tetra silver tetra oxide patents

US Patent # 5,336,499 Molecular Crystal Device for Pharmaceuticals

August 9, 1994 ~ Cl. 424/618

Marvin S. Antelman

Abstract ~

A novel molecular scale device is described which is bactericidal, fungicidal, viricidal and algicidal. The anti-pathogenic properties of the device are attributed to electron activity indigenous to diamagnetic semiconducting crystals of tetrasilver tetroxide ( Ag4O4 ) which contains two monovalent and two trivalent silver ions in each molecular crystal. When the crystals are activated with an oxidizing agent, they release electrons equivalent to 6.4 x 10-19 watts per molecule which in effect electrocute pathogens. A multitude of these devices are effective at such low concentrations as 0.3 PPM used as preservatives in a variety of formulations ranging from cosmetics to pharmaceuticals. Indeed, they are intended as active ingredients for pharmaceuticals formulated to destroy such pathogens as Staphylococcus aureus, and epidermidis, the latter of which it completely destroys in a nutrient broth culture of about 1 million organisms at 0.6 PPM, or Candida albercans, the vaginal yeast infection at 2.5 PPM, and the AIDS virus at 18 PPM.

References Cited ~ �U.S. Patent Documents:

4695353 ~ Sep., 1987 ~ Jansen, et al. ~ 423/604 �4717562~ Jan., 1988~ Jansen, et al. ~ 423/604 �4835077~ May, 1989~ Megahed et al. ~ 423/604 �5017295~ May, 1991~ Antelman ~ 424/618 �5073382~ Dec., 1991~ Antelman ~ 424/601 �5078902~ Jan., 1992~ Antelman ~ 424/601 �5089248~ Feb., 1992~ Akhtar ~ 423/604 �5089275~ Feb., 1992~ Antelman ~ 424/601

Claims ~

What is claimed is:

1. A method of inhibiting the growth of pathogens in pharmaceutical and cosmetic products, said pathogens selected from the group consisting of E. coli, Micrococcus Luteus, Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, Streptococcus pyogenes, Candida Albicans, and Saccharomycetpideae, which comprises introducing molecular semiconductor crystal devices of the molecule tetrasilver tetroxide ( Ag4O4 ) in the presence of an oxidizing agent comprising a persulfate.

Description ~

BACKGROUND OF THE INVENTION

The present invention relates to the employment of molecular crystals as bactericidal, viricidal and algicidal devices, but more particularly to the molecular semiconductor crystal tetrasilver tetroxide Ag.sub.4 O.sub.4 which has two trivalent and two monovalent silver atoms per molecule, and which through this structural configuration enables electronic activity on a molecular scale capable of killing algae and bacteria via the same mechanism as macroscale electron generators. The concept of molecular scale semiconductor devices for the storage of information has been the subject of much activity in recent years so that the concept of a molecular scale device performing such functions as storing information or acting as resistors, capacitors or photovoltaic devices is well accepted. The molecular device of this invention is a multivalent silver diamagnetic semiconductor. Now the bactericidal activity of soluble divalent silver (Ag II) complex bactericides is the subject of U.S. Pat. No. 5,017,285 of the present inventor. The inventor has also been granted U.S. Pat. Nos. 5,078,902, USP # 5,073,382, USP # 5,089,275, and USP # 5,098,582, which all deal with Ag II bactericides but more particularly with (respectively) halides, alkaline pH, stabilized complexes and the divalent oxide. It is the last patent, i.e., U.S. Pat. No. 5,098,582, and its perfection that has led to my original concept of the molecular device of the present invention. Now said patent designated AgO as divalent silver oxide, the popular name of the compound. Indeed, the Merck Index (11th Edition) designates the oxide as silver(II) oxide (AgO) (entry 8469). However, it also states that it is actually a silver(I)-silver(III) oxide with a molecular weight of 123.88. Said oxide is actually on a molecular level Ag4O4 where one pair of silver ions in the molecule is trivalent and another pair is monovalent.

While the formula AgO accurately designates the silver:oxygen ratio, the molecular weight of the compound is actually 495.52. Further elucidation of the molecule's electromagnetic properties reveals that it is a diamagnetic semiconductor. The structure is electronically active because of the trivalent sp.sup.2 electron configuration disparity of the electrons within the crystal.

Further testing of the unique oxide was continued on various types of bacteria, molds, yeasts and algae, beyond the water treatment applications claimed in my previous patents. The phenomenal efficacy of said oxide against pathogens while they were in constant contact with their nutrient source in contradistinction to its efficacy with these same organisms in water, where the pathogen is separated from a constant nutrient source, could only be accounted for by considering each molecule of oxide as a "device". This in turn has led to the final development of this invention, namely, a molecular device for killing viruses, fungi, algae and bacteria, which can be utilized as the active component of pharmaceuticals and as a preservative against said pathogens in pharmaceutical and other products.

OBJECTS OF THE INVENTION

The main object of this invention is to provide for a molecular scale device of a single tetrasilver tetroxide semiconductor crystal capable of killing viruses, bacteria, fungi and algae when operating in conjunction with other such devices.

Another object of the invention is to provide for a molecular device which can be utilized in pharmaceuticals formulated to destroy pathogens.

Still another object of the invention is as a preservative in pharmaceutical, cosmetic, and related chemical specialty products against said pathogens.

Other objects and features of the present invention will become apparent to those skilled in the art when the present invention is considered in view of the accompanying examples. It should, of course, be recognized that the accompanying examples illustrate preferred embodiments of the present invention and are not intended as a means of defining the limits and scope of the present invention.

SUMMARY OF THE INVENTION

This invention relates to a molecular scale device capable of destroying gram positive and gram negative bacteria as well as fungi, viruses and algae. Said molecular scale device consists of a single crystal of tetrasilver tetroxide. Several hundred thousand trillion of these devices may be employed in concert for their bactericidal, fungicidal, and algicidal properties and applied to industrial cooling towers, swimming pools, hot tubs, municipal water supplies and various pharmaceutical formulations.

The molecular crystals which are the subject of this invention are commercially available and can be prepared by reacting silver nitrate with sodium or potassium peroxydisulfate according to the following equation: 4AgNO3 +2Na2S2O8 + 8NaOH = Ag4O4 + 4Na2SO4 + 4NaNO3 + 4H2O The oxide lattice represented by the formula Ag4O4 is depicted in the Drawing FIG. 1. It is a semiconducting electron active diamagnetic crystal containing two monovalent and two trivalent silver ions in combination with four oxygen atoms. The distance between the Ag(III)-O Ag(I)O units equals 2.1 A. Ag(III)-Ag(III) = Ag(I)-Ag(I) = 3.28A and Ag(I)-Ag(III) = 3.39 A. Each trivalent silver ion is coordinated via dsp2 electron bonds to 4 oxygen atoms. The depiction of this lattice is based on several literature references relating to crystallographic studies. Exemplary of this literature are J. A. McMillan's studies appearing in Inorganic Chemistry 13,28 (1960); Nature vol. 195 No. 4841 (1962), and Chemical Reviews 1962, 62, 65. Alvin J. Salkind elucidated studies involving neutron diffraction with his coworkers (J. Ricerca Sci. 30, 1034 1960) proving the Ag(III)/Ag(I) nature of this molecule and states in his classic entitled Alkaline Storage Batteries (Wiley 1969), coauthored with S. Uno Falk, that the formula is depicted by Ag4O4 (page 156).

That same year a scientific communication appeared in Inorganic Nuclear Chemistry Letters (5,337) authored by J. Servian and H. Buenafama which maintained that their neutron diffraction studies also confirmed the tetroxide lattice and the presence of Ag(III) and Ag(I) bonds in the lattice, a conclusion also reported previously by Naray-Szahn and Argay as a result of their x-ray diffraction studies (Acta Cryst. 1965, 19,180). Thus the effects of this invention can be explained in terms of these structural elucidations, namely, that the single molecular semiconductor crystal which inevitably must be electronically active exchanging two electrons per crystals between its mono and trivalent bonds is in reality a device which kills pathogens in the same manner as electrically active large-scale devices utilized in water supplies.

When the tetroxide crystals are utilized to destroy pathogens, they will not do so unless activated by an oxidizing agent. This is analogous to the behavior of single semiconducting photovoltaic molecular devices such as copper indium selenide whose surfaces must be "etched" in order to activate the photovoltaic activity, i.e., for light to facilitate the release of electrons from the molecule. The tetroxide was activated by persulfates. It was found that when the persulfates were tested as a control by themselves, they failed to exhibit any unilateral antipathogenic activity at the optimum level selected of 10 PPM. The persulfates evaluated varied from Oxone (Registered Trademark Du Pont Company) brand potassium monopersulfate to alkali peroxydisulfates

DESCRIPTION OF THE DRAWING

In the drawing which illustrates the best mode presently contemplated for carrying out the present invention:

FIG. 1 is a diagrammatic view showing the crystal lattice of Ag4O4 � attacking a pathogenic bacillus. DESCRIPTION OF THE INVENTION

Turning now to Drawing FIG. 1 depicting the crystal lattice of Ag4O4, the device operates by transferring electrons from the monovalent silver ions 10 to the trivalent silver ions 11 in the crystal 20 through the aqueous media in which it is immersed and which conducts electrons depicted by the path 12, contributing to the death of pathogen 13 with electrons 14, traversing the cell membrane surface 15, said pathogen being "electrocuted" by not only these electrons but by others: 16 and 17 following paths 18, and 19 emanating from other molecular devices in the vicinity of the pathogen. The device is attracted to the cell membrane surface 15 by powerful covalent bonding forces 21 caused by the well-known affinity of silver to certain elements present in the membrane, such as sulfur and nitrogen. Drawing FIG. 1 exaggerates the size of the silver oxide molecular device with respect to that of a microorganism for depiction purposes only.

The electron transfer can be depicted by the following half reactions in which the monovalent silver ion loses an electron and the trivalent silver gains one as follows:

Ag+ -e = Ag+2

Ag+3 +e = Ag+2

The molecular crystal then will become stabilized with each silver ion having a divalent charge.

Stringent testing was performed in which cultures were actually placed in trypticase soy nutrient broth, which allowed the pathogens being tested to replicate without being detached from its own food supply. Under these conditions the devices were able to kill two strains of E. Coli at 2.5 PPM; Micrococcus Luteus at 1.25 PPM; Staphylococcus aureus at 2.5 PPM; Staphylococcus epidermidis at 0.6 PPM; Pseudomonas aeruginosa at 1.25 PPM; and Streptococcus pyogenes at 2.5 PPM.

The devices were then evaluated in analogous nutrient used for yeasts, algae and molds utilizing Sabouraud dextrose broth. The infectious yeast pathogen Candida ALBICANS was totally killed at 2.5 PPM and that of the Saccharomycetpideae variety at 1.25 PPM.

If we are to consider one molecular device in operation, then each molecule would release two electrons having each a charge of 4.8 x 10-10 e.s.u. equivalent to approximately 1.6 x 10-19 coulombs. The EMF given in my Encyclopedia of Chemical Electrode Potentials (Plenum 1982), page 88, for the oxidation of Ag(I) to Ag(II) is 1.98 volts which approximates 2.0 V. The total power output per device can be calculated in watts by multiplying the power output for each electron by 2. Since power is the product of the potential times the charge, P = EI; for each electron it would be

2.0 x 1.6 x 10-19 = 3.2 x 10-19 watts

From this, and using Avogadro's number, we can calculate that the power flux of one liter of solution containing 0.5 PPM of devices would be 0.064 watts. Since the electronic charges of the devices are directly proportional to the number of devices in solution, i.e., the concentration of the oxide in the solution, we can arbitrarily assign our own device power flux constant which can be used to gauge the concentrations of the devices required in order to kill particular organisms in specific environments. I have found the following formula useful for this purpose: Power Flux = EMF generated per molecule x Concentration x 5 (the EMF being 4.0 volts per molecular device; and the concentration is in PPM) United States Patent 5,676,977

Method of Curing AIDS with Tetrasilver Tetroxide Molecular Crystal Devices

October 14, 1997 ~ Cl. 424/618

Marvin S. Antelman

Abstract ~

The diamagnetic semiconducting molecular crystal tetrasilver tetroxide ( Ag4O4 ) is utilized for destroying the AIDS virus, destroying AIDS synergistic pathogens and immunity suppressing moieties (ISM) in humans. A single intravenous injection of the devices is all that is required for efficacy at levels of about 40 PPM of human blood. The device molecular crystal contains two mono and two trivalent silver ions capable of "firing" electrons capable of electrocuting the AIDS virus, pathogens and ISM. When administered into the bloodstream, the device electrons will be triggered by pathogens, a proliferating virus and ISM, and when fired will simultaneously trigger a redox chelation mechanism resulting in divalent silver moieties which chelate and bind active sites of the entities destroying them. The devices are completely non-toxic. However, they put stress on the liver causing hepatomegaly, but there is no loss of liver function.


4415565 ~ Nov., 1983 ~ Wysor ~ 424/618 �4915955 ~ Apr., 1990 ~ Gomori~ 424/618 �4952411 ~ Aug., 1990 ~ Fox, Jr. et al.~ 424/618 �5073382 ~ Dec., 1991 ~ Antelman~ 424/618 �5078902 ~ Jan., 1992 ~ Antelman ~ 424/618 �5089275 ~ Feb., 1992 ~ Antelman ~ 424/618 �5211855 ~ May, 1993 ~ Antelman ~ 424/618 �5223149 ~ Jun., 1993 ~ Antelman ~ 424/618 �5336499 ~ Aug., 1994 ~ Antelman ~ 424/618 �5571520 ~ Nov., 1996 ~ Antelman ~ 424/618

Other References ~

"Is The AIDS Virus A Science Fiction?" by Peter H. Duesberg and Bryan J. Ellison: Policy Review (Summer 1990), pp. 40-51.

Claims ~

What is claimed is:

1. A method of treating AIDS-afflicted humans comprising injecting a multitude of tetrasilver tetroxide molecular crystals into the bloodstream of the human subject.

2. A method for increasing white blood cell counts in AIDS-afflicted humans comprising injecting a multitude of tetrasilver tetroxide molecular crystals into the bloodstream of the human subject.

3. Methods of treating AIDS-affilicted humans according to claims 1-2 where the concentration of said molecular crystals is approximately 40 PPM of the total blood weight of the human subject.

Description ~


The present invention relates to the employment of molecular crystals as anti-AIDS devices, but more particularly to the molecular crystal semiconductor tetrasilver tetroxide Ag4O4 which has two monovalent and two trivalent silver ions per molecule, and which through this structural configuration enables intermolecular electron transfer capable of killing viruses and binding them to the resulting silver entity so that a single intravenous injection will completely obliterate acquired immune deficiency syndrome (AIDS) in humans. Furthermore, said devices are capable of killing pathogens and purging the bloodstream of immune suppressing moieties (ISM) whether or not created by the AIDS virus (HIV); so as to restore the immune system.

The present invention is based on concepts previously elucidated in applicant's U.S. Pat. No. 5,336,499 which discloses the destruction and inhibition of bacteria, algae and the AIDS virus in nutrient life supporting systems by using said silver oxide devices. Example 3 of said patent discloses that 18 PPM of said crystal devices could totally suppress the AIDS virus (page 6, line 5). Subsequent to the filing of the aforementioned patent, further testing revealed complete 100% destruction of the AIDS virus in vitro at 20 PPM, and the fact that said devices were harmless when ingested and inhaled, being non-toxic.

Encouraged by these evaluations and successes, applicant obtained permission to evaluate the crystals in vitro against murine acquired immune deficiency syndrome (MAIDS). Only one facility in the State of Israel is licensed for these evaluations, namely, the Kaplan Hospital in Rehovot, Israel, which is affiliated with the Hebrew University-Hadassah Medical School where said evaluations were done.

The initial evaluations entailed experimenting with various silver moieties cited in applicant's aforementioned patent, concentrations, non-reactive buffers and modes of administration. After about 18 months of judicious efforts and initial failures, success was finally achieved in destroying the MAIDS virus in C57BL mice with a single intravenous injection. The results of this test program comprise Example 5 of U.S. Pat. No. 5,336,499. After success with mice, the inventor was able to test the efficacy of said devices on two select etiological groups of terminal AIDS patients in a clinic in Tegucigalpa, Honduras, Central America. OBJECTS OF THE INVENTION

The main object of the invention is to provide for a molecular scale device of a single tetrasilver tetroxide crystalline molecule capable of restoring the immunity of AIDS afflicted humans of the two AIDS etiological subgroups, candidiasis and wasting syndrome.

Another object of the invention is to provide for immunity restoration in said AIDS afflicted humans through a single injection.

Another object of this invention is to destroy ISM in humans manifesting AIDS diseases of said AIDS etiological subgroups irrespective as to whether said ISM was HIV induced, since it is known that humans may manifest AIDS and still be HIV negative, and thus restore the immune system in said humans.

Another object of this invention is to destroy the AIDS virus when present in the systems of said AIDS afflicted humans.


This invention relates to a molecular scale device not only capable of destroying the AIDS virus, but of purging the human bloodstream of pathogens and restoring immunity to AIDS patients of the candidiasis and wasting syndrome categories. Said molecular device consists of a single crystal of tetrasilver tetroxide (Ag4O4). The crystal lattice of this molecule has a unique structure since it is a diamagnetic semiconducting crystal containing two mono and two trivalent silver ions, which in effect are capable of "firing" electrons under certain conditions which will destroy AIDS viruses, other pathogens and immune suppressing moieties (ISM), not only through the electrocution mode, but also by a binding process which occurs simultaneously with electron firing, namely, binding and chelation of divalent silver, i.e., the resulting product of the electron transfer redox that occur when the monovalent silver ions are oxidized and the trivalent ions are reduced in the crystal. The binding/chelation effect occurs at active sites of the AIDS virus, pathogens and ISM. Because of the extremely minute size of a single molecule of this crystal, several million of these devices may be employed in concert to destroy a virus colony to purge a life support system of ISM and pathogens with the consumption of only parts per trillion of the crystal devices. Thus an optimum of 40 PPM of the devices by weight of human blood was found to be sufficient to completely obliterate AIDS. This concentration is slightly over double of the optimum concentration recommended in applicant's aforementioned U.S. patent for the destruction of the human AIDS virus in vitro. Other details concerning the structure of the crystal and its mechanism against pathogens, the AIDS virus and ISM would analogously hold here, and have already been further elucidated in said patent.

The actual destruction of pathogens, ISM and the AIDS virus is effectuated by injection of a suspension of these devices in distilled or deionized water with a non-reacting electrolyte directly, i.e. intravenously, into the bloodstream. A single injection is all that is required under these conditions. Accordingly, humans injected in this manner, upon being inspected after three weeks or more had elapsed and compared with similar humans that had been given placebos, were completely cured of AIDS. The control group still manifested AIDS. Accordingly, the tetrasilver tetroxide device performed in concert with and in full conformity with the ultimate objects of this invention. Furthermore, three out of four wasting syndrome terminal patients and four out of the five candidiasis terminal patients were still alive in 1995 after a year and a half had elapsed from their initial injection. By that time all the AIDS patients had been released from the clinic and allowed to return home.

Other objects and features of the present invention shall become apparent to those skilled in the art when the present invention is considered in view of the accompanying examples. It should, of course, be recognized that the accompanying examples illustrate preferred embodiments of the present invention and are not intended as a means of defining the limits and scope of the present invention.

EXAMPLE 1

Five patients afflicted with AIDS of the candidiasis etiological category were segregated for Tetrasil treatment. The rationale for selecting them was based on facts presented in an article by Peter H. Duesberg and Brian J. Ellison entitled "Is The AIDS Virus A Science Fiction?" (Policy Review, Summer 1990 pp. 40-51). Only the factual presentations of the article were utilized and the hypothesis of the authors was ignored. The facts presented in the article related to the method of selecting AIDS patients based on the five aforementioned etiological subgroups targeted by the CDC, and the evidence presented, that there is AIDS without HIV as well as with it so that an anti-viral agent in most instances will not necessarily restore the immunity system.

Evaluations with Tetrasil were conducted on AIDS patients at Lucha Contra el Sida, Comayaguela, Honduras. The patients two weeks prior to inoculation were removed from their AZT, AIDS therapy. Tetrasil was administered at approximately 40 PPM of blood volume per patient as a suspension in a proprietary buffer solution (pH = 6.5), supplied by Holipharm Corporation.

The results of evaluations with candidiasis are tabulated in Table I under its disease category. All patients evaluated were terminal. Some, however, were in moderate (m) condition and others in poor (p) as designated in the Table. The I and F designations refer to initial and final values as shown. WBC indicates white cell blood count. The H column, following CD 8, indicates whether hepatomegaly occurred. This was an unfortunate consequence of the treatment which resulted in enlarged livers in all patients except the second one. Despite hepatomegaly, there was no interference with liver function.

The onset of hepatomegaly was not spontaneous and varied from patient to patient, being in the range of 4-16 days.

It should also be noted that shortly after injection of Tetrasil there were indications of fever (symbolized by T in the Ag4O4 column), sometimes accompanied by fatigue (F). The body temperature was invariably 38.5.degree. C. (101.3.degree. F.). This was indicative of restoration of the immune response of the body, since normally the body will destroy pathogens when the immune system is functional by raising the temperature. The patient who died; first responded favorably to Diflucan, which previously gave no response. He was cured of his candidiasis, but unfortunately succumbed to his previous body damage. All the other candidiasis syndrome people who previously did not respond to the indicated medications subsequently responded after the Tetrasil treatment. Further evidence of the recovery of the AIDS patients manifested itself 30 days after the initial injection when white blood cell counts were taken. They are shown in Table I under the WBC column, which gives the initial and final WBC. All candidiasis patients showed a dramatic increase in their white blood cell counts, indicative of the restoration of their immunity systems.

EXAMPLE 2

The above protocol of Example 1 was repeated with AIDS patients exhibiting wasting syndrome. The results of their treatment are tabulated in Table I under the disease category of said syndrome. It should be noted that two of the four wasting syndrome patients showed improved white blood counts. The female patient, whose condition improved from poor and terminal to be among the living, showed a decrease in the WBC. However, she showed an increase in body temperature which was indicative of immune response. The test results indicate that one cannot rely on a single factor to indicate the demise of AIDS. The usual HIV marker CD 4 initial and final are irrelevant. ISM suppression appears to be more critical than the destruction of HIV. AIDS was suppressed, any permanent damage that had been done to the patients in the course of their succumbing to AIDS was not obviously cured or corrected by said crystal device treatment, rather said injury persisted and the patient was improved with respect to AIDS but still suffered from said permanent injury or impairment previously inflicted.

US Patent # 5,223,149 Trivalent Silver Water Treatment Compositions

( June 29, 1993 ~ Cl. 210/764 )

Marvin Antelman

Abstract ~

A method for controlling the growth of bacteria and algae in utilitarian bodies of water such as industrial cooling towers, swimming pools and hot tubs is described. The method comprises adding to the water novel trivalent silver compounds. Said compounds are light stable and can be supplied as liquid concentrates which will not precipitate any silver whatsoever from saline waters nor will the concentrates stain skin or discolor surfaces. Said compounds meet the rigid EPA standards of killing 100% of select coliforms within ten minutes and are efficacious at concentrations as low as 1-2 PPM.

References Cited ~ �U.S. Patent Documents

5073382 ~ Dec., 1991 ~ Antelman ~ 210/764 �5078902 ~ Jan., 1992 ~ Antelman ~ 210/764 �5089275 ~ Feb., 1992 ~ Antelman ~ 210/764 �5098582 ~ Mar., 1992 ~ Antelman ~ 210/759

Claims ~

What is claimed is:

1. A method for limiting the growth of bacteria and algae in the water of swimming pools, industrial cooling towers, hot tubs and reservoirs which comprises adding to the water a stable trivalent silver compound.

2. The method as claimed in claim 1 wherein the trivalent silver compound is a periodate.

3. The method as claimed in claim 1 wherein the said water is salt water, and wherein no silver halide is caused to precipitate.

4. The method as claimed in claim 2 wherein the said water is salt water, and wherein no silver halide is caused to precipitate.

5. The method as claimed in claim 1 wherein said trivalent silver compound is supplied as a liquid concentrate.

6. The method as claimed in claim 2 where said trivalent silver periodate is supplied as a liquid concentrate.

7. The method as claimed in claim 1 wherein said trivalent silver compound is employed without adding an oxidizing agent.

8. The method as claimed in claim 2 wherein said trivalent silver periodate is employed without adding an oxidizing agent.

9. The method as claimed in claim 1 where said trivalent silver compound concentrate will not stain skin or surfaces with which it is in contact.

10. The method as claimed in claim 2 where said trivalent silver periodate concentrate will not stain skin or surfaces with which it is in contact.

11. The method as claimed in claim 1 where said trivalent silver compound is light stable so as not to discolor or leave black silver films on the inner surface of vessels containing the water to be treated.

12. The method as claimed in claim 2 where said trivalent silver periodate is light stable so as not to discolor or leave black silver films on the inner surface of vessels containing the water to be treated.

Description ~


The present invention relates to the employment of trivalent silver (Ag[III]) compounds as bactericidal and algicidal agents in water treatment. Water soluble trivalent silver compounds are part of the class of multivalent silver compounds which have

been the subject of patents granted to the instant inventor for water treatment. To date five such patents have been granted, namely, U.S. Pat. # 5,017,295; USP # 5,073,382; USP # 5,078,902; USP # 5,089,275; and USP # 5,098,582. These patents all deal with divalent silver compounds and compositions that are anti-pathogenic but more particularly with (respectively) soluble complexes, alkaline pH stable compositions, halides, solid stabilized complexes and solid black oxide. All of said compounds more particularly related to treating utilitarian bodies of water defined as bodies of water having an ultimate use such as swimming pools, hot tubs, industrial cooling towers and municipal reservoirs where pathogens are known to proliferate. While all of the cited patents describe multivalent silver compounds which have many novel advantages in treating said bodies of water and while they all conform to regulatory requirements for treating said bodies of water, such as the rules and regulations of the Environmental Protection Agency for treating swimming pools, none of the above inventions provides for an antipathogenic composition which embodies all of the following characteristics:

1. A liquid composition;

2. Not precipitated out by halides present in the water treated;

3. Non-staining in concentrated form to human skin and to the surfaces of the containing vessel of said bodies of water.

None of the previously patented compounds or compositions met all of these three criteria, despite the fact that each invention embodied unique compositions of Ag(II) moieties. The first patent, for example, in its preferred embodiments dealing with Ag(II) complexes, though of liquid composition, stained the skin in concentrated form and precipitated cupious white material when introduced into saline bodies of water. While of all the previous patents the silver halides were free of this nuisance and were nonstaining, they all were solid compositions which were totally insoluble in water. Accordingly, a composition meeting these three criteria was sought. Therefore, attempts were made to synthesize water soluble Ag(III) compounds, and testing and evaluation of their efficacy to see whether they met all the aforementioned criteria. The Ag(II) compositions were all light stable and it was verified as anticipated for Ag(III) as well. Accordingly, the tests and evaluations proved successful which has led to the final development of this invention, namely, trivalent silver compositions capable of killing and/or preventing the replication of gram positive and gram negative bacteria, as well as algae in utilitarian water bodies, such as swimming pools, which can be supplied in liquid concentrate form which will not stain the skin nor precipitate in the presence of halides.

In the course of the testing of the compositions of this invention, another previously unanticipated advantage of these compositions became evident. Whereas all the previous Ag(II) compositions required additions of oxidizing agents, such as alkali metal persulfates, to synergize their efficacy, these compositions required no such additions and were efficacious in themselves.


The main object of this invention is to provide compositions embodying trivalent silver compounds capable of killing and/or inhibiting the growth of bacteria and algae, particularly in utilitarian bodies of water when said compositions are added to said water supply.

Another object of the invention is to provide a source of trivalent silver ions capable of meeting the regular EPA standards for swimming pools and hot tubs, mainly, a bactericide capable of achieving 100% kills within ten minutes.

Still another object of the invention is to provide for a trivalent silver composition which will perform the aforementioned anti-pathogenic functions and will not be subject to the formation of a precipitate in the presence of halides.

Still another object of the invention is to provide a trivalent silver composition having all of the aforementioned functions and characteristics, but which will not stain the skin nor discolor surfaces with which it is in contact in its concentrated liquid form.

Still another object of the invention is to provide a trivalent silver composition having all of the aforementioned functions, but which can be formulated into a marketable concentrated liquid product for utilization in utilitarian bodies of water.

Still another object of the invention is to provide a trivalent silver composition having all of the aforementioned functions and characteristics, but which can perform its anti-pathogenic functions without the need of adding an oxidizing agent to the composition.

A final object of the invention is to provide a trivalent silver composition having all of the aforementioned functions and characteristics, but which is also light stable, unlike monovalent silver compounds.

Other objects, features, functions and characteristics of the present invention will become apparent to those skilled in the art when the present invention is considered in view of the accompanying examples. It should, of course, be recognized that the accompanying examples illustrate preferred embodiments of the present invention and are not intended as a means of defining the limits and scope of the present invention.


This invention relates to the utilization of trivalent silver compounds for bactericidal and algicidal applications in utilitarian bodies of water, such as swimming pools, hot tubs, municipal and industrial water supplies, as for example, cooling towers.

More particularly, this invention concerns stable Ag(III) complexes designated by the principal quantum number, n = 4, and the second quantum number l = 2, delineating sublevel d having eight electrons, the accepted conventional expression being d8 complexes in contradistinction to the d9 divalent complexes and d10 monovalent complexes of silver.

Trivalent silver complexes were prepared by either reacting Ag(I-III) tetrasilver tetroxide with a ligand bearing compound capable of forming Ag(III) complexes or reacting an Ag(I) salt in the presence of said ligand with an oxidizing agent, such as alkali persulfate, or in the alternative, by reacting Ag(III) hydroxide complex formed electrolytically by the anodic oxidation of silver in an alkali solution.

Said trivalent silver complexes were subsequently evaluated as to their efficacy in killing gram positive and gram negative bacteria in algae in accordance with the EPA protocols for swimming pools, which require 100% kills of bacteria within ten minutes. The compounds far exceeded the bacteria requirements at concentrations of one PPM or less of silver. They were evaluated with and without persulfate salts at 10 PPM and were effective without persulfates as bactericides.

The complexes were then evaluated with salt concentrations as high as 10% without precipitating halide.

The complexes, which were colored from deep orange to brown and maroon, were left exposed in clear glass bottles for three months with constant exposure to daylight. The complexes were stable and did not decompose to silver.

Ag(III) complexes were applied to human skin in concentrated form containing as much as 5,000 PPM silver without any silver staining of the skin whatsoever.

Of all the Ag(III) complexes prepared, the easiest to prepare were periodate complexes. Accordingly, a particular Ag(III) periodate complex was selected for evaluation against algae and it proved effective.

The particular Ag(III) periodate selected was prepared by the action of potassium hydroxide on tetrasilver tetroxide (Ag4O4) and is depicted by the following reaction:

Ag4O4 + 6KOH + 4KIO4 = 2K5H2 [Ag(IO6)2 ] + Ag2O + H2O

The Ag(III) periodate complexes can be depicted by the following structure: [ ##STR1## ] Several Ag(III) periodates have been identified which conform to this structure, in addition to the aforementioned one, which was designated by Servian, J. and Buenafama, H.D., Inorganic Nuclear Chemistry Letters. 1969, 5, 337-8. Another formula is:

K3H4 [Ag(IO6)2 ]

(Cohen, G. and Atkinson, G., Inorganic Chemistry 1964, 3, 2, 1741-2.)

DESCRIPTION OF THE PREFERRED EMBODIMENTS

As illustrative of the preferred embodiments of this invention are the following examples.

EXAMPLE 1

An Ag(III) periodate was prepared by calculating the amounts of reactant necessary to form the periodate complex according to the aforementioned reaction equation involving KOH, 0.15 grams; tetrasilver tetroxide 1.0 gram and potassium periodate 2.0 grams. The KOH was first dissolved in 20 ml. of distilled water and the subsequent ingredients were added, and the entire mixture was heated and kept at 65 degrees C. for two hours. At the end of that time, the supernatant liquid, which had a rich orange-maroon color, was separated and was filtered and submitted for analysis to an independent laboratory, after it was diluted to a total volume of 100 ml. in a volumetric flask. The resulting solution assayed 3290 mg./L Ag and represented a 76% yield of Ag(III) periodate based on the aforementioned reaction stoichiometry. Having evaluated the silver concentration via an independent EPA certified laboratory, Ag(III) periodate aliquots were submitted to another EPA certified laboratory for bactericidal evaluation of the Ag(III) complex. Accordingly, good laboratory practice was followed in accordance with FIFRA and ffdca/40 CFR 160, May 2, 1984. The bacteria employed were E. coli, a gram negative pathogenic bacillus. The protocol employed for the evaluations was that as set forth in AOAC (15th) 1990:965:13 at colony densities of 100K/cc.,utilizing two exposure times, i.e., five and ten minutes. Concentrations of Ag(III) evaluated were 0.5, 1.0 and 3.0 PPM. The evaluation pH was 7.5. Testing was done with controls and with and without potassium persulfate at a concentration of 10 PPM. There was 100% inhibition of the colonies after ten minutes at all concentrations and after five minutes except for the 0.5 PPM solution.

Having completed the aforementioned evaluations, another EPA certified laboratory was chosen for more comprehensive testing according to the aforementioned protocols excepting that sodium persulfate at 10 PPM was added to the Ag(III) periodate and tested against said periodate at zero persulfate and testing was also done on cultures of Streptococcus faecalis.

US Patent # 5,211,855 Method of Treating Water Employing Tetrasilver Tetroxide Crystals

May 18, 1993 ~ Cl. 210/758

Marvin Antelman

Abstract ~

A novel molecular scale device is described which is bactericidal, fungicidal and algicidal. The antipathogenic properties of the device are attributed to electron activity indigenous to diamagnetic semiconducting crystals of tetrasilver tetroxide (Ag4O4) which contains two monovalent and two trivalent silver ions in each molecular crystal. When the crystals are activated with an oxidizing agent, they release electrons equivalent to 6.4 x 10-19 watts per molecule which in effect electrocute pathogens. A multitude of these devices are effective at such low concentrations as 0.3 PPM where they can kill 100% of 100 K/cc Streptococcus faecalis, and E. coli colonies in three minutes meeting the ten-minute EPA criteria of 100% kills within ten minutes for swimming pool and hot-tub applications. The devices can be used in utilitarian bodies of water, such as municipal and industrial water reservoirs.


4055655 ~ Oct., 1977 ~ Maurer et al. ~ 514/495 �4092245 ~ May., 1978 ~ Franks et al.. ~ 210/169 �4492618 ~ Jan., 1985. ~ Eder. ~ 210/764 �5017295 ~ May., 1991. ~ Antelman. ~ 210/764 �5073382 ~ Dec., 1991. ~ Antelman. ~ 210/169 �5078902 ~ Jan., 1992. ~ Antelman. ~ 210/764 �5089275 ~ Feb., 1992. ~ Antelman. ~ 210/169 �5098582 ~ Mar., 1992. ~ Antelman. ~ 210/764

Other References �Hawley's Condensed Chemical Dictionary, 11th ed, p. 699 (definition of Ligand). �Hammer & Kleinberg: Inorganic Synthesis vol. IV, p. 12. �J. Servian & H. Buenafama, Inorg. NUC. Letters 5, 337

Claims ~

What is claimed is:

1. A method for killing pathogens including bacteria, viruses and algae in utilitarian water bodies including the water of swimming pools, industrial cooling towers, hot tubs and drinking supply reservoirs, which comprises adding to the water a multitude of tetrasilver tetroxide molecular crystals which are capable of electrocuting said pathogens via an electron transfer

mechanism involving their molecular structure in the presence of oxidizing agents.

2. A method as claimed in claim 1 where the oxidizing agent is a persulfate.

3. A method as claimed in claim 1 where the concentration of the molecular crystals in the water is a maximum of one part per million.

4. A method as claimed in claim 2 where the concentration of the molecular crystals in the water is a maximum of one part per million.

Description ~


The present invention relates to the employment of molecular crystals as bactericidal, viricidal and algicidal devices, but more particularly to the molecular crystal semiconductor tetrasilver tetroxide Ag4O4 which has two trivalent and two monovalent silver atoms per molecule, and which through this structural configuration enables electronic activity on a molecular scale capable of killing algae and bacteria via the same mechanism as macroscale electron generators. The concept of molecular scale semiconductor devices for the storage of information has been the subject of much activity in recent years so that the concept of a molecular scale device performing such functions as storing information or acting as resistors, capacitors or photovoltaic devices is well accepted. The molecular device of this invention is a multivalent silver diamagnetic semiconductor. The bactericidal activity of soluble divalent silver (Ag II) complex bactericides is the subject of U.S. Pat. No. 5,017,295 of the present inventor. The inventor has also been granted U.S. Pat. Nos. 5,078,902, USP # 5,073,382, USP # 5,089,275, and USP # 5,098,582, which all deal with Ag II bactericides but more particularly with (respectively) halides, alkaline pH, stabilized complexes and the divalent oxide. It is U.S. Pat. No. 5,098,582, and its perfection that has led to the present invention. This patent designated AgO as divalent silver oxide, the popular name of the compound. Indeed, the Merck Index (11th Edition) designates the oxide as silver(II) oxide (AgO) (entry 8469). However, it also states that it is actually a silver(I)-silver(III) oxide with a molecular weight of 123.88. After filing my patent application, a comprehensive examination was begun of information relating to the structure of this oxide. Further investigation of the scientific literature revealed that said oxide was actually on a molecular level Ag4O4 where one pair of silver ions in the molecule was trivalent and another pair was monovalent. Said oxide is actually on a molecular level Ag4O4 where one pair of silver ions in the molecule is trivalent and another pair is monovalent.

While the formula AgO accurately designates the silver:oxygen ratio, the molecular weight of the compound is actually 495.52. Further elucidation of the molecule's electromagnetic properties revealed that it is a diamagnetic semiconductor. The structure is electronically active because of the trivalent sp2 electron configuration disparity of the electrons within the crystal. The oxide as presented in my patent was actually capable of killing 100% of standardized E. coli and Strep. faecalis colonies in less than five minutes at concentratiors of 0.5 PPM. My independent evaluations of this oxide in areas unrelated to water treatment resulted in the "molecular device" concept which was substantiated by submission of the oxide for testing with a preferred embodiment of the invention (10 PPM of sodium persulfate) at an Environmental Protection Agency (EPA) certified laboratory which revealed that 0.5 PPM of oxide only yielded 0.003 PPM of silver in solution, a silver concentration entirely too low to cause this level of bactericidal activity. Indeed, the killing of the bacteria was analogous to that obtained by electron generating devices utilized in swimming pools or water towers for killing bacteria. It was therefore postulated that the oxide efficacy at low concentrations could only be attributed to regarding each oxide molecule as a device. Further testing was continued on algae and viruses. The accumulated data of efficacy at low concentrations, coupled together with a reinterpretation of silver oxide efficacy, has led to the final development of this invention, namely, a molecular device for killing algae, bacteria and viruses in utilitarian water bodies, such as swimming pools.


The main object of this invention is to provide for a molecular scale device of a single tetrasilver tetroxide semiconductor crystal capable of killing viruses, bacteria, and algae when operating in conjunction with other such devices.

Another object of the invention is to provide for a device which is so small that several thousand trillion can be added to a water supply to perform their effective functions and still be effective at concentrations of the devices in said supply not exceeding one part per million.

Still another object of the invention is to provide for a device which will perform the aforementioned anti-pathogenic functions without polluting the water supplies it is intended to purify, such as swimming pools, industrial cooling towers, hot tubs and municipal water supplies.

Still another object of the invention is to provide for a device which can be employed in swimming pools, hot tubs and other environments for these aforementioned functions in the presence of humans, without causing them respiratory and eye irritations and other nuisance effects characteristic of active sanitizers based on halogens such as chlorine, one such nuisance affect being the deterioration of bathing suits.



This invention relates to a molecular scale device capable of destroying gram positive and gram negative bacteria as well as viruses and algae. Said molecular scale device consists of a single crystal of tetrasilver tetroxide. Several hundred thousand trillion of these devices may be employed in concert for their bactericidal, viricidal, and algicidal properties and applied to industrial cooling towers, swimming pools, hot tubs, and municipal water supplies.

The molecular crystals which are the subject of this invention are commercially available and can be prepared by reacting silver nitrate with sodium or potassium peroxydisulfate according to the following equation:

4AgNO3 + 2Na2 S2 O8 + 8NaOH = Ag4O4 + 4Na2SO4 + 4NaNO3 + 4H2O

The oxide lattice represented by the formula Ag4O4 is depicted in the Drawing FIG. 1. It is a semiconducting electron active diamagnetic crystal containing two monovalent and two trivalent silver ions in combination with four oxygen atoms. The

distance between the Ag(III)-O Ag(I)O units equals 2.1 A. Ag(III)-Ag(III) = Ag(I)-Ag(I) = 3.28A and Ag(I)-Ag(III) = 3.19 A. Each trivalent silver ion is coordinated via dsp2 electron bonds to 4 oxygen atoms. The depiction of this lattice is based on several literature references relating to crystallographic studies. Exemplary of this literature are J. A. McMillan's studies appearing in Inorganic Chemistry 13,28 (1960); Nature vol. 195 No. 4841 (1962), and Chemical Reviews 1962, 62,65. Alvin J. Salkind elucidated studies involving neutron diffraction with his coworkers (J. Ricerca Sci. 30, 1034 1960) proving the Ag(III)/Ag(I) nature of this molecule and states in his classic entitled Alkaline Storage Batteries (Wiley 1969), coauthored with S. Uno Falk, that the formula is depicted by Ag4O4 (page 156).

That same year a scientific communication appeared in Inorganic Nuclear Chemistry Letters (5,337) authored by J. Servian and H. Buenafama which maintained that their neutron diffraction studies also confirmed the tetroxide lattice and the presence cf Ag(III) and Ag(I) bonds in the lattice, a conclusion also reported previously by Naray-Szahn and Argay as a result of their x-ray diffraction studies (Acta Cryst. 1965, 19,180). Thus the effects of this invention can be explained in terms of these structural elucidations, namely, that the single molecular semiconductor crystal which inevitably must be electronically active exchanging two electrons per crystals between its mono and trivalent bonds is in reality a device which kills pathogens in the same manner as electrically active large-scale devices utilized in water supplies.

When the tetroxide crystals are utilized to destroy pathogens, they will not do so unless activated by an oxidizing agent. This is analogous to the behavior of single semiconducting photovoltaic molecular devices such as copper indium selenide whose surfaces must be "etched" in order to activate the photovoltaic activity, i.e., for light to facilitate the release of electrons from the molecule. The tetroxide was activated by persulfates [ or: hydrogen peroxide ]. It was found that when the persulfates were tested as a control by themselves, they failed to exhibit any unilateral antipathogenic activity at the optimum level selected of 10 PPM. The persulfates evaluated varied from OXONE (Registered Trademark Du Pont Company) brand potassium monopersulfate to alkali peroxydisulfates.

DESCRIPTION OF THE DRAWING

In the drawing which illustrates the best mode presently contemplated for carrying out the present invention:

FIG. 1 is a diagrammatic view showing the molecular crystal Ag4O4 attacking a pathogenic bacillus.

DESCRIPTION OF THE INVENTION

Turning now to Drawing FIG. 1 depicting the crystal lattice of Ag4O4 , the device operates by transferring electrons from the monovalent silver ions 10 to the trivalent silver ions 11 in the crystal 20 through the aqueous media in which it is immersed and which conducts electrons depicted by the path 12, contributing to the death of pathogen 13 with electrons 14, traversing the cell membrane surface 15, said pathogen being "electrocuted" by not only these electrons but by others: 16 and 17 following paths 18, and 19 emanating from other molecular devices in the vicinity of the pathogen. Drawing FIG. 1 exaggerates the size of the silver oxide molecular device with respect to that of a microorganism for depiction purposes only. The device is attracted to the cell membrane surface 15 by powerful covalent bonding forces 21 caused by the well-known affinity of silver to certain elements present in the membrane, such as sulfur and nitrogen.

The electron transfer can be depicted by the following half reactions in which the monovalent silver ion loses an electron and the trivalent silver gains one as follows:

Ag + -e = Ag+2

Ag+3 + e = Ag+2

The molecular crystal then will become stabilized with each silver ion having a divalent charge.

The molecular device was evaluated in concentrations ranging from 0.5 to 5.0 PPM on mixed gram positive and gram negative cultures and mixed coliforms for evaluation in conjunction with EPA protocols for swimming pools in the presence of 10 PPM sodium persulfate. It killed 100% of colonies of Streptococcus faecalis and E. coli within three minutes at 0.5 PPM. The EPA requirement is within ten minutes. The colony concentrations were 100,000/cc.

In order to consider the possibility that silver ions escaping the crystal device may have had an influence on the bactericidal properties of the device especially if those silver ions were of a higher valence state facilitated by the persulfate according to the reaction:

AgO + H2O = Ag+2 + 2OH-

Ag4O4 crystals were sent to an independent EPA certified testing laboratory together with sodium persulfate with specific instructions to prepare Ag4O4 suspensions in 10 PPM persulfate at various concentrations. The preparations were made in one-liter volumetric flasks utilizing 0.5 mg and other concentrations /L of Ag4O4 , where the concentration of mg. per liter equals parts per million of the oxide. After vigorous mixing of the oxide crystals in the flasks, the solutions were allowed to remain undisturbed for 24 hours. After that time period the supernatant liquid was analyzed for silver utilizing atomic absorption spectroscopy with inductively coupled plasma. At 0.5 PPM Ag4O4 there was only silver found equivalent to 0.003 PPM. This concentration is so low that even if it were speculated that the

ions were in a higher valence state, they could never even then be considered bactericidal. Indeed, the inventor's U.S. Pat. No. 5,017,295 involving divalent silver bactericides claims these compounds at the lowest silver ion concentration of 0.5 PPM.

If we are to consider one molecular device in operation, then each molecule would release two electrons having each a charge of 4.8 x 10-10 e.s.u. equivalent to approximately 1.6 x 10-19 coulombs. The EMF given in my Encyclopedia of Chemical Electrode Potentials (Plenum 1982), page 88, for the oxidation of Ag(I) to Ag(II) is 1.98 volts which approximates 2.0 V. The total power output per device can be calculated in watts by multiplying the power output for each electron by 2. Since power is the product of the potential times the charge, P = EI; for each electron it would be

2.0 x 1.6 x 10-19 = 3.2 x 10-19 watts

From this, and using Avogadro's number, we can calculate that the power flux of one liter of solution containing 0.5 PPM of devices would be 0.064 watts. Since the electronic charges of the devices are directly proportional to the number of devices in solution, i.e., the concentration of the oxide in the solution, we can arbitrarily assign our own device power flux constant which can be used to gauge the concentrations of the devices required in order to kill particular organisms in specific environments. I have found the following formula useful for this purpose:

Power Flux = EMF generated per molecule x Concentration x 5

(the EMF being 4.0 volts per molecular device times the concentration in PPM). Utilizing this formula, the power flux to effectuate 100% kills for E. coli and Streptococcus faecalis is equal to 6.0.

Tests were conducted to see whether the molecular crystals posed any harm to the human body. Accordingly, a 3% concentrate of the crystals was prepared for a series of evaluations.

The first evaluation met the requirements of Code of Federal Regulations (CFR) 40 part 160 which consisted of determining the single dose toxicity in rats or LD50. All the animals survived so that the LD50 was greater than 5.0 g./Kg. This was true for concentrations of crystals of a magnitude of 6-60,000 times the actual concentrations that would be used in its utilization. This test classified the device as a category IV substance according to EPA protocols.

The second evaluation was for acute dermal toxicity in rabbits. The protocol, 40 CFR 158.135, 81-2, was to determine the LD50 for dermal application. All animals survived the maximum dose 2.0 g/Kg., classifying the

crystals as category III with a dermal LD50 greater than 2000 mg/Kg.

The third evaluation, entitled "Primary Dermal Irritation in Albino Rabbits", conformed to 40 CFR 160. It consisted of exposing the rabbits for prolonged periods of time and observing edema, erythema, ulceration, necrosis and any other evidence of dermal reactions or tissue destruction. There were none, classifying the crystal concentrate as a category IV dermal agent by EPA criteria.

The fourth evaluation dealt with primary eye irritation. This also was in conformity with 40 CFR part 160. There was absolutely no eye irritation when the crystal concentrate was applied, classifying it as a category IV substance with regard to eye effects according to EPA criteria.

The concentrate submitted for these evaluations, i.e., the 3% suspension of crystals, represented a concentration 1.50% times as great as the end product intended for commercialization, namely, a 2% suspersion of silver oxide crystals.

The crystals were also evaluated by monitoring their performance over a period cf time at various concentrations. Periodically, water samples were taken and shipped in a refrigerated state for bacterial counts. Accordingly, the device performed in concert with its attendant devices in full conformity with the ultimate objects of this invention.


EXAMPLE 1

Tetrasilver tetroxide (Ag4O4 ) crystals were prepared by modifying the procedure described by Hammer and Kleinberg in Inorganic Syntheses (IV,12). A stock solution was prepared by dissolving 24.0 grams of potassium peroxydisulfate in distilled water and subsequently adding to this 24.0 of sodium hydroxide and then diluting the entire solution with said water to a final volume of 500 ml. Into 20 ml. vials were weighed aliquots of silver nitrate containing 1.0 g. of silver. Now 50 ml. of the aforementioned stock solution were heated in a 100 ml. beaker, and the contents of one of the vials was added to the solution upon attaining a temperature of 85.degree. C. The beaker was then maintained at 90.degree. C. for 15 minutes. The resulting deep black oxide obtained consisting of molecular crystal devices was washed and decanted four times with distilled water in order to remove impurities. The purified material was collected for further evaluation and comparison with commercial material. The commercial material was purchased from Johnson Matthey's Catalog Chemicals Division of the Aesar Group of Ward Hill, Massachusetts, under product code 11607 and generically listed in its materials Safety Data Sheet as both silver peroxide and silver suboxide, having a purity of 99.9%.

Both the prepared and commercial device crystals were submitted for bactericidal evaluation following "good laboratory practice" regulations as set forth in Federal Regulations (FIFRA and ffdca/40 CFR 160, May 2, 1984). The protocols consisted of exposures to Streptococcus faecalis, a gram positive pathogenic bacillus utilizing AOAC (15th) 1990:965:13: at colony densities of 100 000 colonies/cc. and two exposure times of five and ten minutes. The devices were tested at concentrations of 0.3, 0.5 and 1.0 PPM in distilled water adjusted to pH = 7.5 and containing Oxone (Registered Trademark Du Pont Company), which is potassium monopersulfate at a level of 10 PPM. The evaluations were repeated at the same persulfate concentration utilizing commercial grade sodium persulfate manufactured by FMC. 100% kills were actually obtained after three minutes at all the aforementioned device concentrations, there being actually zero colonies at the 0.5 and 1.0 PPM levels after five minutes and at the 0.3 PPM level after ten minutes. Analogous testing employing the same colony density of the gram negative bacillus E. coli were carried out. The same results were obtained. EPA criteria require that 100% kills be obtained within ten minutes for a substance to meet EPA criteria for swimming pool utilizatior. In this case, the devices at 0.3 PPM, equivalent to approximately 360,000 trillion devices, were able to far exceed EPA criteria for sanitizing a swimming pool.

EXAMPLE 2

Commercial grade silver oxide prepared according to the method of Example 1, but which is actually the tetrasilver tetroxide molecular devices were tested in a swimming pool under actual-use conditions. The swimming pool contained approximately 27,000 gallons of water. The level of the device crystal concentration was maintained at 1.0-1.5 PPM. The swimming pool was

periodically monitored by removing water samples for pH, silver calcium, algae and bacteria. The swimming pool was utilized on a daily basis over a period of six weeks by an average number of four people per day. The pool was made up fresh with a fresh coating of plaster. The initial pH was 9.7. By the end of the first week, the pH dropped to 8.2. Thereafter the average daily pH of the pool was 7.8. The calcium level of the pool was allowed to rise slowly from an initial 100 PPM to 220-240 PPM. Without any new additions of silver to the solution of the initial 1.5 PPM molecular crystal concentration, the pool had zero bacteria and zero algae. Other extraneous factors were also monitored, such as copper (0.1-0.2 PPM) and iron (initial .0 average .05 PPM), which did not affect the results.

EXAMPLE 3

Tests were performed on residual silver concentration of device crystals in water to see whether the devices could be used to treat municipal drinking water supplies since the devices had proven to be antipathogenic at 0.3 PPM according to Example 1. Now there is no adverse health effect for silver at the present time according to the EPA, and it has been dropped from the 1991 pollutants list according to 56 FR 1470 p.7. A secondary maximum contaminant level for drinking water involving silver was proposed in 1989 (54 FR 22062), May 22, 1989) of 0.1 PPM. The oxidizing agent to activate the crystals for water supplies would be OXONE (Registered Trademark Du Pont Company) or hydrogen peroxide. Accordingly, brand potassium monopersulfate samples of commercial oxide devices of Aesar origin as heretofore described were sent to an EPA certified laboratory for evaluation. The laboratory prepared samples of the devices at concentrations of 0.5, 1.0, 2.0, 5.0 and 10.0 PPM in 10 PPM sodium persulfate solution. The solutions were allowed to stand for 24 hours, after which the supernatant liquid was tested for residual silver content by atomic absorption spectroscopy using inductively coupled plasma as the excitation source. The respective amounts of silver found in the supernatant liquid were respectively 0.003, 0.13, 0.52 and 0.94 PPM. This means that at a concentration of nearly double the pathogenic inhibition requirement level that the secondary silver allowance of 0.1 PPM was hardly reached, which qualifies the devices for drinking water.

EXAMPLE 4

The devices were tested against AIDS virus. The protocol used was that of the Ministry of Health of the State of Israel at their Virology Laboratory located at Tel HaShomer, Israel. AIDS viruses which had been grown in vitro in a tissue culture were isolated and exposed to the devices at device concentrations of 0.05, 1.0, 2.0, 3.0, 5.0 and 10.0 PPM. There was no evidence of AIDS suppression at all until the concentrations reached 5.0 and 10.0 PPM. At 5.0 PPM, 60% of the viruses were killed. AT 10.0 PPM, 75% of the viruses were killed. Extrapolation of this data reveals that at 18.0 PPM there would be total suppression of the virus. These test results indicate that the devices are capable of being used to destroy viruses in applications involving the proliferation and transmittal of the AIDS virus outside of the human body as in cold sterilization.

EXAMPLE 5

An ATTC strain of Chorella was grown in nutrient Medium 866 broth under the required lighting. When optimal growth was reached, the number of organisms per ml. were determined by microscopic count and then subcultured. The molecular crystal devices were applied to the algae at concentrations of 1 and 2 PPM. The algae were left in contact for one hour, one day and ten days. The protocol for these tests involved procedures described in the Water and Waste Water Manual of the United States Public Health Service. The exposure tests involved post inoculation in order to determine whether the devices were algicidal or algistatic. The oxidizing agent for activation was sodium persulfate at a concentration of 10 PPM. The devices were found to be algistatic at 1 PPM and algicidal at 2 PPM after one hour's exposure. After one day and ten days, there were no positive flasks at all. Ten flasks of subculture were utilized for each test, and only one flask was positive out of ten after one hour at 1 PPM.

While there is shown and described herein certain specific examples embodying the invention, it will be manifest to those skilled in the art that various modifications and rearrangements of &he invention may be made without departing from the spirit and scope of the underlying inventive concept and that the same is not limited to the particular forms herein shown and described except insofar as indicated by the scope of the appended claims.

US Patent # 6,485,755 Methods of Using Electron Active Compounds for Managing Cancer

( US Cl. 424/618 ~ November 26, 2002 )

Marvin S. Antelman

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(I,III), Pr(III,IV), and Bi(III,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 conditions include systemic and external cancers, and may also include conditions and symptoms associated with cancer. The present invention also provides a pharmaceutical composition 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 application.


3923982 ~ Dec., 1975 ~ Lamand et al. ~ 424/140 �4447254 ~ May., 1984 ~ Hughes, et al. ~ 71/67 �4574782 ~ Mar., 1986 ~ Borrelli, et al. ~ 600/10 �4735796 ~ Apr., 1988 ~ Gordon ~ 424/9 �4828832 ~ May., 1989 ~ De Cuellar, et al. ~ 424/618 �4952411 ~ Aug., 1990 ~ Fox, Jr., et al. ~ 424/618 �5017295 ~ May., 1991 ~ Antelman ~ 210/764 �5073382 ~ Dec., 1991 ~ Antelman ~ 424/604 �5078902 ~ Jan., 1992 ~ Antelman ~ 210/764 �5089275 ~ Feb., 1992 ~ Antelman ~ 424/602 �5098582 ~ Mar., 1992 ~ Antelman ~ 210/759 �5211855 ~ May., 1993 ~ Antelman ~ 210/758 �5223149 ~ Jun., 1993 ~ Antelman ~ 210/764 �5223149 ~ Jun., 1993 ~ Antelman ~ 210/764 �5320906 ~ Jun., 1994 ~ Eley, et al. ~ 428/402 �5334588 ~ Aug., 1994 ~ Fox, Jr., et al. ~ 514/171 �5336416 ~ Aug., 1994 ~ Antelman ~ 210/764 �5336499 ~ Aug., 1994 ~ Antelman ~ 424/405 �5571520 ~ Nov., 1996 ~ Antelman ~ 424/405 �5612019 ~ Mar., 1997 ~ Gordon, et al. ~ 424/9 �5676977 ~ Oct., 1997 ~ Antelman ~ 424/618 �5772896 ~ Jun., 1998 ~ Denkewicz, Jr., et al. ~ 210/754 �5928958 ~ Jul., 1999 ~ Pilgrimm ~ 436/526

Other References �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,III) 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 Illustrated Medical Dictionary, Philadelphia: W.B. Saunders Company, 1994, 28.sup.th Edition, p. 351, 759, and 760. �Gennaro, A., Remington's Pharmaceutical Sciences, Easton, PA: Mack Publishing Company, 1985, 17.sup.th Edition, p. 1573-1575, 1585-1594, and 1601

Claims ~

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(II,III) oxide, Cu(I,III) oxide, Mn(II,III) oxide, Pr(III,IV) 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 infusion 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.

7. The method of claim 1, wherein the metal oxide compound is administered via intravenous injection or infusion 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 condition 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. A method for preventing, treating, or managing one or more cancerous conditions or dysplastic proliferations associated with a patient's skin, which method comprises administering the at least one metal oxide compound selected from the group consisting of Bi(III,V) oxide, Co(II,III) oxide, Cu(I,III) oxide, Mn(II,III) 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 sufficient 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.sup.2 of skin surface.

26. A method 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,III) oxide, Cu(I,III) oxide, Mn(III,II) oxide, Pr(III,IV) oxide, and Ag(I,III) 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 oxide compound is substantially free of added persulfate.

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

Description ~

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.


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 treatment with chemotherapeutic agents that inhibit cell division or radiation therapy that disrupts DNA in dividing cells. These treatments, however, may also adversely affect normal 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 cytotoxic 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, approximately 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 designated as scirrhus, infiltrative, papillary, ductile, medullary, and lobular, appear as a slowly growing, painless mass, 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 common 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, chemotherapy 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 indicate 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 common malignancy of the female reproductive tract, most commonly affects women aged 40 to 56 years old. The incidence is higher among women from lower socioeconomic groups and among those with a history of early and frequent coitus and multiple sexual partners. Recently, venereal transmission of human papilloma virus (hpv) 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 cervical 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 epithelium showing abnormal proliferation, however, progress to carcinoma in situ, in which a full thickness of the epithelium contains abnormal calls. When cancer cells penetrate 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 cervical 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 more than 50% through recognition and treatment of pre-invasive neoplasia. Treatment of cervical cancer typically involves conization, radiotherapy, surgical therapy, and chemotherapy.

For diagnostic and prognostic purposes, the results of 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 characterized by the presence of cells representative of or suspicious 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 IIB 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 characterized 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 disorders. "Skin cancer" is generally used to describe the three major forms of skin cancer; basal cell and squamous carcinoma 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. 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 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 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. Subcutaneous and bony deformities may also be observed. One third of the patients with neurofibromatosis are asymptomatic and the condition is discovered during routine examination. 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 diagnostic purposes, the presence of six or more of these freckle-like lesions with one larger than 1.5 cm is characteristic 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 management. In view of this discussion, there is a need for pharmaceutical 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.e., management or treatment of the cancer.

Metal oxides, such as electron active metal oxides comprising 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, III) 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 5,772,896.

U.S. 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 formulation of a gynecological cream and douche based on these 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 Proliferation of Lymphocytes: an Alternative to [.sup.3 H]-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. Lippincott 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 Cytotoxic 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 complex 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.

U.S. 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.

U.S. Pat. No. 5,676,977 discloses intravenously injected tetrasilver tetroxide crystals used for destroying the AIDS virus, AIDS synergistic pathogens, and immunity suppressing 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 descriptions 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.TM. (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 U.S. 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 summarized as follows, which is referred to as the Horsfal series:

Ag4O4 > Ag(III) > Ag(II) >>>> Ag(I)

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.


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 preferably comprises administering at least one metal oxide compound 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(II,I) oxide, Cu(I,III) oxide, Fe(II,III) oxide, Mn(II,III) oxide, Pr(III,IV) oxide, or Ag(I,III) oxide.

The metal oxide compound or derivative thereof is preferably 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 administered via intravenous injection or infusion, when the animal is a human. The intravenous injection or infusion is preferably subcutaneous, intramuscular, or comprises infusion into the bloodstream of the animal. Preferably, the administration provides an amount of the metal oxide sufficient 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 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 administering at least one metal oxide compound or a pharmaceutically 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(III,V) oxide, Co(II,III) oxide, Cu(I,III) oxide, Fe(II,III) oxide, Mn(II,III) oxide, Pr(III,IV) oxide, or Ag(I,III) oxide.


The method of the invention is preferably suitable for preventing, treating, or managing cancerous conditions or dysplastic proliferations comprising at least one of dysplastic 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 predisposition to cancer, such as neurofibromatosis.

The administering preferably comprises a carrier medium in which the at least one metal oxide compound or pharmaceutically acceptable derivative thereof, is dispersed. Preferably 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 comprises a thixotropic agent sufficient to increase adherence of the composition to the skin without excessive runoff.

The at least one metal oxide compound or pharmaceutically 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 cm.sup.2 of skin surface. A preferred embodiment of a composition 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 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(I,III) oxide, Fe(II,III) oxide, Mn(II,III) oxide, Pr(III,IV) oxide, or Ag(I,III) oxide.


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 pharmaceutically 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, provides 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 therapeutically 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. 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 compositions comprising at least one oxide compound or a pharmaceutically 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(II,III) oxide, Cu(I,III) oxide, Fe(II,III) oxide, Mn(II,III) oxide, Pr(II,IV) oxide, or Ag(I,III) oxide. Preferred compounds of the invention 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 cancers and conditions associated with cancer. The compositions of the invention include powders comprising metal oxide crystals of the invention.

The compositions and methods of the invention advantageously 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 associated 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 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 contributing 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 (Ag4O4) molecular device operates against cancer, tumors, or cells associated 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 "electrocutes" the cancer cells. The electrons are forced out of their balanced crystals by such labile groups as NH, NH2, 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 (KA) of Ag4O4 is 7.9 x 10-13. 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 membrane 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 membrane 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+ -e = Ag+2

Ag+3 +e = Ag+2

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 concentrations 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 LD.sub.50 Greater than 5,000 mg/Kg � Acute Dermal Toxicity LD.sub.50 Greater than 2,000 mg/Kg � Primary Eye Irritation Mildly irritating � Primary Skin Irritation No irritation � Skin Sensitization Non-Sensitizing

Subsequent evaluations conducted according to the invention showed that unless persons were prone to silver allergies, the

pure tetroxide compositions according to the 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 oxidizing agent. This can perhaps be explained by the stability manifested by the above-noted K.sub.A of the silver compositions. 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 compositions and methods of using the metal oxide compositions 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 undesirable 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 substantially 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 composition promote increased staining. Thus, in one embodiment, the pharmaceutical compositions preferably have an insufficient 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, 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 composition may generally be topically applied at a dosage level of from about 1 mg to 1000 mg per cm2 of skin surface, preferably about 10 mg to 500 mg per cm2 of skin surface.

A preferred carrier for topical formulations and administration 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. Preferred 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 proliferation 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 predisposition to cancer, such as, for example, neurofibromatosis are also included. The present invention preferably allows treatment 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 malignant 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 maturation 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 membranes 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.

Tumors or neoplasms include new growths of tissue in which the multiplication of cells is uncontrolled and progressive. 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 characterized 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 neoplasms 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 glandular 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 combination 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 according to the methods of the invention. Any compatible chemotherapeutic 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 conventional regimens with the benefit of reducing side effects and enhancing efficacy. These other anti-cancer chemotherapeutic agents and modalities may be administered either concurrently or sequentially with the metal oxide compositions 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:

4AgNO3 +2K2 S2O8 + 8NaOH{character pullout}Ag4O4 + 3Na2SO4 + 2NaNO3 + 2KNO3 30 4H2O

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 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 vaginal 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 administered 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 necessary 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 physician 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 invention 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 administration 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 adhesion 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 conditions associated with the skin, the compositions preferably prevent, treat, or manage such conditions or diseases without visibly staining the skin, i.e., 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 composition comprises about 3% metal oxide, such as tetrasilver tetroxide, about 47% white petrolatum, about 36% heavy mineral oil, and about 14% TIVAWAX P Tivian Laboratories 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 injection (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 administration 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 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 carrier 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 contains 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. # 3,845,770; U.S. Pat. # 3,916,899; U.S. Pat. # 3,536,809; U.S. Pat. # 3,598,123; U.S. Pat. # 4,008,719; U.S. Pat. # 5,674,533; U.S. Pat. # 5,059,595; U.S. Pat. # 5,591,767; U.S. Pat. # 5,120,548; U.S. Pat. # 5,073,543; U.S. Pat. # 5,639,476; U.S. Pat. # 5,354,556; and U.S. Pat. # 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 medical treatment is characterized by a minimum of drug substance 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 initially 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 conditions 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 derivatives 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 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 diagnosed as having breast cancer. The subjects had the following 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 carcinoma.

A 1 cm 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 histologic 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 performed: a complete blood count, hemoglobin, hematocracity, vcm, vhcm, complete red blood cells, complete white blood cells, albumin, bilirubin, calcium, and cholesterol, creatine, glucose, ldh, 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 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 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 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 IV 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 magnesium 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 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 mammary 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 carcinoma 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 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 containing 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 cm. 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 containing 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 29th 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 confirmed 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 Rhabdomyosarcoma with extreme infection. Each patient exhibited ulcerative injuries at the inferior member with an extension of 9 cm to 12 cm in diameter. The ulcers exhibited serosanguinous 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 II: Group II was formed of five patients with confirmed biopsy diagnosis of ulcerative Rhabdomyosarcoma 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 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.sup.th day revealed normal muscular tissue with no signs of metaplasia. At the 40.sup.th 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.sup.th 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 neurofibromatosis. 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 clinical 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 plexiform 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 reoccurrences 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.

Conclusions of Neurofibromatosis Study

Tetrasilver tetroxide ointment seems to have had a positive 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:

0 = 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 companies 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 diagnoses 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, i.e., having high grade squamous intraepithelial lesions including moderate 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, i.e., 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 1.2.times.1.5 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 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 recurrences 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

A study 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 IIIA. Two patients exhibited a depth of invasion ranging 0.51 mm to 2.25 mm and were designated group IIIB. 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 designated Group IVA. The remaining patients, Group IVB, exhibited a depth of invasion ranging from minor to 0.76 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 malignant 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 epidermis.

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, i.e., 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 melanocytes.

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 minimum 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 condition 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 acrolentiginous 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 heating 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

A male 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 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 composition 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 tetroxide 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 injuries 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. Biopsies 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.

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 possible. 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. Observations 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 evaluated 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 fifteenth 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 leukemia 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% CO2 in air 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:

IC50 (50% Inhibition Concentration) = 2.2 ppm

TGI (Total Growth Inhibition) = 4.6 ppm

LC50 (50% Lethal Concentration) = 6.0 ppm

The above methodology was applied to a human malignant melanoma cell line of source ATCCHTB-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:

IC50 (50% Inhibition Concentration) = 3.7 ppm

TGI (Total Growth Inhibition) = 4.9 ppm

LC50 (50% Lethal Concentration) = 6.5 ppm

The a IC50 (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.

TABLE 1.1 � Estimated IC.sub.50, TGI and LC.sub.50 � Assay Name .sup.a IC.sub.50 .sup.b TGI .sup.c LC.sub.50 � Theor, Breast, T47D 1.1 ppm 1.6 ppm 2.6 ppm � Tumor, Breast, MCF-7 3.0 ppm 3.9 ppm 5.0 ppm � Tumor. Colon. DLD-i 2.5 ppm 3.0 ppm 3.6 ppm � Tumor, Prostate PC-3 7.7 ppm 14 ppm 25 ppm � Tumor, Kidney, A498 1.8 ppm 2.4 ppm 3.1 ppm � Tumor Pancreas MIA 2.0 ppm 4.0 ppm 8.1 ppm � PaCa2 � Tumor, Leukemia, 2.1 ppm 3.1 ppm 4.6 ppm � HL-60 � Tumor Pancreas 4.8 ppm 6.4 ppm 8.6 ppm � PANC-i � Tumor. Liver. HeDG2 2.6 ppm 3.5 ppm 4.7 ppm � Tumor, Stomach 3.2 ppm 3.6 ppm 4.1 ppm � KATO III � Tumor, Lung A549 4.8 ppm 5.8 ppm 7.0 ppm � Tumor, Lung, pc-6 0.9 ppm 1.0 ppm 1.1 ppm � Tumor, Lymphoma, 0.79 ppm 1.3 ppm 3.8 ppm � H33HJ-.JA1 � Tumor, Lymphoma, 1.3 ppm 2.2 ppm 3.6 ppm � U937

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.

US Patent # 6,258,385

Tetrasilver Tetroxide Treatment for Skin Conditions

( US Cl. 424/618 ~ July 10, 2001 )

Marvin S. Antelman

Abstract ~

The invention relates to the use of electron active molecular crystals comprising tetrasilver tetroxide (Ag.sub.4 O.sub.4) for the treatment and cure of dermatological skin conditions (diseases) ranging from dermatitis, acne and psoiasis to herpes and skin ulcers.

US Patent # 5,571,520 Molecular Crystal Redox Device for Pharmaceuticals

( November 5, 1996 ~ Cl. 424/618 )

Marvin S. Antelman

Abstract ~

The employment of molecular crystals as bactericidal, viricidal and algicidal devices, and specifically the molecular semiconductor crystal tetrasilver tetroxide Ag4O4 which has two trivalent and two monovalent silver atoms per molecule, and which through this structural configuration generates electronic activity on a molecular scale capable of killing algae and bacteria via the same mechanism as macroscale electron generators.

US Patent # 5,098,582 Divalent Silver Oxide Bactericides

March 24, 1992 ~ Cl. 210/759

Marvin S. Antelman

Abstract ~ Divalent silver oxide provides a source for divalent bactericidal silver ions in the presence of persulfate. This oxide is especially effective when applied to water used in industrial cooling towers, hot tubs and swimming pools and conforms to stringent EPA requirements of 100% kills of 100K/cc Streptococcus faecalis within 10 minutes. The oxide also can be used in water with exceptionally high salt content without halide curdy precipitate formation and will not stain the skin of users who may inadvertently be exposed to it.

US Patent # 5,089,275 Stabilized Divalent Silver Bactericides

February 18, 1992 ~ Cl. 424/602

Marvin S. Antelman

Abstract ~ Solid bactericidal compositions are disclosed based on divalent silver (Ag(II)) as the active sanitized agent. The compositions are prepared by reacting acid liquid Ag(II) complexes with anhydrous calcium sulfate so as to form a solid matrix in which the bactericide is entrapped in the resulting hydrated calcium sulfate. Optimum compositions are described consisting of Ag(II) phosphate dissolved in phosphoric acid where the ratio of solid (by weight) to liquid (by volume) is 5:2. The resulting solid bactericides can be used in water cooling installations. They are capable of causing 100% kills within 10 minutes of E. Coli conforms in conformity with EPA protocols, allowing them to quality as swimming pool and hot tub sanitizers. Since the compositions are based on calcium sulfate, they are also suitable as mineralizers, thus providing a dual function.

US Patent # 5,078,902 Divalent Silver Halide Bactericide

January 7, 1992 ~ Cl. 210/764

Marvin S. Antelman

Abstract ~ Divalent silver halides provide a source for divalent bactericidal silver ions in the presence of persulfate. The halides are especially effective when applied to water used in industrial cooling installations, hot tubs and swimming pools and will conform to stringent EPA requirements for waters utilized for bathing as in tubs and pools of 100% kills of 100 K/cc E. Coli coliforms within 10 minutes, exemplary of which are the chloride and bromide which give 100% kills within 5 minutes. The halides, of course, can be used in salty water since they are solids immune from halide action that would otherwise precipitate soluble divalent silver from solution.

US Patent # 5,073,382 Divalent Silver Alkaline Bactericide Compositions

December 17, 1991 ~ Cl. 424/604

Marvin S. Antelman

Abstract ~ Solid alkaline bactericidal compositions are disclosed suitable for compounding alkaline end products such as food and dairy cleaners and surgical scrubbing soaps, formed by the neutralization of acid stabilized inorganic divalent silver complexes and capable of effecting 100% kills upon cultures of anaerobic bacteria colonies of 100K/cc. within 5 minutes.

Inorganic Syntheses IV: 12 (Chapter 1B, # 3) ~

Silver (II) Oxide

by Robert Hammer & Jacob Kleiberg

Silver (II) oxide has been made by the hydrolytic action of boiling water on a substance of the approximate formula Ag7O8NO3, a material which obtained by the electrolytic oxidation of silver (I) nitrate solutions (Ref. 1-4). A more rapid and convenient process for the preparation of this oxide involves the oxidation of silver (I) nitrate by means of potassium peroxydisulfate ("Oxone") in an alkaline medium (Ref. 5, 6).

Procedure ~

72 grams of sodium hydroxide (NaOH, 1.8 mols) in pellet form is added portionwise, with constant stirring, to 1 liter of water, which is maintained at approximately 85°. Seventy-five (75) grams of potassium peroxydisulfate (0.28 mols) in the form of an aqueous slurry is added to the hot alkaline solution; this is followed by the addition of 51 gr of silver (I) nitrate (0.30 mol) dissolved in a minimum amount of water. The temperature of the resulting mixture is raised to 90°, and stirring is continued for approximately 15 minutes.

The precipitate of black silver (II) oxide is filtered on a large Buchner funnel, and sulfate ion is removed by washing with water which has been made slightly alkaline with sodium hydroxide. The product is air-dried. Yield, 35 gr (94%).

Analysis: Calculated for AgO: Ag, 87.08%. Found: Ag, 86.93%, 86.90% (by gravimetric chloride method, after dissolution of the product in 3N nitric acid).

Properties ~

There are many indications that AgO is a true oxide, rather than a peroxide, and is, therefore, properly named silver (II) oxide. The compound does not give free hydrogen peroxide when acidified but behaves in a manner more characteristic of a compound in which the metal ion is present in a strongly oxidized valence state, which may be stabilized by coordination. In dilute acid, oxygen is immediately evolved; in concentrated acid, intensely colored solutions are formed (brown in nitric acid and olive green in sulfuric acid). These latter solutions are relatively stable, though they gradually decompose with an accompanying liberation of oxygen, and have been show to possess paramagnetism which is quantitatively consistent with the expected magnetic moment of the postulated silver (II) species (Ref. 7). In the solid state, this oxide is stable when heated to 100°, but it decomposes at higher temperatures. The solid possesses semiconductor properties and is diamagnetic. These phenomena have been explained by Neiding and Kazarnovskii (Ref. 7) on the assumption that the silver is actually trivalent in its crystal lattice with both O-Ag and Ag-Ag bonds. The difference in the specific volumes of AgO and Ag2O is less than would be expected if AgO were a peroxide (Ref 7). Equilibrium of silver (II) oxide with dilute nitric acid gives the black paramagnetic oxynitrate (Ag7O8NO3), a substance in which part of the silver is apparently in the tripositive state.

References ~

1. Mulder: Rec. Trav. Chim. 17: 129 (1898) �2. Watson: J. Chem. Soc. 89: 578 (1906) �3. Jirsa: Zeit. Anorg. u. Allgem. Chem. 148: 130 (1925) �4. Noyes, et al.: J. Amer. Chem. Soc. 59: 1326 (1937) �5. Barbieri: Chem. Berichte 60: 2427 (1927) �6. British Patent # 579,817; Chem. Abstr. 41: 1401h (1947) �7. Chem. Abstr. 45: 8385h (1951)