assay, Journal of Immunological Methods
1994; 170: 211-224; Boyd, M. R., Status of the NCI
Preclinical Antitumor Drug Discovery Screen, J. B. Lippin-
cott Company, Philadelphia, Principles & Practices of
Oncology Updates 1989; 3 # 10: 1-12, and Boyd, M. R. et
al. Data Display and Analysis Strategies for the NCI
Disease-oriented in Vitro Antitummor Drug Screen in Cyto-
toxic Anti-cancer Drugs: Models and Concepts for Drug,
Discovery and Development, Kluwer Academic, Boston,
1992: 11-34; each of which is hereby incorporated herein in
its entirety by express reference thereto, have been used to
estimate the cyto-toxicity of anti-cancer therapeutics. One of
ordinary skill in the art understands, however, that, although
in vitro testing provides a useful screen for potentially useful
compounds, animals such as humans are sufficiently com-
plex that the actual in vivo cytotoxicity of a compound is
often surprisingly different than that predicted upon the basis
of an in vitro toxicity screen.

US. Pat. No. 5,571,520 discloses the use of molecular
crystals of tetrasilver tetroxide, particularly with oxidizing
agents to enhance the efficiency of such devices, for killing
pathogenic microorganisms, such as staph infections.
Amounts of 10 ppm sodium persulfate as an oxidizing agent
were used with certain amounts of silver tetroxide in the
reported in vitro testing. One human study involved in vivo
curing of a gynecological yeast infection with 10 ppm of the
silver tetroxide and 40 ppm sodium persulfate. Other in vivo
topical studies report in conclusory fashion the cure of a
single case of athlete’s foot with a solution of 100 ppm of the
composition and the cure of a single case of toenail fungus
with a 25% suspension of the composition.

US. Pat. No. 5,676,977 discloses intravenously injected
tetrasilver tetroxide crystals used for destroying the AIDS
virus, AIDS synergistic pathogens, and immunity suppress-
ing moieties (ISM) in humans. The crystals were formulated
for a single injection at about 40 ppm of human blood. This
reference also discloses the compositions cause
hepatomegaly, also known as enlarged liver, albeit with no
reported loss of liver function.

The aforementioned references report detailed descrip-
tions of the mechanism via which the multivalent silver
molecular crystal devices were believed to operate. The
instant inventor also presented a discussion of such results
and concepts at a Seminar entitled “Incurable Diseases
Update” (Weizmann Institute of Science, Rehovot, Israel,
Feb. 11, 1998). The title of this presentation was “Beyond.
Antibiotics, Non Toxic Disinfectants and Tetrasil™
(Trademark of applicant for the tetroxide).”

In this paper, it was reported that the effects of the electron
transfer involved with respect to the tetroxide, rendered it a
more powerful germicide than other silver entities. The
instant inventor holds patents for multivalent silver
antimicrobials, e.g., U.S. Pat. No. 5,017,295 for Ag(II) and
US. Pat. No. 5,223,149 for Ag (III); and while these entities
are stronger antimicrobials than Ag (I) compounds, they pale
by comparison to the tetroxide and so does colloidal silver
that derives its germicidal properties from trace silver (I)
ions it generates in various environments. Accordingly, the
oligodynamic properties of these entities may be summa-
rized as follows, which is referred to as the Horsfal series:

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Ag,0,>Ag(I)>Ag(I)>>>>Ag())

The other unique property of the tetroxide was that it did
not stain organic matter such as skin in like manner as Ag(I)
compounds do. In addition, it was light stable.

Thus, it is desired to find pharmaceutical compositions
and methods for preventing, treating, or managing one or
more cancers or associated conditions. It is also desired to
facilitate the prevention of future outbreaks of one or more
disorders, as well as preventing, treating, and managing one
or more cancerous or related disorder while avoiding the
adverse effects present in many conventional treatments.

SUMMARY OF THE INVENTION

The present invention relates to a method for preventing,
treating, or managing one or more cancerous conditions or
dysplastic proliferations in an animal. The method prefer-
ably comprises administering at least one metal oxide com-
pound or a pharmaceutically acceptable derivative thereof,
to the animal. The metal oxide compound or derivative
thereof preferably comprises a first metal cation having a
first valence state and a second metal cation having a second,
different valence state, such as, for example, an electron
active metal oxide compound. The at least one metal oxide
compound or a pharmaceutically acceptable derivative
thereof is preferably administered in an amount and for a
period of time which is therapeutically effective to treat such
condition(s).

In a preferred embodiment, the at least one metal oxide
compound or pharmaceutically acceptable derivative thereof
comprises at least one of Bi(III,V) oxide, Co(ILI) oxide,
Cu(LI) oxide, Fe(III) oxide, Mn(ILII) oxide, Pr(II,IV)
oxide, or Ag(LII) oxide.

The metal oxide compound or derivative thereof is pref-
erably substantially free of added persulfate.

The invention is preferably adapted to preventing,
treating, or managing systemic cancerous conditions.
Preferably, the animal is an mammal, such as, for example,
a human. The metal oxide compound is preferably admin-
istered via intravenous injection or infusion, when the ani-
mal is a human. The intravenous injection or infusion is
preferably subcutaneous, intramuscular, or comprises infu-
sion into the bloodstream of the animal. Preferably, the
administration provides an amount of the metal oxide suf-
ficient to provide about 1 to about 75 ppm of the metal oxide
compound or derivative thereof in the bloodstream. The
metal oxide is preferably administered via infusion over a
period of time sufficient to inhibit adverse side effects, such
as over a time period of from about 30 minutes to about 300
minutes.

The metal oxide compound or derivative thereof may
preferably be administered by a controlled release vehicle.
The controlled release vehicle is preferably implanted in the
body at a location suitable for providing a therapeutically
effective amount of metal oxide compound or derivative
thereof to the patient, preferably, without affecting proper
functioning of the animal’s liver.

The method of the invention is preferably suitable for
cancers or dysplastic proliferations including at least one of
colon cancer, lung cancer, throat cancer, breast cancer,
kidney cancer, pancreatic cancer, bladder cancer, prostate
cancer, uterine cancer, brain cancer, liver cancer, skin
cancer, testicular cancer, stomach cancer, adrenal gland
cancer, cancer of the ovaries, thyroid cancer, bronchial
cancer, tracheal cancer, eye cancer, bone cancer, cervical
cancer, oral cavity cancer, soft tissue cancer, pituitary gland

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cancer, myeloma, rectal cancer, esophageal cancer,
leukemia, lymphoma, cancerous fibroid tumors, non-
cancerous fibroid tumors, or liver cancer. The method is
preferably suitable for cancers including skin cancer that has
metastasized.

In a preferred embodiment, the metal oxide compound or
derivative thereof is administered in conjunction with at
least one other chemotherapeutic agent. The at least one
other chemotherapeutic agent is preferably administered
concurrently with the metal oxide compound or derivative
thereof.

Another embodiment of the invention relates to a method
for preventing, treating, or managing one or more cancerous
conditions or dysplastic proliferations associated with a
patient’s skin, which method preferably comprises admin-
istering at least one metal oxide compound or a pharmaceu-
tically acceptable derivative thereof to the skin in an amount
and for a period of time which is therapeutically effective to
treat such cancerous or associated condition(s). The metal
oxide compound or derivative thereof preferably comprises
a first metal cation having a first valence state and a second
metal cation having a second, different valence state.

In a preferred embodiment, the at least one metal oxide
compound or pharmaceutically acceptable derivative thereof
comprises at least one of Bi(IIL,V) oxide, Co(ILIID oxide,
Cu(LI) oxide, Fe(III) oxide, Mn(ILI]) oxide, Pr(II,IV)
oxide, or Ag(I,IID) oxide.

The metal oxide compound or derivative thereof is pref-
erably substantially free of added persulfate.

The method of the invention is preferably suitable for
preventing, treating, or managing cancerous conditions or
dysplastic proliferations comprising at least one of dysplas-
tic nevi, neurofibromatosis, basal cell carcinoma, squamous
carcinoma, or melanoma. The method is preferably suitable
for preventing, treating, or managing conditions comprising,
symptoms of cancer or conditions associated with a predis-
position to cancer, such as neurofibromatosis.

The administering preferably comprises a carrier medium
in which the at least one metal oxide compound or pharma-
ceutically acceptable derivative thereof, is dispersed. Pref-
erably the therapeutically effective amount of the metal
oxide or derivative thereof is from about 50 ppm to 500,000
ppm, such as from about 400 ppm to about 100,000 ppm,
based on the weight of the carrier medium. The carrier
medium may preferably comprise petroleum jelly. The
administering of the composition is preferably topical or
transdermal, such as directly to the skin.

Preferably, the at least one metal oxide compound or
pharmaceutically acceptable derivative thereof, further com-
prises a thixotropic agent sufficient to increase adherence of
the composition to the skin without excessive runoff.

The at least one metal oxide compound or pharmaceuti-
cally acceptable derivative thereof may, preferably, be
administered in the form of a powder, such as in the form of
metal oxide crystals. The administering of the powder is
preferably topical or transdermal, such as directly to the
skin. Preferably the metal oxide or derivative thereof is
administered at a dosage level of about 10 mg to 500 mg per
em? of skin surface. A preferred embodiment of a compo-
sition suitable for application as a powder comprises about
5% metal oxide, such as tetrasilver tetroxide, and about 95%
bismuth subgallate.

‘Yet another embodiment of the invention relates to a
method for preventing, treating, or managing one or more
cancerous conditions associated with a cervix of a female
animal. The method preferably comprises administering at

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least one metal oxide compound or a pharmaceutically
acceptable derivative thereof to the cervix in an amount and
for a period of time which is therapeutically effective to treat
such cancerous or associated condition(s). Each metal oxide
compound or derivative thereof preferably comprises a first
metal cation having a first valence state and a second metal
cation having a second, different valence state.

In a preferred embodiment, the at least one metal oxide
compound or pharmaceutically acceptable derivative thereof
comprises at least one of Bi(III,V) oxide, Co(II,III) oxide,
Cu(LI) oxide, Fe(II) oxide, Mn(ILII) oxide, Pr(II,IV)
oxide, or Ag(LII) oxide.

The metal oxide compound or derivative thereof is pref-
erably substantially free of added persulfate.

The metal oxide compound or derivative thereof are
preferably applied directly to the cervix. The administering,
preferably comprises a carrier medium, such as petroleum
jelly, in which the at least one metal oxide compound or
pharmaceutically acceptable derivative thereof, is dispersed,
preferably in a therapeutically effective amount from about
50 ppm to 500,000 ppm, based on the weight of the carrier
medium. The at least one metal oxide compound or phar-
maceutically acceptable derivative thereof is preferably
applied in an amount sufficient to obtain a desired effect and
to substantially inhibit undesirable side effects.

Definitions Section

Suitable definitions are provided herein for some of the
terms relating to the present invention.

The terms “patient” or “subject” as used herein refer to
animals, particularly to mammals. In a preferred
embodiment, the terms “patient” or “subject” refer to
humans.

As used herein, the terms “adverse effects,” “adverse side
effects,” and “side effects” include, but are not limited to,
staining of the skin, headache, dry mouth, constipation,
diarrhea, gastrointestinal disorders, dry skin, staining of the
skin, hepatomegaly, fever, fatigue, and the like.

The phrase “therapeutically effective amount” when used
herein in connection with the compositions and methods of
the invention, means that amount of metal oxide
composition, or a derivative thereof, which, alone or in
combination with other drugs or treatment modalities, pro-
vides a therapeutic benefit in the prevention, treatment, or
management, of one or more of forms of cancer or a
symptom or related condition thereof. Preferably, the thera-
peutically effective amount of a component yields the
desired therapeutic benefit without undue adverse side
effects (such as toxicity, irritation, or allergic response)
commensurate with a reasonable benefit/risk ratio when
used in the manner of this invention.

The term “substantially free” means less than about 10
weight percent, preferably less than about 5 weight percent,
more preferably less than about 1 weight percent, and most
preferably less than about 0.1 weight percent of added
persulfate is present according to the invention. In another
embodiment, the term “substantially free” refers to the same
amounts of other added oxidizing agents present in the
compositions.

The term “controlled-release component” in the context
of the present invention is defined herein as a compound or
compounds, including polymers, polymer matrices, gels,
permeable membranes, liposomes, microspheres, or the like,
or a combination thereof, that facilitates the controlled-
release of the active ingredient (e.g., tetrasilver tetroxide) in
the pharmaceutical composition.

The term “about,” as used herein, should generally be
understood to refer to both numbers in a range of numerals.

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Moreover, all numerical ranges herein should be understood
to include each whole integer within the range.

DETAILED DESCRIPTION OF THE
PREFERRED EMBODIMENTS

It has now been discovered that pharmaceutical compo-
sitions comprising at least one oxide compound or a phar-
maceutically acceptable derivative thereof can be used as
advantageous active ingredients in the prevention,
treatment, or management of various cancerous conditions
The oxide compound preferably comprises a metal oxide,
such as an electron active metal oxide. The metal oxide
compound or pharmaceutically acceptable derivative thereof
preferably comprise a first metal cation having a first
valence state and a second metal cation having a second,
different valence state. One of ordinary skill in the art
understands that, in general, the valence state of a species,
such as a metal cation, is related to the charge associated
with or assigned to the species.

Preferably, the at least one metal oxide compound or a
pharmaceutically acceptable derivative comprises at least
one electron active metal oxide compound, such as, for
example, at least one of Bi(III,V) oxide, Co(IL,III) oxide,
Cu(II oxide, Fe(II, oxide, Mn(ILIIM) oxide, Pr(II,IV)
oxide, or Ag(LIII) oxide. Preferred compounds of the inven-
tion comprise at least one metal tetroxide, such as silver
tetroxide. The terms metal tetroxide and metal tetraoxide,
are synonymous as used herein.

In one preferred embodiment, the metal oxide compound
compositions are substantially free of added persulfate or
other added oxidizing agents, since, when applied topically,
such agents may cause adverse effects, such as skin irritation
and skin over-drying. In another preferred embodiment, the
compositions are substantially free of any oxidizing agents.
More particularly, the invention relates to methods for
preventing, treating, and managing cancerous conditions
and conditions associated with cancer.

In one embodiment, the compositions include a molecular
scale device comprising at least one crystal of a metal oxide
compound. A plurality of these metal oxide crystals, such as
on the order of trillions, may be employed in various
pharmaceutical formulations and therapies to effectuate the
prevention, treatment, and/or management of various can-
cers and conditions associated with cancer. The composi-
tions of the invention include powders comprising metal
oxide crystals of the invention.

The compositions and methods of the invention advanta-
geously provide a desired effect such as preventing, treating,
or managing cancer or conditions associated with cancer.
“Management,” as used herein, includes controlling one or
more cancers, or conditions associated with such cancer(s),
that cannot be cured completely, reducing the severity of
affliction of such cancers or related conditions, and the like.
Thus, a preferred embodiment of the invention relates to a
method of inducing cytotoxicity (cell killing) in cancer cells
or reducing the viability of cancer cells. In one embodiment,
the invention relates to the treatment or management of
cancer and/or diseases or conditions associated with cancer,
while in another embodiment the invention relates to the
prevention, of cancer and/or diseases or conditions associ-
ated with cancer.

Preferred metal oxides of the invention comprise a first
metal cation having a first valency state and a second metal
cation having a second valency state, which differs from the
first valency, preferably by at least one charge. The first and
second metal cations are preferably the same metal. Without

”

0

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being bound by theory, it is believed that the metal oxides of
the present invention operate by transferring electrons
between cations of differing valency, the electrons contrib-
uting to the death of the cancer cells by traversing the cell
membrane. By way of non-limiting example, it is believed
that the crystal lattice of a silver tetroxide (Ag,0,) molecu-
lar device operates against cancer, tumors, or cells associ-
ated with cancer by transferring electrons from its two
monovalent silver ions to the two trivalent silver ions in the
crystal, contributing to the death of the cancer cells by
traversing, their cell membrane surface. This in effect “elec-
trocutes” the cancer cells. The electrons are forced out of
their balanced crystals by such labile groups as NH, NH,,
S—S, and SH associated with the cellular surface. Normal
cells are not believed to be affected, because they are not
believed to proliferate fast enough to expose these labile
bonds.

The metal oxides of the invention are preferably stable as
determined by the dissociation constants of the compounds.
For example, the dissociation constant (K,) of Ag,O,, is
7.9x10-'°. Therefore the molecule is not believed to be
disturbed unless more stable complexes are formed with
such ligands as those associated with the cancer cell mem-
brane surface in a dynamic state. Indeed, the end result of the
electron transfer, which is a redox reaction, is believed to
result in the metal ions of a lower valency being oxidized to
a higher valency state and metal ions of a higher valency
state being reduced to a lower valency state.

Returning to the non-limiting example of silver tetroxide,
it is believed that monovalent Ag ions are oxidized to Ag(II)
and the trivalent Ag ions are reduced to the same end
product, Ag(II). Accordingly, the well-known affinity of
monovalent silver for certain elements such as sulfur and
nitrogen is believed to be far exceeded here, for divalent
silver is believed to not merely bind to these elements as
does silver, but to actually form chelate complexes with their
ligands. The molecular crystal attraction for the cell mem-
brane surfaces is thus believed to be driven by powerful
covalent bonding forces.

The electron transfer occurring in the example of silver
tetroxide can be depicted by the following redox half
reactions:

Ag*-c=Ag**
Ag**+e=Ag*?

It was found by rigorous testing that certain silver tetroxide
containing-compositions were comparatively non- toxic in
comparison to monovalent silver salts. Since these silver
tetroxide compositions were effective at certain ppm con-
centrations in killing pathogens in nutrient broth and for
water treatment, commercial concentrates were formulated
with 2% of the tetroxide. Prior to the acceptance of the oxide
in commerce, for which EPA registration No. 3432-64 was
obtained, it was necessary for the oxide to undergo a series
of toxicity tests. A 3% concentrate was used and evaluated
by a certified laboratory employing good laboratory practice
(GLP) according to the Code of Federal Regulations for this
purpose.
The results were as follows:

Acute Oral Toxicity
Acute Dermal Toxicity

LDso Greater than 5,000 mg/Kg
LDso Greater than 2,000 mg/Kg

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-continued

Primary Eye Irritation
Primary Skin Irritation
Skin Sensitization

Mildly irritating
No irritation
Non-Sensitizing

Subsequent evaluations conducted according to the inven-
tion showed that unless persons were prone to silver

allergies, the pure tetroxide compositions according to the 10

invention could be applied to, for example, the skin without
any ill effects or evidence of irritation, despite the fact that
the compositions of the invention can be a powerful oxidiz-
ing agent. This can perhaps be explained by the stability
manifested by the above-noted K, of the silver composi-
tions. Accordingly, in a preferred embodiment, the metal
oxides of the invention are applied directly in a powder or
composition form to afflicted areas, such as the skin, cervix,
or cervical pelvic region of an animal afflicted with cancer.
Preferred routes of administration include topically and
application to mucosa. Application can be made, for
example, digitally or using a suitable applicator.

One embodiment of the present invention relates to com-
positions and methods of using the metal oxide composi-
tions of the invention while minimizing the amount of
additional oxidizer, such as persulfate. It has been found in
accordance with the present invention that the additional
oxide is not required and in some circumstances is undesir-
able when the oxide is applied to, for example, the skin or
cervix, in part due to the undesirable side effect of irritation.
In one embodiment, the compositions are substantially free
of added persulfates, while in a preferred embodiment, the
compositions are completely free of added persulfates. In
one preferred embodiment, the compositions are substan-
tially free of added oxidizer, while in another preferred
embodiment they are completely free of added oxidizer. The
aforementioned compositions may be applied topically or to
mucosa associated with, for example, the skin, cervix,
vagina, or colon.

The metal oxide compound, such as tetrasilver tetroxide,
may be black in color, such that care must be taken when
formulating suitable topical pharmaceutical compositions
according to the invention to inhibit or avoid blackening or
staining of the skin. Without being bound by theory, it is
believed that larger amounts of the silver tetroxide compo-
sition promote increased staining. Thus, in one embodiment,
the pharmaceutical compositions preferably have an insuf-
ficient amount of metal oxide compound to cause visible
skin staining.

Where the metal oxide compositions according to the
invention are applied to the skin, they may be combined with
a carrier at an amount from about 5 ppm to 500,000 ppm,
more preferably from about 50 ppm to 250,000 ppm of the
metal oxide composition, based on the weight of the carrier.
In various embodiments, the compositions are provided in
amounts from about 400 ppm to 100,000 ppm, from about
1,000 ppm to 70,000 ppm, from about 10,000 ppm to 50,000
ppm, or from about 20,000 ppm to 40,000 ppm. In one
preferred embodiment, the compositions are formulated
with about 25,000 ppm to 35,000 ppm of metal oxide. It will
be readily understood by those of ordinary skill in the art that
the administration of 0.005 g of metal oxide to an adult
human being provides about 1 ppm of the metal oxide in the
bloodstream of the human. In another embodiment, the
concentration of the metal oxide crystals dispersed in the
carrier ranges from about 0.1 to 10% by weight, more
preferably from about 0.25 to 5% by weight and most
preferably from about 2 to 4% by weight. The compositions,

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when applied topically, can be applied to the skin about 1 to
3 times per day until the condition is suitably cured or
satisfactorily controlled. In one embodiment, the composi-
tion may generally be topically applied at a dosage level of
from about 1 mg to 1000 mg per cm? of skin surface,
preferably about 10 mg to 500 mg per cm? of skin surface.

A preferred carrier for topical formulations and adminis-
tration includes petroleum jelly, such as white petroleum
jelly. For example, a suitable white petroleum jelly is
available from Penreco of Houston, Tex.

A preferred mode of application of the oxide of the
invention is as an ointment. Suitable formulations include,
but are not limited to, salves and the like. If desired, these
may be sterilized or mixed with auxiliary agents, e.g.,
thixotropes, stabilizers, wetting agents, and the like. Pre-
ferred vehicles include ointment bases, e.g., polyethylene
glycol-1000 (PEG-1000); conventional ophthalmic
vehicles; creams; and gels, as well as petroleum jelly and the
like.

The cancerous conditions and diseases that may be
prevented, treated, or managed with the compositions of the
invention vary and include, but are not limited to, cancers
including any of the various malignant neoplasms, tumors,
or cells, such as, for example, those marked by a prolifera-
tion of anaplastic cells. In particular, the term cancer
includes any cancers that involve specific organs or regions
of the body such as the colon, lung, throat, breast, kidney,
pancreas, bladder, prostate, uterus, brain, liver, skin,
testicles, stomach, adrenal gland, ovaries, thyroid, rectum,
bronchus, trachea, eye, bone, cervix, oral cavity, soft tissue,
pituitary gland, myeloma, rectum, esophagus or liver. The
invention is also suited for the prevention, treatment, or
management of cancerous fibroid tumors and non-cancerous
fibroid tumors. Prevention, treatment, or management of any
of the above conditions, as well as any others described
herein, individually or in any combination, simultaneously
or concurrently, is contemplated according to the invention.

Also included are various cell proliferations such as
leukemia, which is a malignant overproduction of white
blood cells, lymphoma, and metastasized melanoma which
has proliferated from skin via blood and/or the lymphatic
system. Conditions or diseases associated with a predispo-
sition to cancer, such as, for example, neurofibromatosis are
also included. The present invention preferably allows treat-
ment or management of conditions or diseases associated
with a predisposition to cancer even if those conditions or
diseases have not fully progressed to a cancerous or malig-
nant stage.

The present invention is also adapted to treating or
managing atypical proliferations of cells, such as those
characterized by nuclear enlargement and failure of matu-
ration and differentiation. Such proliferations may be short
of malignancy. Atypical proliferations suitable for treatment,
management, or prevention by the present invention include
dysplasia or dysplastic proliferations, such as dysplastic nevi
or neurofibromatosis, which are recognized by alterations in
the appearance of cells (cytology). Dysplastic cells may
have some of the features of malignant cells but the changes
are less pronounced. As the dysplasia progresses, the nuclei
of cells become more hyperchromatic and the nuclear mem-
branes become more irregular; the size of the nucleus
increases and the cytoplasm does not increase
proportionately, so the that the nuclear:cytoplasmic ratio
increases.

Different therapeutically effective amounts and deliver
systems may be applicable for each disorder, as will be
readily known or determined by those of ordinary skill in the
art.

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Tumors or neoplasms include new growths of tissue in
which the multiplication of cells is uncontrolled and pro-
gressive. Some such growths are benign, but others are
termed “malignant,” leading to death of the organism.
Malignant neoplasms or “cancers” are distinguished from
benign growths in that, in addition to exhibiting aggressive
cellular proliferation, they invade surrounding tissues and
metastasize. Moreover, malignant neoplasms are character-
ized in that they show a greater loss of differentiation
(greater “dedifferentiation”), and a greater loss of their
organization relative to one another and their surrounding
tissues. This property is also called “anaplasia.”

Neoplasms preventable, treatable, or manageable by the
present invention include all solid tumors, i.e., carcinomas
and sarcomas. Carcinomas include those malignant neo-
plasms derived from epithelial cells which tend to infiltrate
(invade) the surrounding tissues and give rise to metastases.
Adenocarcinomas are carcinomas derived from glandular
tissue or in which the tumor cells form recognizable glan-
dular structures. Sarcomas broadly include tumors whose
cells are embedded in a fibrillar or homogeneous substance
like embryonic connective tissue.

The invention can also be practiced by administering the
metal oxide compositions in conjunction with one or more
other anti-cancer compatible chemotherapeutic agents, such
as any conventional chemotherapeutic agent. The combina-
tion of the metal oxide with such other agents can potentiate
the chemotherapeutic protocol. Numerous chemotherapeutic
protocols will present themselves in the mind of the
ordinary-skilled practitioner as being capable of use accord-
ing to the methods of the invention. Any compatible che-
motherapeutic agent can be used, including antimetabolites,
hormones and antagonists, radioisotopes, as well as natural
products. For example, the metal oxide can be administered
with taxol and its natural and synthetic derivatives, and the
like, and combinations thereof. As another example, in the
case of mixed tumors, such as adenocarcinomas of the breast
and prostate, in which the tumors can include gonadotropin-
dependent and gonadotropin-independent cells, the metal
oxide can be administered in conjunction with leuprolide or
goserelin (synthetic peptide analogs of LH-RH), or both.
Other antineoplastic protocols include the use of a metal
oxide with another treatment modality, e.g., surgery,
radiation, other chemotherapeutic agent, etc., referred to
herein as “adjunct antineoplastic modalities.” Thus, the
method of the invention can be employed with such con-
ventional regimens with the benefit of reducing side effects
and enhancing efficacy. These other anti-cancer chemothera-
peutic agents and modalities may be administered either
concurrently or sequentially with the metal oxide composi-
tions of the invention.

A preferred metal oxide for use according to the
invention, tetrasilver tetroxide, has been commercially sold
under the poorly named “Ag(II) OXIDE” tradename. It may
also be obtained from Aldrich Chemical Co., Milwaukee,
Wis. The chemical synthesis of silver oxide compounds
according to the invention can be performed according to the
method described on page 148 in M. Antelman, “Anti-
Pathogenic Multivalent Silver Molecular Semiconductors,”
Precious Metals, vol. 16:141-149 (1992) by reacting silver
nitrate with potassium peroxydisulfate according to the
following equation in alkali solutions:

4AgNO,+2K,$,0,+8NaOH=Ag,O,+3Na,S0,+2NaNO3+
2KNO;30 4H0

The magnitude of a prophylactic or therapeutic dose of
metal oxide composition(s), or a derivative thereof, in the
acute or chronic management of diseases and disorders

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described herein will vary with the severity of the condition
to be prevented, treated, or managed and the route of
administration. For example, oral, mucosal (including vagi-
nal and rectal), parenteral (including subcutaneous,
intramuscular, bolus injection, and intravenous, such as by
infusion), sublingual, transdermal, nasal, buccal, and like
may be employed. Dosage forms include tablets, troches,
lozenges, dispersions, suspensions, suppositories, solutions,
capsules, soft elastic gelatin capsules, patches, and the like.
The dose, and perhaps the dose frequency, will also vary
according to the age, body weight, and response of the
individual patient. Suitable dosing regimens can be readily
selected by those of ordinary skill in the art with due
consideration of such factors.

In general, for topical and mucosal application, such as
application to the skin or cervix, the total daily dosage for
the conditions described herein can be from about 1 mg to
500 mg of the metal oxide or derivative thereof, while in
another embodiment, the daily dosage can be from about 2
mg to 200 mg of the metal oxide composition. A unit dosage
can include, for example, 30 mg, 60 mg, 90 mg, 120 mg, or
200 mg of metal oxide composition. Preferably, the active
ingredient is administered in single or divided doses from
one to four times a day.

In another embodiment, the compositions are adminis-
tered by an oral route of administration. The oral dosage
forms may be conveniently presented in unit dosage forms
and prepared by any methods available to those of ordinary
skill in the art of pharmacy.

In managing the patient, the therapy may be initiated at a
lower dose, e.g., from about 1 mg, and increased up to the
recommended daily dose or higher depending on the
patient’s global response. It is further recommended that
children, patients over 65 years, and those with impaired
renal or hepatic function, initially receive low doses when
administered systemically, and that they be titrated based on
individual response(s) and blood level(s). It may be neces-
sary to use dosages outside these ranges in some cases, as
will be apparent to those of ordinary skill in the art.
Furthermore, it is noted that the clinician or treating physi-
cian will know how and when to interrupt, adjust, or
terminate therapy in conjunction with individual patient
response.

Any suitable route of administration may be employed for
providing the patient with an effective dosage of metal
oxide, or a pharmaceutically acceptable derivative thereof.
The most suitable route in any given case will depend on the
nature and severity of the condition being prevented, treated,
or managed. One preferred route is parenterally, preferably
intravenously. In this embodiment, a preferred intravenous
route of administration is by infusion.

In practical use, metal oxide, or a derivative thereof, can
be combined as the active ingredient in intimate admixture
with a pharmaceutical carrier according to conventional
pharmaceutical compounding techniques. The carrier may
take a wide variety of forms and may include a number of
components depending on the form of preparation desired
for administration. The compositions of the present inven-
tion include, but are not limited to, suspensions, solutions
and elixirs; aerosols; or carriers, including, but not limited
to, starches, sugars, microcrystalline cellulose, diluents,
granulating agents, lubricants, binders, disintegrating
agents, and the like.

Another suitable route of administration of the silver
tetroxide compositions of the invention is topically, e.g.,
either directly as a powder or in non-sprayable or sprayable
form. Topical administration is a preferred route of admin-

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istration for treating topical cancerous conditions, such as
skin cancer that has not metastasized or cervical cancer. In
one embodiment, the metal oxide may be applied topically
to the affected skin areas directly in powder form or in
compounded formulations.

Non-sprayable forms can be semi-solid or solid forms
including a carrier indigenous to topical application and
preferably having a dynamic viscosity greater than that of
water. Suitable formulations include, but are not limited to,
suspensions, emulsions, creams, ointments, powders,
liniments, salves and the like. If desired, these may be
sterilized or mixed with any available auxiliary agents,
carriers, or excipients, e.g., thixotropes, stabilizers, wetting
agents, and the like. One or more thixotropic agents can be
included in types and amounts sufficient to increase adhe-
sion of topically applied compositions of the invention to a
surface or mucosa associated with a treatment zone such as,
for example, the skin, vagina, or cervix, so as to inhibit or
prevent runoff or other loss of the composition from the
treatment zone, particularly when the compositions are
formulated for topical administration. With respect to con-
ditions associated with the skin, the compositions preferably
prevent, treat, or manage such conditions or diseases without
visibly staining the skin, i.c., no staining to the naked eye.

Preferred vehicles for non-sprayable topical preparations
include ointment bases, e.g., polyethylene glycol-1000
(PEG-1000); conventional ophthalmic vehicles; creams; and
gels, as well as petroleum jelly and the like. In one preferred
topical embodiment, the carrier includes a petroleum jelly.
In another preferred topical embodiment, the carrier is
formulated as a cream, gel, or lotion. A preferred composi-
tion comprises about 3% metal oxide, such as tetrasilver
tetroxide, about 47% white petrolatum, about 36% heavy
mineral oil, and about 14% TIVAWAX P Tivian Laborato-
ries Inc., Providence, R.I. These topical preparations may
also contain emollients, perfumes and/or pigments to
enhance their acceptability for various uses.

In a preferred embodiment, a metal oxide, or a derivative
thereof, is formulated for parenteral administration by injec-
tion (subcutaneous, bolus injection, intramuscular, or
intravenous, such as by infusion), and may be dispensed in
a unit dosage form, such as a multidose container or an
ampule. Parenteral administration is a preferred administra-
tion route when the cancer is systemic, i.e., has a locus inside
the body. Preferably, the formulation adapted for parenteral
administration includes an insufficient amount of persulfate
to induce irritation or adverse side effects. In one preferred
embodiment, the formulation is substantially free of added
persulfate, while in another more preferred embodiment, the
formulation is completely free of added persulfate.

When administered intravenously, such as by infusion, the
dosage preferably provides a concentration of the metal
oxide in the blood stream of about 1 ppm to about 75 ppm,
more preferably from about 5 ppm to about 50 ppm, such as
from about 10 ppm to about 40 ppm or about 50 to 200 mg.
In a preferred embodiment, a one-time dosage is infused or
injected directly into the bloodstream.

The intravenous dosage is preferably delivered over a
period of time sufficient to substantially inhibit or even avoid
the occurrence of side effects. For example, the dosage can
be delivered by intravenously or by infusion over a time
from about 10 minutes to about 300 minutes, preferably
from about 20 minutes to about 240 minutes.

Compositions of the metal oxide, or a pharmaceutically
acceptable derivative thereof, for parenteral administration
may be in the form of suspensions, solutions, emulsions, or
the like, in aqueous or oily vehicles, and in addition to the

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active ingredient may contain one or more formulary agents,
such as dispersing agents, suspending agents, stabilizing
agents, preservatives, and the like.

Pharmaceutical compositions of the present invention
may be orally administered in discrete pharmaceutical unit
dosage forms, such as capsules, cachets, soft elastic gelatin
capsules, tablets, or aerosols sprays, each containing a
predetermined amount of the active ingredient, as a powder
or granules, or as a solution or a suspension in an aqueous
liquid, a non-aqueous liquid, an oil-in-water emulsion, or a
water-in-oil liquid emulsion. Such compositions may be
prepared by any of the methods of pharmacy, but all
methods include the step of bringing into association the
active ingredient with the pharmaceutically acceptable car-
rier which constitutes one or more necessary ingredients. In
general, the compositions are prepared by uniformly and
intimately admixing the active ingredient with liquid carriers
or finely divided solid carriers or both, and then, if
necessary, shaping the product into the desired presentation.
Suitable types of oral administration include oral solid
preparations, such as capsules or tablets, or oral liquid
preparations. If desired, tablets may be coated by standard
aqueous or non-aqueous techniques.

For example, a tablet may be prepared by compression or
molding, optionally, with one or more accessory ingredients.
Compressed tablets may be prepared by compressing in a
suitable machine the active ingredient in a free-flowing form
such as powder or granules, optionally mixed with a binder,
lubricant, inert diluent, granulating agent, surface active
agent, dispersing agent, or the like. Molded tablets may be
made by molding, in a suitable machine, a mixture of the
powdered compound moistened with an inert liquid diluent.
In one embodiment, each tablet, capsule, cachet, or gel cap
contains from about 0.5 mg to about 500 mg of the active
ingredient, while in another embodiment, each tablet con-
tains from about 1 mg to about 250 mg of the active
ingredient. The amount of active ingredient found in the
composition, however, may vary depending on the amount
of active ingredient to be administered to the patient.

Another suitable route of administration is transdermal
delivery, for example, via an abdominal skin patch

The metal oxide, or a suitable derivative thereof, may be
formulated as a pharmaceutical composition in a soft elastic
gelatin capsule unit dosage form by using conventional
methods well known in the art, such as in Ebert, Pharm.
Tech, 1(5):44-50 (1977). Soft elastic gelatin capsules have
a soft, globular gelatin shell somewhat thicker than that of
hard gelatin capsules, wherein a gelatin is plasticized by the
addition of plasticizing agent, e.g., glycerin, sorbitol, or a
similar polyol. The hardness of the capsule shell may be
changed by varying the type of gelatin used and the amounts
of plasticizer and water. The soft gelatin shells may contain
a preservative, such as methyl- and propylparabens and
sorbic acid, to prevent the growth of fungi. The active
ingredient may be dissolved or suspended in a liquid vehicle
or carrier, such as vegetable or mineral oils, triglycerides,
surfactants such as polysorbates, or a combination thereof.

In the case of tumors having loci inside the body, e.g.,
brain tumors, prostate tumors, and the like, the metal oxide
can be delivered via a controlled release delivery vehicle. In
a preferred embodiment, the controlled release vehicle
includes a polymeric material, delivered or surgically
implanted at or near the lesion site. One of ordinary skill in
the art will be familiar with controlled release means and
delivery devices, such as those described in U.S. Pat. Nos.:
3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719;
5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543;

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5,639,476; 5,354,556; and 5,733,566, the disclosures of
which are hereby incorporated herein by express reference
thereto. These pharmaceutical compositions can be used to
provide slow or controlled-release of the active ingredient
therein using, for example, hydropropylmethyl cellulose in
varying proportions to provide the desired release profile,
other polymer matrices, gels, permeable membranes,
osmotic systems, multilayer coatings, microparticles,
liposomes, microspheres, or the like, or a combination
thereof. Suitable controlled-release formulations available
to those of ordinary skill in the art, including those described
herein, may be readily selected for use with the metal oxide
compositions of the invention. Thus, single unit dosage
forms suitable for topical, parenteral, or oral administration,
such as infusions, intravenous drips, gels, lotions, cremes,
tablets, capsules, gelcaps, caplets, and the like, that are
adapted for controlled-release are encompassed by the
present invention.

All controlled-release pharmaceutical products have a
common goal of improving drug therapy over that achieved
by their non-controlled counterparts. Ideally, the use of an
optimally designed controlled-release preparation in medi-
cal treatment is characterized by a minimum of drug sub-
stance being employed to cure or control the condition in a
minimum amount of time. Advantages of controlled-release
formulations may include: 1) extended activity of the drug;
2) reduced dosage frequency; and 3) increased patient
compliance.

Most controlled-release formulations are designed to ini-
tially release an amount of drug that promptly produces the
desired therapeutic effect, and gradual and continual release
of other amounts of drug to maintain this level of therapeutic
effect over an extended period of time. In order to maintain
this constant level of drug in the body, the drug should be
released from the dosage form at a rate that will replace the
amount of drug being metabolized and excreted from the
body.

The controlled-release of the active ingredient may be
stimulated by various inducers, for example pH,
temperature, enzymes, water, or other physiological condi-
tions or compounds. The pharmaceutical compositions for
use in the present invention include the metal oxide, or a
derivative thereof, as the active ingredient, and may also
contain a pharmaceutically acceptable carrier, and
optionally, other therapeutic ingredients. Suitable deriva-
tives include any available “pharmaceutically acceptable
salts,” which refer to a salt prepared from pharmaceutically
acceptable non-toxic acids including inorganic acids,
organic acids, solvates, hydrates, or clathrates thereof.
Preferably, in the case of silver (I,III), the salts do not
comprise halides. Examples of such inorganic acids are
hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, and
phosphoric. Appropriate organic acids may be selected, for
example, from aliphatic, aromatic, carboxylic and sulfonic
classes of organic acids, examples of which are formic,
acetic, propionic, succinic, citric, fumaric, gluconic,
isethionic, lactic, malic, mucic, tartaric, para-
toluenesulfonic, glycolic, glucuronic, maleic, furoic,
glutamic, salicylic, mandelic, methanesulfonic,
ethanesulfonic, benzenesulfonic (besylate), sulfanilic,
alginic, galacturonic, and the like. Particularly preferred
acids phosphoric, methanesulfonic, and glycolic.

EXAMPLES

These and other aspects of the present invention may be
more fully understood with reference to the following non-
limiting examples, which are merely illustrative of the

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preferred embodiment of the present invention, and are not
to be construed as limiting the invention, the scope of which
is defined by the appended claims.

Example 1

Treatment of Breast Cancer According to the
Invention

A subject group was formed of thirty female residents of
Central America aged 32 to 52 years who had been diag-
nosed as having breast cancer. The subjects had the follow-
ing general characteristics: 38% were older than 45 years
old; 47% had never borne children; 60% were around
menopause;18% had their first period before age 13 years;
60% of had used oral contraceptives; 38% of the subjects
had cancers associated with the left breast; and 40% of the
subjects had a family history of breast cancer. The diagnosis
of each subject was confirmed by biopsy and a mammogram
was acquired from each subject.

Each subject was evaluated daily by an oncologist(s) and
each received a single dosage of tetrasilver tetroxide by IV,
i.e., intravenously, sufficient to provide a concentration in
the bloodstream of 10 ppm. One-half of the patients received
the dosage in 10 minutes by IV injection. The other half of
the subjects received the dosage by IV injection over a
4-hour period.

As discussed below, the subjects were arranged in three
histology groups. Within each histologic group, 50% of the
subjects received the dosage via the 10 minute IV and the
other 50% of the subjects received the dosage over the 4
hour period of time.

Prior to initiating treatment, the tetrasilver tetroxide was
subjected a quality assurance protocol to reduce side effects.

Group I: Group I included 10 patients who had been
diagnosed as having infiltrative canalicular breast carci-
noma.

A1cm diameter biopsy fragment was sent to a pathologist
laboratory. The pathologist reported an increase of the dense
fibrous tissue, anaphasic cells in the gland ducts, forming
lines, tubes, ducts, glands and cell anastomosis. The histo-
logic report confirmed the diagnosis of the 10 patients in this
group: infiltrative canalicular breast carcinoma.

Group II: Group II included 10 subjects were diagnosed
as having ductile carcinoma special type, medular breast
cancer.

Group III: Group III included ten patients diagnosed as
having infiltrative lobular breast cancer.

For each of the three groups, the dosage was 10 ppm for
every subject. The patients had 24-hour evaluations by three
oncologists who were each responsible for an 8-hour time
period. Every 4 hours, a professional nurse acquired vital
signs from the subjects. Twenty-four hour hemodynamic
monitoring was performed. The subjects walked 2 hours
after they received the dosage and they were prescribed a
free diet. Every twenty-four hours, urine was collected.
Every seven days, the following laboratory tests were per-
formed: a complete blood count, hemoglobin,
hematocracity, vem, vhem, complete red blood cells, com-
plete white blood cells, albumin, bilirubin, calcium, and
cholesterol, creatine, glucose, Idh, potassium, sodium,
triglyceride, uric acid, urea nitrogen, AST and SGOT.
Results of IV Tetrasilver Tetroxide Injection

Group I: Forty-eight hours after treatment, the texture of
the nodules had changed from hard as a stone to a mild, soft
nodule, the redness was almost gone, and the retraction of

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the nipple was the same. At 12 days after treatment, the
redness was gone, the nodule was no longer discernable by
touch, and the nipple retraction had disappeared. Three of
the patients who had received 10 minute IV injection exhib-
ited an increase in body temperature and a slight liver
enlargement. Liver function was not affected, however, as
demonstrated by normal liver function tests, a normal red
blood cell count, and a normal white blood cell count. An
electrocardiogram did not reveal abnormalities. Sodium,
potassium, and magnesium blood levels decreased.
Albumin, bilirubin calcium, cholesterol, creatinine, LDH,
AST, SGOT, and triglyceride remained normal.

At 19 days after the treatment, the oncologist ordered a
new biopsy of this group. The pathologist reported 100% of
the biopsies as intralobular ducts normal in number and size.
No change in shapes. Cylindric cells in the mammary ducts
were normal in shape and in size. Basal membranes were
intact. Diagnosis: normal mammary tissue.

After 21 days of treatment, the patients were again
evaluated and all of them had tissue retractions in the area
where the nodule was located. The subjects had no more
symptoms. The patients were allowed to return home after
25 days and given a return appointment in 30 days. The final
biopsy revealed no difference between the group that
received direct injection and the group that received IV
solution. A little quicker response in the I'V solution patients
was observed in comparison with the direct injection group.

Group II: At 36 hours after treatment, the formerly 10 cm
on average tumors had decreased to an average of 8.4 cm
and the lymph nodes were smaller and the texture was
changed. At day number 16 after treatment, the huge tumor
mass was gone, the nodule was no longer palpable, and the
lymph enlargement had disappeared. One patient of the
sub-group that received direct IV injection exhibited an
increase in body temperature and a slight liver enlargement.
Liver function was not affected, however, as demonstrated
by normal liver function tests, a normal red blood cell count,
and a normal white blood cell count. An electrocardiogram
did not reveal abnormalities. Sodium, potassium, and mag-
nesium blood levels decreased. Albumin, bilirubin calcium,
cholesterol, creatinine, LDH, AST, SGOT, and triglyceride
remained normal.

At day number 23 after the treatment, the oncologist
ordered a new biopsy of Group II. The biopsy was acquired
after 24 days of treatment. The oncologist reported that there
were no more hemorrhaging and necrosis zones in the breast
tissue. The pathologist reported 90% of the biopsy as
intralobular ducts normal in number and size. No change in
shape and normal mitosis was observed. Cilindric cells in
the mammary ducts were normal in shapes and in sizes and
basal membranes were intact. Diagnosis: normal mammary
tissue.

‘Two days later, the patients were evaluated and all of them
had tissue retractions in the area where the nodule was
located. No more symptoms were exhibited. Six days later,
the doctor allowed them to return home with a follow-up
appointment scheduled for 30 days. The final biopsy result
did not present a difference between the group that received
direct injection and the group that received IV solution. A
slightly quicker response was observed in the IV solution
patients in comparison with the direct injection group.

Group III: At 5 days after treatment, the nipple retraction,
bleeding from the nipple, the distorted areola, and the
attachment of the mass to surrounding tissues were almost
gone. The average nodule size decreased from 4 cm to 2.6
cm. At day number 20 after treatment, the retracted nipples,
the bleeding from the nipple, the distorted areola and the

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attachment of the mass to surrounding tissues was in 90%
remission. The average size of the nodules had decreased
further from 2.6 cm to 1 cm.

None of the patients of this group that had received direct
injection exhibited an increase in the body temperature or
even slight liver enlargement. The red blood cells count was
normal, and the white blood cells remained normal. The
electrocardiogram did not reveal abnormalities. Sodium,
potassium, and magnesium blood levels deceased. Albumin,
bilirubin calcium, cholesterol, creatinine, LDH, AST, SGOT
and triglyceride remained normal.

At day number 29 after the treatment, the oncologist
ordered a new biopsy of this group. The pathologist reported
80% of the biopsies as intralobular ducts normal in number
and size. No change in shape. Cilindric cells in the mam-
mary ducts normal in shape and in size and the basal
membranes were intact. Diagnosis: normal mammary tissue

Seven days later, the patients were evaluated and all of
them had tissue retractions in the area where the nodule was
located and did not exhibit any more symptoms. One day
later, the patients were allowed to return home and given a
follow up appointment in 30 days. The final biopsy result did
not indicate a difference between the group that received
direct injection and the group that received IV solution. A
slightly quicker response was observed, however, for the IV
solution patients in comparison with the direct injection
group.

Conclusions of IV Tetrasilver Tetroxide Study

1. Tetrasilver tetroxide is preferably delivered in an IV
solution to inhibit undesirable side effects.

2. Tetrasilver tetroxide administered by IV appears to stop
the growth of the breast cancer.

3. Tetrasilver tetroxide appears to stimulate the normal
breast cells and allows them to replace the anaphasic cells in
the breast carcinoma.

4. Tetrasilver tetroxide appears to cure infiltrative breast
carcinoma in a 24 day period.

5. Tetrasilver tetroxide appears to cure ductile carcinoma
special type, medular breast carcinoma in a 30 day period.

6. Tetrasilver tetroxide appears to cure infiltrative lobular
breast cancer in a 30 days period.

7. Although certain patients developed mild cases of
hepatomegaly, the liver functioning was not impaired as
evidenced by the normal levels of liver function enzymes in
the blood stream.

Example 2
Treatment of Paget’s Disease of the Nipple

A study was performed to determine the affect of the
tetrasilver tetroxide compositions of the invention on
patients suffering from Paget’s disease of the nipple. The
compositions were applied in ointment form in this study.
Paget’s disease of the nipple is a rare type of carcinoma that
appears as a unilateral dermatitis of the nipple and represents
extension to the epidermis of an underlying mammary duct
carcinoma. The redness, oozing, and crusting closely
resemble dermatitis, but the physician should suspect car-
cinoma because the lesion is unilateral.

This study were performed in 25 patients, between 42 to
59 years old. Each patient suffered from Paget’s of the
nipple, a diagnosis confirmed by biopsy. As discussed below,
each patient was placed in one of two groups.

Group 1: Group I included 13 patients with Paget’s
disease of the nipple, with an average depth of invasion of
0.76 to 1.5 mm. All of the laboratory results indicated the
same diagnosis and were taken weekly for 4 weeks. Each

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patient in this group exhibited metastasis. The lesions were
all ulcered and sized on average from 2.3 cm to 3.4 cm. The
treatment protocol began with 200 mg of ointment contain-
ing 3% tetrasilver tetroxide 3 times per day as applied by a
physician. All of the patients were evaluated daily for 4
weeks. None of the patients received anterior treatment.

Group II: Group II included 12 patients suffering from
Paget’s disease of the nipple, with an average depth of
invasion of 2.26 cm to 3.0 em. All the laboratory results for
4 weeks confirmed the diagnosis. The lesions were all
ulcered and sized from an average of 4.3 cm to 5.2 cm. The
treatment protocol began with 200 mg of ointment contain-
ing 3% tetrasilver tetroxide 3 times per day as applied by a
physician. All of the patients were evaluated daily for 4
weeks. None of the patients had anterior treatment.
Results of Paget’s Disease Treatment

Group I: Over a period of 15 days, the lesions from
Paget’s disease began to regress and dry out in all the
patients. Pain was gone and the patients began to regain an
appetite. The color of the lesions changed from a red more
to white. At day 27 of the study, all of the lesions were
healed and the lesions were not visible at all. No recurrences
of lesions were observed. The last biopsy showed minimum
amount of atypical cells, and the mammary ducts were
normal.

Group II: Over a period of 23 days the lesions began to
regress and became dryer. By the 29” day of the study, it was
almost impossible to distinguish the lesions. All the patients
began to eat normally again and the last biopsy revealed
18% of atypical cells. No recurrences of lesions were found.
None of the patients had exhibited side effects.
Conclusions of Paget’s Disease Study

The final biopsies, however, revealed 18% atypical cells,
suggesting that additional time is required for the tetrasilver
tetroxide to completely eliminate the presence of atypical
cells.

Example 3

Treatment of Rhabdomyosarcoma with Tetrasilver
TetroxideOintment 3%

A study group was formed of twelve patients aged
between 45 and 65 years. Each patient had been diagnosed
with ulcerative Rhabdomyosarcoma. A pathologist con-
firmed the diagnosis of each patient based upon a biopsy. All
the patients were Caucasian and had similar exposures to
sunlight during their lifetimes. All patients had infections
demonstrating the presence of pathogens received during
chemotherapy and surgical resection treatment. None of the
patients exhibited signs of metastasis. As discussed below,
the patients were divided into two groups.

Group I: Group I was formed of seven patients with
confirmed biopsy diagnosis of ulcerative Rhabdomyosar-
coma with extreme infection. Each patient exhibited ulcer-
ative injuries at the inferior member with an extension of 9
em to 12 cm in diameter. The ulcers exhibited serosan-
guinous secretions in abundance. The evaluation period
began from 4 to 7 months prior to initiating treatment with
3% tetrasilver tetroxide. Each patient started treatment with
200 mg of ointment 3%, three times a day for 30 days.

Group Il: Group II was formed of five patients with
confirmed biopsy diagnosis of ulcerative Rhabdomyosar-
coma with extreme infection. Each case presented extensive
ulcerative injuries with indurated edges larger than 12 cm in
diameter. The period of evaluation was more than 7 months
and all the patients received chemotherapy and surgical

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resection. Each patient was treated with ointment of 3% of
tetrasilver tetroxide of the invention three times a day for
thirty days.

Results

Group I: All patients experienced a commencement of
healing of the ulcers by day 27 from the start of the
treatment. The regions of irritation receded and the color of
the lesions became darker and more similar to normal skin
color. By day 30, the ulcers were dry and began the scarring
process. A biopsy control preformed at the 30” day revealed
normal muscular tissue with no signs of metaplasia. At the
40” day of treatment, a biopsy control was preformed and
indicated that the injured metaplastic cells had been replaced
by cells of normal appearance. By the 45” day, the ulcers
were no longer visible. The post-treatment evaluations
showed no signs of recidivism.

Group II: All patients showed a commencement of the
healing of the ulcers by day 28 from the start of the
treatment. By day 40, the ulcers had almost disappeared and
a biopsy confirmed that 80% of the diseased tissue had been
replaced with healthy tissue. From a clinical standpoint, the
ulcers were no longer visible.

The tests demonstrated that the topical application of
tetrasilver tetroxide was effective in curing infections and
healing skin ulcers associated with Rhabdomyosarcoma, and
without significant adverse effects.

Example 4

Topical Treatment with Tetrasilver Tetroxide on
Neurofibromatosis

This study was performed to determine the effect of
topical treatment with tetrasilver tetroxide on neurofibroma-
tosis. A study group was formed of twelve patients aged 5
months to 3 years who had been diagnosed as having
neurofibromatosis. These diagnoses were reconfirmed in
conjunction with this study. Diagnoses were made by clini-
cal study and by biopsy of the lesions. None of the patients
had received prior treatment. None of the patients exhibited
skeletal anomalies or lesions of the optic nerve or acoustic
nerve. The patients were arranged in 2 groups as discussed
below.

Group I: Group I included eight patients having von
Recklinghausen’s disease and neurofibromatosis type plexi-
form neuromas. All of them were symptomatic. The brown
spots of the skin were located in the trunk. Each patient
applied 200 mg of ointment with 3% tetrasilver tetroxide, 3
times per day for 30 days. Daily evaluations were made to
observe progress and to determine the presence of side
effects.

Group II: Group II included four patients who had been
diagnosed as having von Recklinohausen’s disease and
neurofibromatosis type neurofibroma. Each diagnosis was
confirmed by biopsy. All of the patients were symptomatic.
The lesions were located in the trunk, pelvis, and elbows. All
of the patients of this group applied 200 mg of ointment with
3% of tetrasilver tetroxide 2 times per day for 30 days. Daily
evaluations were made to observe progress and determine
the presence of side effects.

Results of Neurofibromatosis Study

Group I: By day 20, five of the eight patients were cured
of the spot-type skin lesions. No more symptoms were
found. The biopsy result showed normal cells and no reoc-
currences were observed. The biopsy results of the other 3
patients showed some atypical cells and the spots, although
reduced in color, were still visible.

Group II: At the end of the study, these patients were still
symptomatic and the biopsies confirmed the presence of
atypical Schwann tumor cells.

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Conclusions of Neurofibromatosis Study

Tetrasilver tetroxide ointment seems to have had a posi-
tive effect in neurofibromatosis of the plexiform neuromas
type. Higher dosages produced a better effect for treatment
and management of plexiform neurofibromas.

Tetrasilver tetroxide ointment did not generally seem to
produce as thorough a curative result for neurofibroma.

Example 5

Topical Treatment with Tetrasilver Tetroxide on
Cervical Carcinoma

In the following examples, the cervical cancer afflictions
are divided into two main categories. The first is based on
cervical smear (PAP smear) test results following the
Bethesda System for reporting cervical cytologic diagnoses
bearing designations CIN— the acronym for cervical
intraepithelial neoplasia. The second is based on designated
NIC stages of which:

O=carcinoma in situ, intraepithelial carcinoma;

1=carcinoma strictly confined to the cervix; and

1A indicates microinvasive carcinoma.

Exetec Lab S.A. located in Honduras, Central America,
which performs clinical tests for major pharmaceutical com-
panies did the clinical evaluations of tetrasilver tetroxide on
the patients having various cervical cancers. All the clinical
testing involved applying 300 mg of an ointment comprising,
3% tetrasilver tetroxide dispersed in a hydrocarbon base
comprising mostly white petrolatum and mineral oil once a
day to the affected cervical/pelvic area.

Five patients classified with CIN 1 cervical cancer,
according to cytologic diagnoses were selected. The diag-
noses were conducted two months prior to the tetrasilver
tetroxide clinical trials. The ointment was applied directly to
the cervix and its entrance (endocervix and exocervix) by a
skilled physician. The period of administration was tend
days per patient. Evaluations were made for any side effects.
A biopsy was taken at the end of the treatment. The biopsies
indicated that all of the patients were cured without any
recurrences.

Five patients who were confirmed as CIN 2, ie., having
high grade squamous intraepithelial lesions including mod-
erate dysplasia 3 months prior to the clinical studies. Two of
the patients had familial history of the cervical cancers. This
group was treated as outlined by the protocol shown above
for 10 days. All patients were cured. The cytologist reported
no more atypical cells present and the cytopathologist
reported normal cells with no recurrences.

Five patients were confirmed as CIN 3, ie., having high
grade squamous intraepithelial lesions, severe dysplasia and
carcinoma in situ one month prior to clinical studies. The
ointment was administered to the patients in conformity with
the protocol of Example 1 for 10 days. All patients were
cured as confirmed by both cytologist and cytopathologist.

Five patients were confirmed as Stage 0 cervical cancer.
Three of the patients selected had a familial history of
cervical cancer. One patient had a non-bleeding cervical
ulcer 1.2x1.5 centimeters. The diagnoses were made 15 days
prior to clinical evaluations. The ointment was administered
to the patients in conformity with the protocol of Example
1 for 10 days. All patients were cured, including the one with
the ulcer, said ulcer healing in 5 days. This was confirmed.
by both cytologist and cytopathologist with no recurrences.

Five patients were selected who suffered from Stage 1
cervical cancer. Three of the patients had bleeding ulcers.
Four had a familial history of cervical cancers. Diagnoses

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were made 12 days prior to the commencement of clinical
trials. The ointment was administered in accordance with the
protocol of Example 1 for 15 days. Four out of the five
patients were cured. The fifth did not respond. As for the
patients with the bleeding ulcers, the ulcers stopped bleeding
on the fourth day of the treatment. There were no recur-
rences in those who were cured.

Five patients with Stage 1A cervical cancer were selected
for therapy. Four of the five had bleeding ulcers. Diagnoses
were made 3 weeks prior to clinical evaluations. Treatment
entailed the protocol of Example 1 over a 20 day period.
Three of the patents were completely cured. Those with
bleeding ulcers, including the one who was not cured, had all
bleeding arrested on the sixth day of therapy. There were no
side effects in this group as with all the other groups cited in
the previous examples.

All of the 30 patients in these examples were in the age
range of 40-60 years old.

Example 6

Treatment of Malignant Melanoma with Tetrasilver
Tetroxide

Astudy group was formed of thirty-one patients between
the ages of 48 and 78 years who had been diagnosed with
malignant melanomas. The diagnoses were confirmed by
biopsy before the study was conducted. The study group
included four subgroups as discussed below.

Group I: Group I included fourteen female patients
between the ages of 52 to 70 years. Biopsies confirmed
superficial spreading melanomas with a depth of invasion
ranging from minor to 0.76 mm. The melanomas were
located in the interior extremities of the females. Each of the
patients began treatment with 200 mg of the 3% tetrasilver
tetroxide composition in lotion form applied twice a day.
The fourteen patients indicated that they had not previously
been treated for the melanoma.

Group II: Group II included eight patients ranging
between the ages of 65 to 78 years. A biopsy confirmed the
presence of lentigo maligna melanoma. Seven of the eight
patients had a depth invasion of 0.76 mm and one of them
exhibited a 1.5mm depth of invasion. Each patient was
Caucasian and indicated that they had not previously
received treatment. Additional laboratory tests demonstrated
no pain or secondary effects in the patients. Each of the
patients began treatment with 200 mg of the lotion at 3%
tetrasilver tetroxide applied three times a day.

Group III: Group III included five patients ranging from
ages 60 to 70 years old who had been diagnosed with
nodular melanoma. The patients had not previously received
treatment. Three of the patients having a depth invasion
ranging from minor to 0.76 mm were placed in a subgroup
TILA. Two patients exhibited a depth of invasion ranging
0.51 mm to 2.25 mm and were designated group IIB. Group
IIIB included patients ranging in age from 64 to 68 years old.
Two of these patients exhibited discomfort associated with
the lungs. Group III initiated treatment with 200 mg of the
lotion at 3% tetrasilver tetroxide applied three times per day
for 30 days.

Group IV: Group IV included four patients between the
ages of 45 to 54 years old who had been diagnosed with
acrolentiginous melanoma. Two of the patients had received
prior treatment with no success. The depth invasion ranged
between 1.51 to 2.25 mm. These two patients were desig-
nated Group IVA. The remaining patients, Group IVB,
exhibited a depth of invasion ranging from minor to 0.76

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mm. No discomfort was reported by Group IV patients.
Group IV began treatment with 200 mg of the lotion at 3%
tetrasilver tetroxide applied three times per day for thirty
days.

Results of the Melanoma Study

Each patient from Group I exhibited improvement by the
sixth day of treatment. The dark blue spots were losing color.
By the eighth day of treatment, the border on the injuries
indicated improvement. By the fourteenth day of treatment,
none of the injuries exhibited inflammation. On the fifteenth
day of treatment, a biopsy was conducted, which indicated
that the malignant melanomas had been replaced by normal
epidermis while the dermis showed a decrease in the malig-
nant melanomas compared to the first biopsy. By day 22, the
blue spots had disappeared completely and the borders of the
spots were not visible at all. A new biopsy was conducted at
the thirtieth day of treatment, which showed the absence of
the malignant melanomas from both the dermis and epider-
mis.

The eight patients of Group II exhibited improvement by
the eighth day of treatment. The melanomas of the dermis
had changed from black and/or dark brown to a lighter color.
By the fourth day, the injuries had disappeared. At the fifth
day, a new biopsy was conducted. The biopsy indicated that
the ratio of malignant melanomas to normal melanocytes,
ie., benign melanomas, had decreased in relation to the
pre-study biopsy. The patients observed that the injuries had
disappeared and healed. A biopsy conducted at the twentieth
day of treatment indicated normal melanocytes. The patients
have been monitored without any changes from the above
described results.

The patients of Group IIIA observed that their injuries had
begun to heal between the 9th and 10th day of the treatment.
By the fourteenth day of treatment, the grey colored spots
were no longer visible. At the sixteenth day of treatment, a
new biopsy was obtained showing just a few malignant
melanomas and the appearing of normal melanocytes. By
the twenty-sixth day, the injuries were hardly visible,
appearing only as small scars. A biopsy obtained at the
thirtieth day indicated the presence of only normal melano-
cytes,

The patients of group IIIB exhibited few changes by the
twenty-second day of treatment. A biopsy obtained at the
twenty-fifth day of treatment indicated the presence of
malignant melanomas. No significant changes were reported
at the thirtieth day. A biopsy obtained at the this time
indicated the presence of malignant melanomas and mini-
mum inflamation characteristics.

The patients of group IVA exhibited no change by the
thirtieth day of the treatment. A biopsy obtained at the this
time indicated the presence of malignant melanomas. The
patients of group IVB, however, exhibited changes to the
border and color of the injuries by the second day of
treatment. By the sixth day of treatment, the injuries were
not visible and a biopsy acquired at the fifteenth day
indicated normal melanocytes.

Conclusions of the Melanoma Study

The present compositions, in ointment form, healed
superficial spreading melanomas within 8 to 14 days of
treatment when the depth of invasion was less than 0.76 mm.
The biopsies indicated that the cancer was eliminated. The
compositions healed the lentigo-maligna having an invasion
depth between 0.76 mm to 1.5 mm. No discomfort or side
effects reported. The compositions also eliminated nodular
melanoma with a depth invasion of 0.76 mm or less within
a sixteen day treatment period. The compositions did not
eliminate the nodular melanoma having a metastasis condi-

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tion with a depth of invasion of 1.51 mm to 2.25 mm within
thirty days in this study.

The compositions of the invention were highly effective at
treating the acrolentiginous melanoma condition with a
depth invasion ranging from minor to 0.76 mm (without
metastasis). The compositions eliminated the cancer in
100% of these cases. The present compositions were an
effective treatment for the melanomas where chemotherapy
and surgical resources were ineffective. The compositions
did not, however, have a noticeable effect upon acrolentigi-
nous melanoma with a depth of invasion ranging from 1.5
mm to 2.25 mm within a period of 30 days of treatment.

Example 7

Preparation of a 3% Tetrasilver Tetroxide Ointment

A paraffinic hydrocarbon ointment was prepared by heat-
ing with agitation a mixture comprising about 33 wt %
heavy mineral oil and about 67 wt % of petroleum jelly to
a temperature of 70° C. and then dispersing in this mixture
the finely divided tetrasilver tetroxide powder sufficient to
provide a 3% by weight concentration of the oxide in the
carrier. The mixture was then cooled to room temperature
with continuous stirring until the mixture was no longer
liquefied. It should be understood that the methods of this
example can be used in preparing the ointments and lotions
of Examples 1-6, as well as other compositions according to
the invention, as will be readily understood by those of
ordinary skill in the art.

Example 8
Treatment of Melanoma

Amale age 47 was diagnosed as having melanoma at least
for three years. He exhibited at least 15 blotchy brown
lesions scattered on both forearms. The size of the affected
areas varied from 0.3 mm to 1.2 mm. The ointment of
Example 7 was applied to the affected skin areas of the arms.
at least once a day. After one week, the brown blotches had
been modified or replaced by pink ones. After 2 weeks, the
pink areas were gone. After 3 and 4 weeks, there was no
evidence of any melanoma.

Example 9
Treatment of Basal Cell Carcinoma

Two patients, one a male age 83 and the other a female
age 63, were treated in the same manner as in Example 8 for
basal cell carcinoma. The female had one large brown cancer
growth varying from 0.6-1.4 mm by 0.9-3.6 mm on top of
the scalp. The male had several white head pimples 0.3-0.7
mm. One was on the right ear. Five were on the scalp and
another was on the left leg. After one week the female
observed that her tumor had diminished to just a minor pink
skin irritation. After two weeks, the pink irritation had
vanished. After four weeks had elapsed, the skin was clear
and normal in appearance. As for the male, after one week
all white head pimples had regressed to a pink inflammation
except for the ear, which appeared to be completely healed.
After the second week, all pink areas were gone, as well as
any indications of inflammation. After the third and fourth
weeks, all previously afflicted areas showed no evidence of
basal cell carcinoma.

Example 10

Treatment of Squamous Cell Carcinoma

A male patient, age 74, was afflicted with squamous cell
carcinoma. The sores were on both arms, with five on the

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right and seven on the left. Their appearance was oval
shaped ranging from 2.5-5.5 mm in length. This patient was
treated in the same manner as in Example 8 by applying the
ointment of Example 7 to the affected skin areas. After one
week of treatment, all open sores had closed and were in the
process of healing. During the second week, sores continued
to heal at a rapid pace. Scabs were completely gone by the
end of the second week. At the end of the third week, only
slight pink areas remained in the place of the previous sores.
By the end of the fourth week, there were no traces of the
previous affliction.

Example 11

Treatment of Basal Cell Carcinoma with Tetrasilver
Tetroxide Ointment 3%

This study included twenty patients ranging in age from
45 to 65 years old, all of whom had been diagnosed with
basal cell carcinoma. The diagnoses were confirmed by a
pathologist via biopsy. All the patients were Caucasian and
commonly experienced a similar exposure level to sunlight
during their lives.

Group I: Group I included ten patients exhibiting injuries
of less then 1 cm in size with nodules that were bright and
ulcerated. At the time of diagnosis, no form of treatment had
been implemented. The patients had been evaluated for one
month prior to treatment with tetrasilver tetroxide compo-
sition of the invention formulated as an ointment of 3%
tetrasilver tetroxide. Each of the affected areas was located
in a region of the body exposed to sunlight. Each patient
began treatment with 200 mg tetrasilver tetroxide ointment
3%, three times a day for thirty days.

Group II: Group II was formed by 10 patients having
injuries larger than 1 cm. The injuries were clinically present
as nodules that were ulcerated and with indurated edges. In
each case, the period of evaluation exceeded one month.
Each patient began treatment with 200 mg tetrasilver tetrox-
ide ointment 3%, three times a day for 30 days.

Results

Group I: Each patient within this group displayed a
healing process of the ulcerated nodules by the seventh day
of treatment. It was no longer possible to visualize the
irritations and the bright color became darker and more
similar to the normal skin. By the twelfth day of treatment,
the ulcers were not visible at all and the scarring process had
begun. Controlled biopsies taken at the fifteenth day of
treatment indicated that the metaplastic cells from the inju-
ries had been replaced by normal appearing cells. The
nodules were smaller than 0.5 cm. By the twenty-fourth day
of treatment, the nodules were not visible and only showed
a light zone of papular tissue. The biopsy control performed
at 30 days revealed normal basal cellular tissue with no signs
of metaplastic cells. No recidivism was observed at the thirty
day examination.

Group II: Each patient in this group exhibited changes in
the nodules up to the fifteenth day of treatment when the
beginning of the drying process began and the nodules
stopped exhibiting signs of peripheral irritation areas. Biop-
sies performed on the 16th day of treatment indicated a
reduction in metaplastic cell with newly formed cells. The
ration of metaplastic cells to the normal cells began to invert
by the thirtieth day of treatment, and the ulcerated nodules
had disappeared and were only indicated by a few light
zones. Biopsies performed on the thirtieth day revealed that
80% of the affected tissue was occupied by normal basal
cells, but also indicated the presence of metaplastic cells.
The post-treatment evaluation at 30 days did not clinically
indicate any of the previous skin injuries.

10

15

20

30

40

66

28

In general, the results of the Group I and Group II studies
indicate that tetrasilver tetroxide ointment 3% was effective
in the treatment of basal cell carcinoma on injuries both
smaller and larger than 1 cm. The results, however, indicated
that in the treatment of basal cell carcinoma, it is most
important to obtain and begin treatment as rapidly as pos-
sible. Treatment was most effective the earlier the time of
diagnosis.

Example 12

Treatment of Dysplastic Nevi According to the
Invention

Ten patients between the ages of 25 to 40 were clinically
diagnosed by biopsy with dysplastic nevi. The patients were
divided into two groups.

Group I had six patients with dermal injuries of 5 to 10
mm.

Group II had four patients with dermal injuries of more
than 12 mm. The illness was well developed on the skin.

A petroleum jelly containing 3 wt % tetrasilver tetroxide
was applied to both groups at a dosage of about 100 mg to
all affected skin areas of each patient twice daily. Observa-
tions of both groups were made for a 30 day period to ensure
there were no additional changes in the condition.
Summary of Results

Group I: Within 36 hours of the onset of treatment, the
color and size of the injuries began to change, i.e., turn into
smaller spots. By the sixth day, the dysplastic nevi were no
longer visible. By the eighth day, a biopsy was conducted
revealing new normal melanocytes. The patients were evalu-
ated for the duration of the period, with no further changes.
reported.

Group II: By the fourth day of treatment, changes had
started to occur. The color from the spots had started to
disappear, and they were also turning smaller. By the fif-
teenth day, a new biopsy was taken showing normal
melanocytes, with the injuries no longer visible. Patients did
not experience any further changes in their condition over
the 30 days.

In conclusion, it is believed that early diagnosis resulted
in better and faster treatment results according to the
invention, with no significant adverse effects reported. Also,
the larger the injuries, the longer the treatment time required.
The above test also showed that the tetrasilver tetroxide
treatment was effective to prevent the malignant melanoma,
since 90% of them derive from dysplastic nevi.

Example 13

Cytotoxicity Tumor Cell Proliferation Studies and
Evaluations

An independent laboratory performed cytotoxicity tumor
cell proliferation studies and evaluations. A culture of leu-
kemia K562 was tested in vitro against media concentrations
of tetrasilver tetroxide at: 0.5, 1,5, 10, 50, 100, 500 and 1000
ppm.

The tetroxide was dispersed in pure dimethyl sulfoxide
and then diluted with Holipharm NPS buffer PH=7.4
(Holipharm International Co., Wilmington, Del.) in culture
media to achieve the aforesaid final assay concentrations.
The acronym NPS refers to non phosphate non saline. The
culture media comprised RPMI 1640, 90% and fetal bovine
serum, 10%. The cancer cultures were obtained from a cell
line provided by the American Type Culture Collection
(ATCC) and were incubated at 37° C. with 5% CO, in air

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atmosphere. The culture was a human chronic myelogenous
leukemia, of cell line source ATCCCCL-243.

As for the actual evaluation, cell proliferation analysis
was based on the ability of viable cells to cause alamar blue
to change from oxidized (non-fluorescent, blue) to reduced.
(fluorescent, red) form. Details of the procedure are
described in an article by S. Ansar Ahmed et. al. in the
Journal of Immunological Methods 170 (1994). The results
were as follows:

ICx, (50% Inhibition Concentration)=2.2 ppm

TGI (Total Growth Inhibition)=4.6 ppm

LC. (50% Lethal Concentration)=6.0 ppm

The above methodology was applied to a human malig-
nant melanoma cell line of source AT'CCHTB-70 having the
cell name SK-MEL-5. The culture media comprised 90%
Minimum Essential Medium and fetal bovine serum, 10%.
The results were as follows:

ICso (50% Inhibition Concentration)=3.7 ppm

TGI (Total Growth Inhibition)=4.9 ppm

LCs, (50% Lethal Concentration)=6.5 ppm

The “IC5, (50% Inhibition Concentration) is the test
compound concentration where the increase from times in
the number or mass of treated cells was only 50% as much
as the corresponding increase in the vehicle-control at the
end of experiment. The bTGI (Total Growth Inhibition) is
the test compound concentration where the number or mass
of treated cells at the end of experiment was equal to that at
time. The CLC (50% Lethal Concentration) is the test
compound concentration where the number or mass of
treated cells at the end of experiment was half that at time.
Table 1.1 shows other results from this study.

Although preferred embodiments of the invention have
been illustrated in the foregoing Summary, Detailed
Description, and Examples, it will be understood that the
invention is not limited to the embodiments disclosed, but is
capable of numerous rearrangements and modifications of
parts and elements without departing from the spirit of the
invention. It will be further understood that the chemical and
pharmaceutical details of the compositions and methods of
prevention, treatment, or management herein may be
slightly different or modified by one of ordinary skill in the
art without departing from the claimed invention.

What is claimed is:

1. A method for preventing, treating, or managing one or
more cancerous conditions or dysplastic proliferations in an
animal, which method comprises:

administering at least one metal oxide compound selected

from the group consisting of Bi(III,V) oxide, Co(ILIIH)
oxide, Cu(II) oxide, Mn(ILIII) oxide, Pr(III,[V)
oxide, and Ag(I,III) oxide to the animal in an amount
and for a period of time which is therapeutically
effective to treat such condition(s).

2. The method of claim 1, wherein the metal oxide
compound is administered via intravenous injection or infu-
sion and the animal is a human.

3. The method of claim 2, wherein the administering is
subcutaneous, intramuscular, or by infusion into a blood
stream of the animal.

4. The method of claim 3, wherein the metal oxide
compound is administered via infusion over a period of from
about 30 minutes to about 300 minutes to inhibit adverse
side effects.

5. The method of claim 4, wherein the at least one other
chemotherapeutic agent is administered concurrently with
the metal oxide compound.

6. The method of claim 2, wherein the cancer includes
skin cancer that has metastasized.

10

20

30

40

60

30

7. The method of claim 1, wherein the metal oxide
compound is administered via intravenous injection or infu-
sion and the animal is a human.

8. The method of claim 7, wherein the metal oxide
compound is administered in an amount sufficient to provide
about 1 to about 75 ppm of the metal oxide compound in the
bloodstream.

9. The method of claim 1, wherein the metal oxide
compound is administered in conjunction with at least one
other chemotherapeutic agent.

10. The method of claim 1, wherein the cancerous con-
dition or dysplastic proliferation includes at least one of
colon cancer, lung cancer, throat cancer, breast cancer,
kidney cancer, pancreatic cancer, bladder cancer, prostate
cancer, uterine cancer, brain cancer, liver cancer, skin
cancer, testicular cancer, stomach cancer, adrenal gland
cancer, cancer of the ovaries, thyroid cancer, bronchial
cancer, trachea cancer, eye cancer, bone cancer, cervical
cancer, oral cavity cancer, soft tissue cancer, pituitary gland
cancer, myeloma, rectal cancer, esophageal cancer,
leukemia, lymphoma, cancerous fibroid tumors, non-
cancerous fibroid tumors, or liver cancer.

11. The method of claim 10, wherein the controlled
release vehicle is implanted in the body at a location suitable
for providing a therapeutically effective amount of metal
oxide compound to the patient without affecting proper
functioning of the animal's liver.

12. The method of claim 1, wherein the metal oxide
compound is administered by a controlled release vehicle.

13. The method of claim 1, wherein the metal oxide
compound is substantially free of added persulfate.

14. Amethod for preventing, treating, or managing one or
more cancerous conditions or dysplastic proliferations asso-
ciated with a patient’s skin, which method comprises admin-
istering the at least one metal oxide compound selected from
the group consisting of Bi(III,V) oxide, Co(II,II) oxide,
Cu(LI) oxide, Mn(IL,IT) oxide, Pr(III,IV) oxide, and Ag(I,
III) oxide to the skin in an amount and for a period of time
which is therapeutically effective to treat such cancerous
condition(s).

15. The method of claim 14, wherein the at least one metal
oxide compound is substantially free of added persulfate.

16. The method of claim 14, wherein the cancerous
condition or dysplastic proliferation comprises at least one
of dysplastic nevi, neurofibromatosis, basal cell carcinoma,
squamous carcinoma, or melanoma.

17. The method of claim 14, wherein the cancerous
condition or dysplastic proliferation comprises symptoms of
cancer or conditions associated with a predisposition to
cancer.

18. The method of claim 14, further comprising a carrier
medium in which the at least one metal oxide compound is
dispersed, wherein the therapeutically effective amount is
from about 50 ppm to 500,000 ppm, based on the weight of
the carrier medium.

19. The method of claim 18, wherein the carrier medium
comprises petroleum jelly or mineral oil.

20. The method of claim 14, wherein the at least one metal
oxide compound is administered in the form of a powder.

21. The method of claim 14, wherein the therapeutically
effective amount is from about 400 ppm to 100,000 ppm.

22. The method of claim 14, wherein the administering is
topical or transdermal.

23. The method of claim 22, wherein the composition is
topically administered directly to the skin.

24. The method of claim 23, wherein the at least one metal
oxide compound further comprises a thixotropic agent suf-

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ficient to increase adherence of the composition to the skin
without excessive runoff.

25. The method of claim 14, wherein the administering
comprises application of the at least one metal oxide to the
skin at a dosage level of about 10 mg to 500 mg per cm? of 5
skin surface.

26. Amethod for preventing, treating, or managing one or
more cancerous conditions associated with a cervix of a
female animal, which method comprises administering at
least one metal oxide compound selected from the group
consisting of Bi(III,V) oxide, Co(II) oxide, Cu(II)
oxide, Mn(IILID) oxide, Pr(IILIV) oxide, and Ag(LII) oxide
to the cervix in an amount and for a period of time which is
therapeutically effective to treat such condition(s).

27. The method of claim 26, wherein the at least one metal 15
oxide compound is substantially free of added persulfate.

32

28. The method of claim 27, wherein the at least one metal
oxide compound is applied directly to the cervix.

29. The method of claim 28, further comprising a carrier
medium in which the at least one metal oxide compound is
dispersed, wherein the therapeutically effective amount is
from about 50 ppm to 500,000 ppm, based on the weight of
the carrier medium.

30. The method of claim 29, wherein the carrier medium
comprises petroleum jelly.

31. The method of claim 26, wherein the at least one metal
oxide compound is applied in an amount sufficient to obtain
a desired effect and to substantially inhibit undesirable side
effects.