# Patent

## Title
Method of supplementing the diet and ameliorating oxidative stress

## Abstract

A method of supplementing a diet and ameliorating oxidative stress in a mammal includes administering a pharmaceutically effective amount of an active compound having the chemical structure:




    
    
        where n=1-4 and X is selected from the group consisting of hydrogen, lithium sodium, potassium, rubidium, cesium and francium.

## Background
This document is a divisional application of U.S. patent application Ser. No. 14/583,892, filed Dec. 29, 2014, which is a continuation of U.S. patent application Ser. No. 12/630,259 filed on Dec. 3, 2009, which claims the benefit of U.S. Provisional Patent Application Ser. No. 61/201,060 filed on Dec. 6, 2008, the full disclosures of which are incorporated herein by reference.


TECHNICAL FIELD
The present invention relates generally to the field of dietary supplements for mammals and, more particularly, to methods of supplementing a diet, removing heavy metals and other toxins and ameliorating oxidative stress.
BACKGROUND OF THE INVENTION
Heavy metals such as mercury, lead, cadmium and silver can bind to proteins on the proteins' incorporated cysteine residues which contain sulfhydryl or —SH groups. This abnormally inhibits or activates their biological properties. Further, a heavy metal binding specific proteins can induce damage that leads to overproduction or leakage of reactive oxygen species (ROSs) from their normal locations. These ROSs, mostly produced in the mitochondria of the cells of the body, then react with protein, nucleic acid (DNA, RNA) and lipid molecules in the healthy cell changing their property/chemistry and leading to unhealthy cells that may die or at least be unable to defend themselves from other stress factors such as viral infection. In addition to heavy metals there are many other chemical toxicants that can induce oxidative stress including, for example, radiation toxicity, acetominophin and dioxin. Further, it is well known that the oxidation of reduced glutathione (GSH) to oxidized glutathione (G-S-S-G) is one of the first biochemical signals for apoptotic cell death (or programmed cell death). The inadvertent oxidation of GSH by toxin produced ROSs could lead to increased GSSG and cell death also.
In order to medically prevent or reduce the problem, heavy metals must be excreted by natural means or complexed by medically based chelator compounds that render them biologically unavailable to elicit their toxic effects. To effect this removal and tightly bind the heavy metals, the treating compound must be able to effectively remove the metal from the single sulfur residue and bind it more tightly than is capable with only one sulfur to metal bond. That is, the compound must make more than one sulfur to metal bond to be able to prevent subsequent reaction or exchange of the complexed metal with other biomolecules. Additionally, the ideal chelating compound must have degrees of freedom of rotation of the sulfur bonds to be able to bind different heavy metals that have different coordination chemistries (e.g. different bond angles that confer tighter bonding). For example, Hg2+ and Pb2+ both can form two bonds with —SH groups, but the most stable binding of each metal would have different bond angles.
To be effective at treating both intracellular heavy metal toxicity and radiation toxicity as well as oxidative stress associated therewith, the treating compound has to be able to cross the cellular membrane with efficiency and, if the brain is involved, the treating compound must be able to cross the blood brain barrier. In order to be able to do this the compound has to be quite hydrophobic in nature in order to be able to pass through the lipid bilayer of the cell membrane to reach the site of heavy metal binding and intercept the ROS produced by the mitochondria before they react and damage cellular constituents. Further, the ideal treating compound must be of very low toxicity to cells and not disrupt membranes or biological pathways. In addition, the treating compound must be efficiently excreted from all tissues of the body in a non-toxic form. For example, if the treating compound binds mercury cation (Hg2+) it must carry this metal ion out of the body and not distribute it to other organs such as the kidney.
The ideal treatment compound must also exhibit stability to air oxidation and breakdown so that the treating compound can be effectively stored and packaged for delivery to the patient in original, active form. The treating compound ideally must also be suited for ease of administration to a patient. Further, the treating compound must not deplete the body of essential metals such as zinc and copper. In addition, it should also have an adequately long plasma half-life such that it is possible to take eight hours rest and not have the treating compound significantly depleted from the plasma and tissues.
The present invention relates to methods of supplementing the diet of a mammal, removing heavy metals and other toxins from a mammal and ameliorating undesirable oxidative stress in a mammal.
SUMMARY OF THE INVENTION
In accordance with the purposes of the present invention as described herein, a method of supplementing a diet of a mammal is provided. That method comprises: administering to said mammal a pharmaceutically effective amount of a compound having a chemical formula:




where n=1-4 and X is selected from the group consisting of hydrogen, lithium sodium, potassium, rubidium, cesium and francium.
In accordance with yet another aspect of the present invention, a method to remove heavy metals and toxins from a mammal comprises: administering to said mammal a pharmaceutically effective amount of a compound having a chemical formula:




where n=1-4 and X is selected from the group consisting of hydrogen, lithium sodium, potassium, rubidium, cesium and francium.
In accordance with yet another aspect of the present invention a method is provided for relieving oxidative stress in a mammal. That method comprises: administering to said mammal a pharmaceutically effective amount of a compound having a chemical formula:




where n=1-4 and X is selected from the group consisting of hydrogen, lithium sodium, potassium, rubidium, cesium and francium.
In the following description there is shown and described several different embodiments of the invention, simply by way of illustration of some of the modes best suited to carry out the invention. As it will be realized, the invention is capable of other different embodiments and its several details are capable of modification in various, obvious aspects all without departing from the invention.


DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION
The present invention relates to various methods of supplementing the diet of a mammal, removing heavy metals and other toxins from a mammal and relieving or ameliorating oxidative stress in a mammal. Each of the methods relies upon administering to said mammal a pharmaceutically effective amount of a compound having a chemical formula:




where n=1-4 and X is selected from the group consisting of hydrogen, lithium sodium, potassium, rubidium, cesium and francium. The active compounds and their synthesis are described in detail in issued U.S. Pat. No. 6,586,600 to Atwood et al, the full disclosure of which is incorporated herein by reference.
While U.S. Pat. No. 6,586,600 discloses use of the compounds in question for removing heavy metals from the environment such as the natural water supply, it provides no teaching or suggestion that the compounds could be utilized in mammals as a dietary supplement, to ameliorate oxidative stress, to raise in vivo glutathione levels or to treat heavy metal or other toxicity. In fact, the compounds in U.S. Pat. No. 6,586,600 were mostly ineffective at treating environmental contaminations of heavy metal due to their insolubility in water and many organic solvents. The conventional wisdom is that any metal chelator has to be water soluble to be effective is evidenced by the currently known chelators such as dimercapopropane sulfonate (DMPS), dimercaptosuccinic acid (DMSA), ethylenediaminetetraacetic acid (EDTA) and even the natural mammalian heavy metal chelator glutathione. These observations made the use of the compounds questionable for any mammalian based treatment regarding the removal of charged toxic metals like Hg2+, Pb2+, and Cd2+ which are water soluble and would most likely be located in the aqueous aspects of mammalian tissues. Additionally, any compound that is not water soluble nor soluble in most organic solvents would not be expected to pass the intestinal endothelial membrane barrier and enter the blood and tissues of the mammal. Further, the compound(s) would have to cross the cell membrane to be able to interact with and bind the intracellular located heavy metal responsible for the toxic effects. It would also have to be able to cross the blood brain barrier to be effective for any neurotoxic heavy metal effect. Then the excretion of the chelator-metal complex and the resulting toxicity of this complex would have to be effective and not cause any toxic effects. The disclosure in U.S. Pat. No. 6,586,600 suggests none of these desired performance parameters.
The pharmaceutically effective amount of the compounds in question may be administered in any appropriate manner including, but not limited to, oral administration, transdermal administration, nasal administration, intravenous administration and administration by suppository. The method of supplementing a diet of a mammal includes administering between about 0.5 and about 40.0 mg of the compound per kilogram of the mammal's total body weight per day although, due to the lack of toxicity higher dose levels are acceptable. The compound may be administered in combination with another antioxidant or chelator. That antioxidant may be selected from a group including but not limited to vitamin-E, vitamin-D, cysteine, cysteine, glutathione, lipoic acid and combinations thereof. In one particularly useful embodiment the compound has the chemical formula




In the method of removing heavy metals and other toxins from a mammal, the compound is administered in an amount between about 0.5 and about 60.0 mg per kilogram of the mammal's total body weight per day. In this method the compound may be administered with a water soluble metal chelator. That water soluble metal chelator may be selected from a group consisting of glutathione (GSH), dihydrolipoic acid (DLPA), lipoic acid (LPA), N-acetylcysteine (NAC), dimercaptopropane sulfonate (DMPS), dimercaptosuccinic acid (DMSA), ethylenediaminetetraacetic acid (EDTA), and mixtures thereof. It should be appreciated, however, that other water soluble metal chelators besides those listed could be utilized.
In the method of relieving oxidative stress in a mammal the compound may be administered orally, transdermally, nasally, intravenously, by suppository and other appropriate. Typically the compound is administered in an amount of between about 0.5 and about 100.0 mg of the compound per kilogram of the mammal's total body weight per day. The exceptionally low level of mammalian toxicity would also allow higher doses to be used in cases of acute toxicity or high oxidative stress. Here, it should also be noted that the present method may be used to treat oxidative stress resulting from virtually any cause or source including, but not limited to, heavy metal toxicity, drugs such as acetaminophen, xenobiotics, aging, infection, physical injury and disease.
These compounds are not used to directly produce intracellular glutathione and work primarily by salvaging naturally produced reduced glutathione (GSH) by the process of scavenging the intracellular ROSs preventing the oxidation to oxidized glutathione (GSSG). Also, the inhibitory binding of Hg2+ and Pb2+ and their removal from enzyme involved in the synthesis (e.g. glutamine synthetase) and recovery of GSH (e.g. glutathione reductase) would additionally aid in the recovery of GSH to optimal levels. In accordance with an additional aspect of the present invention the compound may be administered with a precursor of glutathione. That glutathione precursor may be selected from a group of precursors consisting of cysteine, glycine, glutamate and combinations thereof.
In yet another possible embodiment the compound is administered with a dietary supplement that supports glutathione synthesis. Such dietary supplements include, but are not limited to, whey protein, N-acetylcysteine, cysteine, glutathione, nicotine adenine dinucleotide (NAD+), reduced nicotine adenine dinucleotide (NADH), glycylcysteine (gly-cyc), glutamylcysteine (glu-cys), and combinations thereof. In one particularly useful embodiment the compound used for relieving oxidative stress has the chemical formula




The compounds used in the present invention provide a number of unique benefits that make them attractive for use in methods of (a) supplementing the diet, (b) removing heavy metals and other toxins and (c) ameliorating oxidative stress in mammals. The compounds, and particularly, the compound




known as N,N′-bis(2-mercaptoethyl)isophthalamide or OSR, exhibit very low if any toxicity and do not adversely affect commonly used blood/urine tests commonly used to measure human health.

More specifically, OSR is without toxicity when administered in test animals at levels up to 5,000 mg per day. In fact, OSR is so non-toxic that an LD-50 could not be identified and was established as greater than 5 grams per kilogram body weight.
Advantageously OSR is lipid soluble and, accordingly, after entering the plasma can enter cells of all tissues, cross the blood brain barrier and enter the bone marrow. This is important because the damage caused by heavy metals and the oxidative stress produced by hydroxyl free radicals and other free radicals of the reactive oxygen species mostly occur in the intracellular space. In contrast, most dietary antioxidants are water soluble and cannot enter into cells effectively nor can they cross the blood/brain barrier.
As a further advantage, the lipid solubility of OSR increases the time it spends in the body allowing it to be more effective at chelating heavy metals and scavenging hydroxyl free radicals. The half-life of OSR in plasma of test animals was about six to seven hours whereas most water soluble antioxidants and chelators, such as resveratrol, DMPS, DMSA, and glutathione have a half-life of less than one to two hours as they are rapidly cleared by the kidneys or liver as they do not enter the cells and remain in the plasma.
It should also be appreciated that OSR is a pure compound that is not used as a substrate in any synthetic biochemical pathway of mammals. As such it does not disrupt any biochemical process. It simply partitions into the hydrophobic areas, binds heavy metals, reacts with free radicals eliminating them and is then excreted from the body primarily through the biliary transport system of the liver. It is also important to note that the two component parts of OSR consists of naturally, non-toxic, occurring benzoates and a catabolic product of cysteine metabolism that are combined to produce a product that has very low if any toxicity.
As should be appreciated from the following table, OSR has an exceptionally high ORAC (oxygen-radical-absorbance-capacity) score.













Compound
Score (μmoleTE/100 g)


















OSR#1
192,400



Acai
18,500



Dark Chocolate
13,120



Pomegranates
3,307



Blueberries
2,400



Garlic
1,939



Cranberries
1,750



Spinach
1,260



Broccoli Florets
890



Kiwi Fruit
610









The ORAC score is measured by a compound or elixer's ability to intercept reactive oxygen species, free radicals preventing them from oxidizing a water soluble fluorescent vitamin-E derivative. OSR has the ability in the body to protect vitamin-E (a fat soluble vitamin) and other fat soluble natural compounds such as lipids from damage by oxidizing free radicals since it partitions into the hydrophobic areas where they exist and reacts with free radicals more effectively than they do, thereby scavenging the hydroxyl free radicals and preventing them from doing damage. Significantly, vitamin-E has been recommended for Alzheimer's diseased subjects to prevent oxidizing damage to their brain membranes or membrane lipids due to vitamin-E's reactivity with hydroxyl free radicals. OSR is more capable of reacting with these radicals than vitamin-E and, accordingly, OSR should provide even better protection. In fact, OSR should salvage vitamin E and D in vivo.
Additionally, it is significant to note that when OSR is taken regularly, it does significantly increase the reduced (GSH) over oxidized (GSSG) glutathione ratio and increases total glutathione in the whole blood. Thus, more glutathione is available to scavenge free radicals and participate in the P-450 system to remove insoluble organic toxins from the membranes and cells. Thus, the body is better able to maintain a healthy glutathione level when the diet of the mammal is supplemented with OSR or other compounds of the present invention.
OSR has also been shown to bind injected mercury from mercury chloride and render this mercury non-toxic. Rats injected with 1-5 levels (or higher) of lethal doses of mercury chloride were protected from death by a single 10-fold excess above the mercury level of OSR dissolved in DMSO.
Rats given a 0.6 lethal dose of mercury chloride were protected from mercury induced toxic effects (blood in urine and feces, death, weight loss, ataxia) when given a 10-fold excess of OSR twenty-thirty minutes later. After five days, the mercury levels of many organs known to be mercury sensitive was measured. A toxic level of mercury still existed in the OSR treated rats but no toxic effects could be detected whereas the rats not given OSR showed these toxic effects. The OSR bound mercury was shown to be primarily excreted through the fecal route at a rate consistent with the P-450 system being involved.
OSR also has excellent stability when stored in sealed plastic test tubes with less than three percent breakdown occurring at sixteen months of storage at room temperature. Most antioxidants break down very rapidly when exposed to air or water but OSR is exceptional in this regards.
OSR also has only a very low odor level, much lower than most other sulfhydryl containing dietary compounds. Advantageously, this characteristic makes OSR more palatable for oral administration.
OSR also has an exceptionally high affinity for mercury, lead, arsenic and cadmium. Although OSR has good affinitive for the essential elements of copper, iron and zinc it seems as if the respective binding proteins of the body bind them tighter and treatment with OSR does not result in a significant lowering of these essential elements. Also, copper and zinc are primarily found in a water environment (hydrophilic aspects) of the body whereas OSR partitions into the hydrophobic aspects. This separation may play a role in the lack of OSR removing copper and zinc. However, in diseases with excess free copper, iron or zinc, OSR is likely to be able to bind and decrease the toxicity of these metals.
A kinetic study of OSR shows that it crosses the blood brain barrier, enters the intercellular space of all tissues tested which places OSR in the vicinity of the mitochondria and the cytoplasm. The mitochondria, especially if abnormal or damaged by heavy metals or radiation, are the main producers of the free radicals that cause cellular damage to the membranes, proteins or nucleic acids (DNA, RNA). Therefore, OSR is positioned to intercept these free radicals before they do damage and the ORAC scores show us OSR is exceptional at scavenging these toxic chemicals. Thus, OSR operates as an antioxidant in a more efficient and effective level than antioxidants generally known in the art.
It should also be appreciated that OSR is cleared from all tissues tested by over 90% twenty-four hours after ingestion. Therefore, no toxic build-up of OSR occurs in the mammal.
OSR also has a reactive site available for oxidation by the P-450 enzymes which allow OSR to be oxidized and modified as a sulfated, glycosylated or glutathione modified derivative by natural processes.
At the same time, OSR is better than glutathione delivered by IV or transdermally for increasing the intracellular level of glutathione. The rational behind this is based on the very low level of glutathione found in the plasma versus the intracellular levels which are 1,000 to 10,000 times higher. Any glutathione molecule that enters the blood by IV or transdermal delivery would be immediately bound and removed by the glutathione receptors in the liver that take glutathione labeled toxins out of the plasma and place them in the bile (biliary transport system). Glutathione in the blood would not remain long enough to enter cells where it could be used, plus it would have to enter in the face of a significant concentration gradient that would prevent this. This statement is based on the fact that many water insoluble toxicants are removed from the body by first oxidizing them, attaching glutathione (by the enzyme glutathione-s-transferase) to this oxidized site on the toxin, then actively transporting the glutathione labeled toxicant out of the cell and into the blood where it is removed by the glutathione receptors of the biliary transport system. In contrast, OSR enters all cells and due to its hydrophobic nature, inserts in some degree into the lipid membrane or other hydrophobic sites where it can scavenge hydroxyl free radicals, the major chemical species that oxidize glutathione and cause its levels to drop. OSR salvages naturally produced glutathione intracellularly enhancing its longevity and raising glutathione levels in vivo without having to battle transport across a membrane against a high gradient of glutathione.
Pharmaceutical compositions of the present invention may be prepared by combining a pharmaceutical effective amount of a compound having a chemical formula




where n=1-4 and X is selected from the group consisting of hydrogen, lithium sodium, potassium, rubidium, cesium and francium, with an excipient. Substantially any suitable excipient may be utilized including but not limited to albumin, almond oil, ascorbic acid, benzoic acid, calcium stearate, canola oil, calcium carboxymethylcellulose, sodium carboxymethylcellulose, castor oil, hydrogenated castor oil, microcrystalline cellulose, corn oil, cotton seed oil, cyclodextrins, ethylene glycol palmitostearate, gelatin, glycerin, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, lanolin, linoleic acid, magnesium silicate, magnesium stearate, medium-chain triglycerides, mineral oil, olive oil, peanut oil, pectin, compressible sugar, sunflower oil, hydrogenated vegetable oil and water. In order to provide multiple antioxidant potential, the pharmaceutical compositions may further include other antioxidants including, but not limited to vitamin-E, vitamin-D, cysteine, glutathione, lipoic acid and combinations thereof. Further the pharmaceutical compositions may include a water soluble metal chelator to enhance removal of toxic metals both through the liver and kidney and with an enhanced rate. Substantially, any suitable water soluble metal chelator may be utilized including but not limited to glutathione (GSH), dihydrolipoic acid (DLPA), lipoic acid (LPA), N-acetylcysteine (NAC), dimercaptopropane sulfonate (DMPS), dimercaptosuccinic acid (DMSA), ethylenediaminetetraacetic acid (EDTA), and mixtures thereof. Further, in order to further enhance the levels of glutathione in the subject, the pharmaceutical compositions may include a precursor of glutathione which may be selected from a group including but not limited to cysteine, glycine, glutamate and combinations thereof. Further pharmaceutical compositions may include a dietary supplement that supports glutathione synthesis. Substantially any appropriate dietary supplement that supports glutathione synthesis may be utilized including but not limited to whey protein, N-acetylcysteine, cysteine, glutathione, nicotine adenine dinucleotide (NAD+), reduced nicotine adenine dinucleotide (NADH), glycylcysteine (gly-cys), glutamylcysteine (glu-cyc), and combinations thereof. Pharmaceutical compositions may also include various binders, preservatives, mineral supplements, bulking agents, diluents, carriers, flavoring agents that are widely known to be used in pharmaceutical compositions. Exemplary pharmaceutical compositions include between about 95.5 and about 85 weight percent active compound, between about 0.5 and about 15 weight percent excipient. The optional additional antioxidant(s) may be provided at between about 0 and about 50 weight percent. The optional additional water soluble metal chelator may be provided at between about 0 and about 20 weight percent. The optional additional precursor of glutathione may be provided at between about 0 and about 50 weight percent. Further the optionally additional dietary supplement that supports glutathione synthesis may be provided at between about 0 and about 50 weight percent. One or more of any of the optional additives may be included. The optional additive replaces a like percentage of the compound in the final composition.

Preferred dosage forms for oral administration include the isolated compounds in powder form. Such powders may be taken up with a swoop and spread onto food or mixed into drinks for easy consumption without bad taste. The pure compounds may be pre-mixed with certain dietary ingredients such as butter, olive oil, corn oil, albumin, whey or other foods which will help in absorption of the compounds by the mere process of dissolving them. Using OSR dissolved in corn oil, it was determined that it takes two hours post ingestion for the maximum level of OSR to show up in the plasma of all tested animals. Further, after 24 hours post-ingestion the OSR levels were shown to drop between 4-12% of the peak values seen at hour 2.
Some of the commercially available solubilizers that can be used for parenteral (injectable), oral, topical or intranasal delivery in different combinations and ratios according to need include: (a) co-solvents such as polyethylene glycol 300/400, Macrogol 300/400, Lutrol E300/E400, propylene glycol, Soluphor P and NMP; (b) PEG derivatives such as Cremophor RH40, Cremophor EL/ELP and Solutol HS-15; and (c) polyoxamers such as Lutrol F68, Lutrol F127, Lutrol Micro 68 and Lutrol Micro 127.
The pure compound may be encapsulated in several weight forms (e.g. 50, 100, 200, 500 mg/capsule) and taken orally. The pure compound may be mixed with excipients (e.g. microcrystalline cellulose, hypermellose, magnesium stearate) to provide a mixed material that can be efficiently encapsulated by machines for mass production at a rapid rate.
The pure compound may also be made into tablet form by mixing with common agents or binders used to induce adhesive properties for tablet formation.
OSR and any of the other hydrophobic compounds may be dissolved in simple oils and applied to the skin. The compounds dissolved in DMSO (dimethylsulfoxide) are rapidly taken up through the skin without local irritation.
OSR and the other compounds may be placed in suppository capsules either in powder form or dissolved in oils or as mixed with protein based material (e.g. human serum albumin) for delivery. OSR and the other compounds may also be dissolved in human serum albumin for intravenous delivery. Similarly, blood could be pulled from a patient and OSR or other compounds added to that blood before being returned to the patient.
The compositions and methods of the present invention may be accomplished by various means which are illustrated in the examples below. These examples are intended to be illustrative only as numerous modifications and variations will be apparent to those skilled in the art.
Example 1
In this example, 3.14 grams of 2-aminoethanethiol hydrochloride was dissolved in chloroform, and 3.88 ml of triethylamine were added. 2.81 grams of isophthaloyl chloride was then dissolved in chloroform under nitrogen. 2-aminoethanethiol hydrochloride and 1,3-isophthaloyl chloride, prepared as described supra, were then slowly mixed, and the resulting solution was stirred under nitrogen in an ice bath for several hours. The resulting solution was then filtered under nitrogen, and several water/chloroform extractions performed. Following removal of excess solvent by rotary evaporation or distillation, the resulting product was passed through a silica gel column using ethyl acetate/chloroform. Excess solvent was removed by rotary evaporation and vacuum-drying, resulting in a white precipitate. The resulting 1,3 benzene-thiol product had the formula:




where R is an alkyl thio chain containing two methyl groups coupled through the carboxyl by an amide linkage.

Example 2
In this example, 2.76 grams of aminomethanethiol hydrochloride are dissolved in chloroform, and 7.72 ml of triethylamine are added. 2.81 grams of isophthaloyl chloride are then dissolved in chloroform under nitrogen. Aminomethanethiol hydrochloride and isophthaloyl chloride, prepared as described supra, are then slowly mixed, and the resulting solution is stirred under nitrogen in an ice bath for several hours. The resulting solution is then filtered under nitrogen, and several water/chloroform extractions are performed. Excess solvent is removed by rotary evaporation or distillation, and the resulting product is passed through a silica gel column using ethyl acetate/chloroform. Excess solvent is removed by rotary evaporation and vacuum-drying, resulting in a white precipitate. The resulting 1,3 benzene-thiol product has the formula:




where R is an alkyl thiol chain containing one methyl group coupled through the carboxyl by an amide linkage.

Example 3
This example, 3.53 grams of 3-aminopropanethiol hydrochloride are dissolved in chloroform, and 7.72 ml of triethylamine are added. 2.81 grams of isophthaloyl chloride are then dissolved in chloroform under nitrogen. 3-aminopropanethiol hydrochloride and isophthaloyl chloride, prepared as described supra, are then slowly mixed, and the resulting solution is stirred under nitrogen in an ice bath for several hours. The resulting solution is then filtered under nitrogen, and several water/chloroform extractions are performed. Excess solvent is removed by rotary evaporation or distillation, and the resulting product is passed through a silica gel column using ethyl acetate/chloroform. Excess solvent is removed by rotary evaporation and vacuum-drying, resulting in a white precipitate. The resulting 1,3 benzene-thiol product has the formula:




where R is an alkyl thiol chain containing three methyl groups coupled through the carboxyl by an amide linkage.

Example 4
In this example, 3.92 grams of 4-aminobutanethiol hydrochloride are dissolved in chloroform, and 7.72 ml of triethylamine are added. 2.81 grams of isophthaloyl chloride are then dissolved in chloroform under nitrogen. 4-aminobutanethiol hydrochloride and isophthaloyl chloride, prepared as described supra, are then slowly mixed, and the resulting solution is stirred under nitrogen in an ice bath for several hours. The resulting solution is then filtered under nitrogen, and several water/chloroform extractions are performed. Excess solvent is removed by rotary evaporation or distillation, and the resulting product is passed through a silica gel column using ethyl acetate/chloroform. Excess solvent is removed by rotary evaporation and vacuum-drying, resulting in a white precipitate. The resulting 1,3 benzene-thiol product has the formula:




where R is an alkyl thiol chain containing four methyl groups coupled through the carboxyl by an amide linkage.

Example 5
In this example, 5 grams of 2,6 pyridine dicarbonyl dichloride were dissolved in chloroform under nitrogen. 5.56 grams of 2-aminothioethane thiol hydrochloride were also dissolved in chloroform under nitrogen, and slowly added to the acid chloride solution in an ice bath. Approximately 13.66 ml of triethylamine were added. The resulting mixture was stirred under nitrogen for 2-4 hours. The resulting yellow/brown solution was filtered under nitrogen, extracted three times with water/chloroform, refiltered under nitrogen, and excess solvent was removed by rotary evaporation or distillation. The resulting product was redissolved in chloroform and passed through a silica gel column using 70% ethyl acetate/30% chloroform. The resulting white precipitate was a 2,6 pyridine thiol product with the formula:




where R is an alkyl thiol chain containing two methyl groups coupled through the carboxyl by an amide linkage.

Example 6
Effect of daily administration of OSR on key biochemical parameters. Table 6-1 shows that the redox ratio (GSH/GSSG) was dramatically improved in 10 subjects taking 200 mg of OSR per day for a period of approximately 60 days. Improvement was seen in the first 30 days and continued into the second month. Also, the major improvement seemed to result from the very significant decrease in oxidized glutathione (GSSG) instead of a total increase in all forms of glutathione. This would be best explained by OSR scavenging hydroxyl free radicals salvaging the GSH by preventing its oxidation to GSSG. This change occurred in 10 of 10 subjects.







TABLE 6-1







Effect of OSR on blood GSH, GSSG levels and GSH/GSSG ratios.











tGSH/GSSG
GSSG
GSH









Time (months)
















Patient #
0
1
2
0
1
2
0
1
2



















1
40.3
53.6
87.1
0.133
0.129
0.065
5.4
6.9
5.7


2
42.9
37.5
87.7
0.159
0.209
0.117
6.8
7.8
10.3


3
24.8
32.3
64.5
0.167
0.154
0.083
4.1
5.0
5.4


4
14.8
22.1
28.6
0.482
0.282
0.189
7.1
6.2
5.4


5
66.9
73.7
93.7
0.108
0.103
0.067
7.2
7.6
6.3


6
14.1
33.4
38.5
0.308
0.154
0.137
4.3
5.2
5.3


7
36.9
40.3
44.9
0.127
0.113
0.081
4.7
4.6
3.6


8
17.3
36.2
28.7
0.236
0.146
0.195
4.1
5.3
5.6


9
11.4
16.9
48.9
0.521
0.396
0.139
5.9
6.7
6.8


10
15.8
42.8
69.6
0.283
0.165
0.119
4.5
7.1
8.3


Average
28.5
38.9
59.2
0.252
0.185
0.119
5.4
6.2
6.3









This data was collected from a single clinic where the subjects varied in age from 8 to 73 years old and were 5 male and 5 female. All were in reasonable health with no obvious bacterial infections. GSH/GSSG ratios increased in all primarily due to the drop in GSSG levels in all subjects. GSH levels remained relatively constant and increased slightly in 7 of 10. The average tGSH/GSSG ratio almost doubled caused by a near average halving of the GSSG levels.
To determine if OSR changed the level of cysteine, the rate limiting amino acid in glutathione synthesis, the level of all thiol containing amino acids was done for the same 10 patients for a two month period. As seen in Table 6-2, there was no significant change in the amino acid levels for any of the patients with one exception. The homocysteine level was high in patient #9, a 72 year old male diagnosed with Alzheimer's disease, over the two month testing his levels dropped to near normal levels. These results imply that OSR increases GSH levels by scavenging hydroxyl free radicals and salvaging GSH, not by supplying more cysteine for GSH synthesis.







TABLE 6-2







Effect of OSR on blood sulfur containing amino acid levels (cysteine, methionine,


homocysteine).











Cysteine
Methionine
Homocysteine









AGE Time (months)

















Patient #
0
1
2
0
1
2
0
1
2





















1
200
212
202
14.8
15.4
16.4
4.63
5.51
5.31
 8 wm


2
170
167
169
20.7
22.7
26.0
5.74
5.13
5.04
 9 wf


3
240
231
260
22.1
22.6
26.3
5.16
5.91
6.32
 9 wf


4
237
250
185
22.1
19.4
30.9
7.92
8.36
9.18
11 wm


5
231
225
244
20.9
24.0
30.4
6.07
5.31
5.75
12 wm


6
269
217
248
16.02
16.4
32.0
9.95
8.61
6.18
32 wf


7
282
246
251
23.5
26.6
27.2
7.26
7.45
8.78
45 wm


8
304
243
290
15.4
17.2
25.4
9.69
9.27
9.11
71 wf


9
344
255
317
20.5
28.3
31.2
21.2
13.9
12.8*
72 male AD


10
288
253
324
21.1
23.1
33.7
11.4
12.6
16.1
73 wf









No significant consistent changes in cysteine, methionine or homocysteine levels were observed. The possible exception was the homocysteine levels in patient #9, a male with Alzheimer's disease.
As seen in Table 6-3, glutathione-S-transferase (GST) was consistently elevated in all 10 patients in this study after OSR treatment. GST is an enzyme that uses glutathione (GSH) as a substrate to covalently modify certain organic toxins by ‘transferring GSH’ to a P-450 enzyme oxidized site on the toxin. This results in a GSH-toxin complex that is now water soluble and capable of being excreted from the body. GST was non-detectable in all 10 patients at the start of the study and was detectable in all 10 patients at the end of the study. The change in the redox level most likely had something to do with the appearance of this enzyme. It is a common mechanism in cellular regulation that the lowering of a substrate (e.g. glutathione) needed at several locations results in the suppressed expression of the enzyme (e.g. GST) that use this substrate for reactions that are less necessary to support survival. The buildup of GSH most likely induces the expression of GST and this buildup accounts for the induction of new GST synthesis.







TABLE 6-3







Effect of OSR on Glutathione-S-transferase (GST) levels (ng/ml)


GST









Time (months)












Patient #
0
1
2















1
L
L
0.48



2
L
L
0.48



3
L
0.46
0.43



4
L
L
0.53



5
L
L
0.43



6
L
L
0.37



7
L
L
0.32



8
L
0.58
0.43



9
L
L
0.63



10
L
L
0.43





GST activities increased in every patient. Detection levels were 0.4 for normals to 3.1 for a high level for GST.






Example 7
Protective effects of OSR on rats injected subcutaneously with mercuric chloride.




The mercury chloride LD 50 for rats is reported to be 3.2 mg/kg body weight intraperitoneal. Our experiments were designed around this value.
For each of the experiments nine, 5-7 weeks old, rats were chosen. They were divided into three groups and they were fed rat chow and water ad libitum.
The mercuric chloride was dissolved in PBS/DMSO and injected intraperitoneally at time zero.
The compound OSR was dissolved in 0.75 ml DMSO and 0.25 ml PBS. Injection was subcutaneous under the skin covering the stomach. These were done 20 min. after the injection of the mercuric chloride.







TABLE 7-1







Dosage of Mercury chloride at 2 mg/kg body weight.










OSR GROUP
CONTROL GROUP














Rat 1
Rat 2
Rat 3
Rat 1
Rat 2
Rat 3
















Weight (gram)
230
242
238
237
242
246


Mercury
0.46
0.48
0.48
0.47
0.48
0.49


chloride








(mg)*








OSR (mg)**
32.66
34.4
33.8
0
0
0


 0 hr
A
A
A
A
A
A


 6 hr
A
A
A
A
A
A


12 hr
A
A
A
A
A
D


24 hr
A
A
A
D
D
—


48 hr
A
A
A
—
—
—


 1 week
A
A
A
—
—
—





*= Equivalent to 2 mg/kg body weight.


**= Equivalent to 0.5 millimoles/kg body weight


D = Dead; A = Alive













TABLE 7-2







Dosage of mercury 14 mg/kg










OSR GROUP
CONTROL GROUP














Rat 1
Rat 2
rat 3
Rat 1
Rat 2
Rat 3
















Weight (in gram)
229.0
243.0
242.0
243.0
238.0
246.0


Mercury chloride*1
3.2
3.4
3.4
3.4
3.3
3.4


OSR (mg)*2
65.0
69.0
68.7
0.0
0.0
0.0


 0 hr
A
A
A
A
A
A


 6 hr
A
A
A
D
D
A


12 hr
A
A
A
—
—
D


24 hr
A
A
A
—
—
—


48 hr
D
A
A
—
—
—


 1 week
—
A
A
—
—
—





*1= Equivalent to 14 mg/kg body weight.


*2= Equivalent to 1 mM/kg body weight


D = Dead; A = Alive






Example 8
Mixture with oil. OSR may be admixed with emu oil or another oil not typically used as a pharmaceutical-grade excipient but known in the art to be useful in the cosmetic and or non-allopathic medical arts, thereby making an OSR-oil mixture useful as an antioxidant and/or detoxicant.
Example 9
Functional food. OSR may be admixed with a food known in the art, thereby making an OSR-food mixture useful as an antioxidant or detoxicant functional food.
Example 10
Medicament useful for treating disease. A therapeutically effective medicament composition containing OSR may be administered orally to a human subject in whom it is desired to ameliorate the effect of any disease known to be associated with oxidative stress, including without limitation each disease listed in Chapter 9 of Halliwell and Gutteridge 2007, op. cit. (Aspects of the relationship between oxidative stress and aging are discussed in Chapter 10 of that work.)
Example 11
Medicament and/or preparation of dosage form. To prepare a medicament and/or suitable dosage form, OSR may be admixed and/or contacted with one or more of the excipients listed in Table 11-1.







TABLE 11-1





Excipients

















Acacia



Acesulfame Potassium



Acetic Acid, Glacial



Acetone



Acetyltributyl Citrate



Acetyltriethyl Citrate



Agar



Albumin



Alcohol



Alginic Acid



Aliphatic Polyesters



Alitame



Almond Oil



Alpha Tocopherol



Aluminum Hydroxide Adjuvant



Aluminum Oxide



Aluminum Phosphate Adjuvant



Aluminum Stearate



Ammonia Solution



Ammonium Alginate



Ascorbic Acid



Ascorbyl Palmitate



Aspartame



Attapulgite



Bentonite



Benzalkonium Chloride



Benzethonium Chloride



Benzoic Acid



Benzyl Alcohol



Benzyl Benzoate



Boric Acid



Bronopol



Butylated Hydroxyanisole



Butylated Hydroxytoluene



Butylparaben



Calcium Alginate



Calcium Carbonate



Calcium Phosphate, Dibasic Anhydrous



Calcium Phosphate, Dibasic Dihydrate



Calcium Phosphate, Tribasic



Calcium Stearate



Calcium Sulfate



Canola Oil



Carbomer



Carbon Dioxide



Carboxymethylcellulose Calcium



Carboxymethylcellulose Sodium



Carrageenan



Castor Oil



Castor Oil, Hydrogenated



Cellulose, Microcrystalline



Cellulose, Powdered



Cellulose, Silicified Microcrystalline



Cellulose Acetate



Cellulose Acetate Phthalate



Ceratonia



Cetostearyl Alcohol



Cetrimide



Cetyl Alcohol



Cetyrpyridinium Chloride



Chitosan



Chlorhexidine



Chlorobutanol



Chlorocresol



Chlorodifluoroethane (HCFC)



Chlorofluorocarbons (CFC)



Chloroxylenol



Cholesterol



Citric Acid Monohydrate



Colloidal Silicon Dioxide



Coloring Agents



Copovidone



Corn Oil



Cottonseed Oil



Cresol



Croscarmellose Sodium



Crospovidone



Cyclodextrins



Cyclomethicone



Denatonium Benzoate



Dextrates



Dextrin



Dextrose



Dibutyl Phthalate



Dibutyl Sebacate



Diethanolamine



Diethyl Phthalate



Difluoroethane (HFC)



Dimethicone



Dimethyl Ether



Dimethyl Phthalate



Dimethyl Sulfoxide



Dimethylacetamide



Disodium Edetate



Docusate Sodium



Edetic Acid



Erythorbic Acid



Erythritol



Ethyl Acetate



Ethyl Lactate



Ethyl Maltol



Ethyl Oleate



Ethyl Vanillin



Ethylcellulose



Ethylene Glycol Palmitostearate



Ethylene Vinyl Acetate



Ethylparaben



Fructose



Fumaric Acid



Gelatin



Glucose, Liquid



Glycerin



Glyceryl Behenate



Glyceryl Monooleate



Glyceryl Monostearate



Glyceryl Palmitostearate



Glycofurol



Guar Gum



Hectorite



Heptafluoropropane (HFC)



Hexetidine



Hydrocarbons (HC)



Hydrochloric Acid



Hydroxyethyl Cellulose



Hydroxyethylmethyl Cellulose



Hydroxypropyl Cellulose



Hydroxypropyl Cellulose, Low-substituted



Hydroxypropyl Starch



Hypromellose



Hypromellose Acetate Succinate



Hypromellose Phthalate



Imidurea



Inulin



Iron Oxides



Isomalt



Isopropyl Alcohol



Isopropyl Myristate



Isopropyl Palmitate



Kaolin



Lactic Acid



Lactitol



Lactose, Anhydrous



Lactose, Monohydrate



Lactose, Spray-Dried



Lanolin



Lanolin, Hydrous



Lanolin Alcohols



Laurie Acid



Lecithin



Leucine



Linoleic Acid



Macrogol 15 Hydroxystearate



Magnesium Aluminum Silicate



Magnesium Carbonate



Magnesium Oxide



Magnesium Silicate



Magnesium Stearate



Magnesium Trisilicate



Malic Acid



Maltitol



Maltitol Solution



Maltodextrin



Maltol



Maltose



Mannitol



Medium-chain Triglycerides



Meglumine



Menthol



Methylcellulose



Methylparaben



Mineral Oil



Mineral Oil, Light



Mineral Oil and Lanolin Alcohols



Monoethanolamine



Monosodium Glutamate



Monothioglycerol



Myristic Acid



Neohesperidin Dihydrochalcone



Nitrogen



Nitrous Oxide



Octyldodecanol



Oleic Acid



Oleyl Alcohol



Olive Oil



Palmitic Acid



Paraffin



Peanut Oil



Pectin



Petrolatum and Lanolin Alcohols



Petrolatum



Phenol



Phenoxyethanol



Phenylethyl Alcohol



Phenylmercuric Acetate



Phenylmercuric Borate



Phenylmercuric Nitrate



Phosphoric Acid



Polacrilin Potassium



Poloxamer



Polycarbophil



Polydextrose



Polyethylene Glycol



Polyethylene Oxide



Polymethacrylates



Poly(methyl vinyl ether/maleic anhydride)



Polyoxyethylene Alkyl Ethers



Polyoxyethylene Castor Oil Derivatives



Polyoxyethylene Sorbitan Fatty Acid Esters



Polyoxyethylene Stearates



Polyvinyl Acetate Phthalate



Polyvinyl Alcohol



Potassium Alginate



Potassium Benzoate



Potassium Bicarbonate



Potassium Chloride



Potassium Citrate



Potassium Hydroxide



Potassium Metabisulfite



Potassium Sorbate



Povidone



Propionic Acid



Propyl Gallate



Propylene Carbonate



Propylene Glycol



Propylene Glycol Alginate



Propylparaben



2-Pyrrolidone



Raffinose



Saccharin



Saccharin Sodium



Saponite



Sesame Oil



Shellac



Simethicone



Sodium Acetate



Sodium Alginate



Sodium Ascorbate



Sodium Benzoate



Sodium Bicarbonate



Sodium Borate



Sodium Chloride



Sodium Citrate Dihydrate



Sodium Cyclamate



Sodium Hyaluronate



Sodium Hydroxide



Sodium Lactate



Sodium Lauryl Sulfate



Sodium Metabisulfite



Sodium Phosphate, Dibasic



Sodium Phosphate, Monobasic



Sodium Propionate



Sodium Starch Glycolate



Sodium Stearyl Fumarate



Sodium Sulfite



Sorbic Acid



Sorbitan Esters (Sorbitan Fatty Acid Esters)



Sorbitol



Soybean Oil



Starch



Starch, Pregelatinized



Starch, Sterilizable Maize



Stearic Acid



Stearyl Alcohol



Sucralose



Sucrose



Sugar, Compressible



Sugar, Confectioner's



Sugar Spheres



Sulfobutylether β-Cyclodextrin



Sulfuric Acid



Sunflower Oil



Suppository Bases, Hard Fat



Talc



Tartaric Acid



Tetrafluoroethane (HFC)



Thaumatin



Thymol



Titanium Dioxide



Tragacanth



Trehalose



Triacetin



Tributyl Citrate



Triethanolamine



Triethyl Citrate



Vanillin



Vegetable Oil, Hydrogenated



Water



Wax, Anionic Emulsifying



Wax, Carnauba



Wax, Cetyl Esters



Wax, Microcrystalline



Wax, Nonionic Emulsifying



Wax, White



Wax, Yellow



Xanthan Gum



Xylitol



Zein



Zinc Acetate



Zinc Stearate









Example 12
Dosage form. A suitable dosage form for administration of OSR or other active compound may be chosen from among the dosage forms listed in Table 12-1.







TABLE 12-1







Dosage forms








NAME
DEFINITION





AEROSOL
A product that is packaged under pressure and



contains therapeutically active ingredients that are



released upon activation of an appropriate valve



system; it is intended for topical application to the



skin as well as local application into the nose



(nasal aerosols), mouth (lingual aerosols), or lungs



(inhalation aerosols).


AEROSOL, 
A product that is packaged under pressure and


POWDER
contains therapeutically active ingredients, in the



form of a powder, that are released upon



activation of an appropriate valve system.


BAR, 
A solid dosage form usually in the form of a


CHEWABLE
rectangle that is meant to be chewed.


CAPSULE
A solid oral dosage form consisting of a shell and



a filling. The shell is composed of a single sealed



enclosure, or two halves that fit together and



which are sometimes sealed with a band. Capsule



shells may be made from gelatin, starch, or



cellulose, or other suitable materials, may be soft



or hard, and are filled with solid or liquid



ingredients that can be poured or squeezed.


CAPSULE, 
A solid dosage form in which the drug is enclosed


COATED
within either a hard or soft soluble container or



“shell” made from a suitable form of gelatin;



additionally, the capsule is covered in a designated



coating.


CAPSULE, 
A solid dosage form in which the drug is enclosed


COATED
within either a hard or soft soluble container or


PELLETS
“shell” made from a suitable form of gelatin; the



drug itself is in the form of granules to which



varying amounts of coating have been applied.


CAPSULE, 
A solid dosage form in which the drug is enclosed


COATED,
within either a hard or soft soluble container or


EXTENDED 
“shell” made from a suitable form of gelatin;


RELEASE
additionally, the capsule is covered in a designated



coating, and which releases a drug (or drugs) in



such a manner to allow at least a reduction in



dosing frequency as compared to that drug (or



drugs) presented as a conventional dosage form.


CAPSULE, 
A solid dosage form in which the drug is enclosed


DELAYED
within either a hard or soft soluble container made


RELEASE
from a suitable form of gelatin, and which releases



a drug (or drugs) at a time other than promptly



after administration. Enteric-coated articles are



delayed release dosage forms.


CAPSULE, 
A solid dosage form in which the drug is enclosed


DELAYED
within either a hard or soft soluble container or


RELEASE 
“shell” made from a suitable form of gelatin; the


PELLETS
drug itself is in the form of granules to which



enteric coating has been applied, thus delaying



release of the drug until its passage into the



intestines.


CAPSULE, 
A solid dosage form in which the drug is enclosed


EXTENDED
within either a hard or soft soluble container made


RELEASE
from a suitable form of gelatin, and which releases



a drug (or drugs) in such a manner to allow a



reduction in dosing frequency as compared to that



drug (or drugs) presented as a conventional dosage



form.


CAPSULE, FILM
A solid dosage form in which the drug is enclosed


COATED, 
within either a hard or soft soluble container or


EXTENDED
“shell” made from a suitable form of gelatin;


RELEASE
additionally, the capsule is covered in a designated



film coating, and which releases a drug (or drugs)



in such a manner to allow at least a reduction in



dosing frequency as compared to that drug (or



drugs) presented as a conventional dosage form.


CAPSULE, 
A solid dosage form in which the drug is enclosed


GELATIN
within either a hard or soft soluble container made


COATED
from a suitable form of gelatin; through a banding



process, the capsule is coated with additional



layers of gelatin so as to form a complete seal.


CAPSULE, 
A solid dosage form in which the drug is enclosed


LIQUID
within a soluble, gelatin shell which is plasticized


FILLED
by the addition of a polyol, such as sorbitol or



glycerin, and is therefore of a somewhat thicker



consistency than that of a hard shell capsule;



typically, the active ingredients are dissolved or



suspended in a liquid vehicle.


CONCENTRATE
A liquid preparation of increased strength and



reduced volume which is usually diluted prior to



administration.


CORE, 
An ocular system placed in the eye from which the


EXTENDED
drug diffuses through a membrane at a constant


RELEASE
rate over a specified period.


CREAM
An emulsion, semisolid3 dosage form, usually



containing >20% water and volatiles5 and/or 



<50% hydrocarbons, waxes, or polyols as the



vehicle. This dosage form is generally for



external application to the skin or mucous



membranes.


CREAM, 
A cream dosage form that enhances drug delivery.


AUGMENTED
Augmentation does not refer to the strength of the



drug in the dosage form. NOTE: CDER has



decided to refrain from expanding the use of this



dosage form due to difficulties in setting specific



criteria that must be met to be considered



“augmented”.


DRUG 
Modern technology, distributed with or as a part


DELIVERY
of a drug product that allows for the uniform


SYSTEM
release or targeting of drugs to the body.


ELIXIR
A clear, pleasantly flavored, sweetened



hydro alcoholic liquid containing dissolved



medicinal agents; it is intended for oral use.


EMULSION
A dosage form consisting of a two-phase system



comprised of at least two immiscible liquids1, one



of which is dispersed as droplets (internal or



dispersed phase) within the other liquid (external



or continuous phase), generally stabilized with one



or more emulsifying agents. (Note: Emulsion is



used as a dosage form term unless a more specific



term is applicable, e.g. cream, lotion, ointment.)


ENEMA
A rectal preparation for therapeutic, diagnostic, or



nutritive purposes.


EXTRACT
A concentrated preparation of vegetable or animal



drugs obtained by removal of the active



constituents of the respective drugs with a suitable



menstrua, evaporation of all or nearly all of the



solvent, and adjustment of the residual masses or



powders to the prescribed standards.


FIBER, 
A slender and elongated solid thread-like


EXTENDED
substance that delivers drug in such a manner to


RELEASE
allow a reduction in dosing frequency as



compared to that drug (or drugs) presented as a



conventional dosage form.


FILM, SOLUBLE
A thin layer or coating which is susceptible to



being dissolved when in contact with a liquid.


FOR SOLUTION
A product, usually a solid, intended for solution



prior to administration.


FOR 
A product, usually a solid, intended for suspension


SUSPENSION
prior to administration.


FOR 
A product, usually a solid, intended for suspension


SUSPENSION,
prior to administration; once the suspension is


EXTENDED 
administered, the drug will be released at a


RELEASE
constant rate over a specified period.


GEL
A semisolid3 dosage form that contains a gelling



agent to provide stiffness to a solution or a



colloidal dispersion.4 A gel may contain



suspended particles.


GLOBULE
Also called pellets or pilules, are made of pure



sucrose, lactose, or other polysaccharides. They



are formed into small globular masses of various



sizes, and are medicated by placing them in a vial



and adding the liquid drug attenuation in the



proportion not less than one percent (v/w). After



shaking, the medicated globules are dried at



temperatures not to exceed 40 degrees Centigrade.


GRANULE
A small particle or grain.


GRANULE, 
A small medicinal particle or grain to which an


DELAYED
enteric or other coating has been applied, thus


RELEASE
delaying release of the drug until its passage into



the intestines.


GRANULE,
A small particle or grain containing a medicinal


EFFERVESCENT
agent in a dry mixture usually composed of



sodium bicarbonate, citric acid, and tartaric acid



which, when in contact with water, has the



capability to release gas, resulting in



effervescence.


GRANULE, FOR
A small medicinal particle or grain made available


SOLUTION
in its more stable dry form, to be reconstituted



with solvent just before dispensing; the granules



are so prepared to contain not only the medicinal



agent, but the colorants, flavorants, and any other



desired pharmaceutic ingredient.


GRANULE, FOR
A small medicinal particle or grain made available


SUSPENSION
in its more stable dry form, to be reconstituted



with solvent just before dispensing to form a



suspension; the granules are so prepared to contain



not only the medicinal agent, but the colorants,



flavorants, and any other desired pharmaceutic



ingredient.


GRANULE, FOR
A small medicinal particle or grain made available


SUSPENSION,
in its more stable dry form, to be reconstituted


EXTENDED 
with solvent just before dispensing to form a


RELEASE
suspension; the extended release system achieves



slow release of the drug over an extended period



of time and maintains constant drug levels in the



blood or target tissue.


INJECTABLE,
An injection, which either consists of or forms


LIPOSOMAL
liposomes (a lipid bilayer vesicle usually



composed of phospholipids which is used to



encapsulate an active drug substance).


INJECTION
A sterile preparation intended for parenteral use;



five distinct classes of injections exist as defined



by the USP.


INJECTION,
An emulsion consisting of a sterile, pyrogen-free


EMULSION
preparation intended to be administered



parenterally.


INJECTION, 
[definition pending]


LIPID



COMPLEX



INJECTION, 
A sterile preparation intended for reconstitution to


POWDER, FOR 
form a solution for parenteral use.


SOLUTION



INJECTION, 
A sterile preparation intended for reconstitution to


POWDER, FOR 
form a suspension for parenteral use.


SUSPENSION



INJECTION, 
A dried preparation intended for reconstitution to


POWDER, FOR 
form a suspension for parenteral use which has


SUSPENSION,
been formulated in a manner to allow at least a


EXTENDED 
reduction in dosing frequency as compared to that


RELEASE
drug presented as a conventional dosage form



(e.g., as a solution).


INJECTION, 
A sterile freeze dried preparation intended for


POWDER,
reconstitution for parenteral use which has been


LYOPHILIZED, 
formulated in a manner that would allow


FOR 
liposomes (a lipid bilayer vesicle usually


LIPOSOMAL
composed of phospholipids which is used to


SUSPENSION
encapsulate an active drug substance, either within



a lipid bilayer or in an aqueous space) to be



formed upon reconstitution.


INJECTION,
A liquid preparation, suitable for injection, which


SUSPENSION,
consists of an oil phase dispersed throughout an


LIPOSOMAL
aqueous phase in such a manner that liposomes (a



lipid bilayer vesicle usually composed of



phospholipids which is used to encapsulate an



active drug substance, either within a lipid bilayer



or in an aqueous space) are formed.


INJECTION,
A liquid preparation, suitable for injection, which


SUSPENSION,
consists of solid particles dispersed throughout a


SONICATED
liquid phase in which the particles are not soluble.



In addition, the product is sonicated while a gas is



bubbled through the suspension, and this results in



the formation of microspheres by the solid



particles.


JELLY
A class of gels, which are semisolid systems that



consist of suspensions made up of either small



inorganic particles or large organic molecules



interpenetrated by a liquid-in which the structural



coherent matrix contains a high portion of liquid,



usually water.


KIT
A packaged collection of related material.


LINIMENT
A solution or mixture of various substances in oil,



alcoholic solutions of soap, or emulsions intended



for external application.


LIQUID,
A liquid that delivers a drug in such a manner to


EXTENDED 
allow a reduction in dosing frequency as


RELEASE
compared to that drug (or drugs) presented as a



conventional dosage form.


LOTION
An emulsion, liquid1 dosage form. This dosage



form is generally for external application to the



skin.2


LOTION, 
A lotion dosage form that enhances drug delivery.


AUGMENTED
Augmentation does not refer to the strength of the



drug in the dosage form. NOTE: CDER has



decided to refrain from expanding the use of this



dosage form due to difficulties in setting specific



criteria that must be met to be considered



“augmented”.


LOZENGE
A solid preparation containing one or more



medicaments, usually in a flavored, sweetened



base which is intended to dissolve or disintegrate



slowly in the mouth. A lollipop is a lozenge on a



stick.


MOUTHWASH
An aqueous solution which is most often used for



its deodorant, refreshing, or antiseptic effect.


OIL
An unctuous, combustible substance which is



liquid, or easily liquefiable, on warming, and is



soluble in ether but insoluble in water. Such



substances, depending on their origin, are



classified as animal, mineral, or vegetable oils.


OINTMENT
A semisolid3 dosage form, usually containing



<20% water and volatiles5 and >50%



hydrocarbons, waxes, or polyols as the vehicle.



This dosage form is generally for external



application to the skin or mucous membranes.


OINTMENT,
An ointment dosage form that enhances drug


AUGMENTED
delivery. Augmentation does not refer to the



strength of the drug in the dosage form. NOTE:



CDER has decided to refrain from expanding the



use of this dosage form due to difficulties in



setting specific criteria that must be met to be



considered “augmented”.


PASTE
A semisolid3 dosage form, containing a large



proportion (20-50%) of solids finely dispersed in



a fatty vehicle. This dosage form is generally for



external application to the skin or mucous



membranes.


PASTILLE
An aromatic preparation, often with a pleasing



flavor, usually intended to dissolve in the mouth.


PATCH
A drug delivery system that often contains an



adhesive backing that is usually applied to an



external site on the body. Its ingredients either



passively diffuse from, or are actively transported



from, some portion of the patch. Depending upon



the patch, the ingredients are either delivered to



the outer surface of the body or into the body. A



patch is sometimes synonymous with the terms



‘extended release film’ and ‘system’.


PATCH, 
A drug delivery system in the form of a patch that


EXTENDED
releases the drug in such a manner that a reduction


RELEASE
in dosing frequency compared to that drug



presented as a conventional dosage form (e.g., a



solution or a prompt drug-releasing, conventional



solid dosage form).


PATCH, 
A drug delivery system in the form of a patch


EXTENDED
which is controlled by an electric current that


RELEASE,
releases the drug in such a manner that a reduction


ELECTRICALLY
in dosing frequency compared to that drug


CONTROLLED
presented as a conventional dosage form (e.g., a



solution or a prompt drug-releasing, conventional



solid dosage form).


PELLET
A small sterile solid mass consisting of a highly



purified drug (with or without excipients) made by



the formation of granules, or by compression and



molding.


PELLETS, 
A solid dosage form in which the drug itself is in


COATED,
the form of granules to which varying amounts of


EXTENDED 
coating have been applied, and which releases a


RELEASE
drug (or drugs) in such a manner to allow a



reduction in dosing frequency as compared to that



drug (or drugs) presented as a conventional dosage



form.


PILL
A small, round solid dosage form containing a



medicinal agent intended for oral administration.


PLASTER
Substance intended for external application made



of such materials and of such consistency as to



adhere to the skin and attach to a dressing; plasters



are intended to afford protection and support



and/or to furnish an occlusion and macerating



action and to bring medication into close contact



with the skin.


POULTICE
A soft, moist mass of meal, herbs, seed, etc.,



usually applied hot in cloth that consists of gruel-



like consistency.


POWDER
An intimate mixture of dry, finely divided drugs



and/or chemicals that may be intended for internal



or external use.


POWDER, FOR
An intimate mixture of dry, finely divided drugs


SOLUTION
and/or chemicals, which, upon the addition of



suitable vehicles, yields a solution.


POWDER, FOR
An intimate mixture of dry, finely divided drugs


SUSPENSION
and/or chemicals, which, upon the addition of



suitable vehicles, yields a suspension (a liquid



preparation containing the solid particles dispersed



in the liquid vehicle).


SALVE
A thick ointment or cerate (a fat or wax based



preparation with a consistency between an



ointment and a plaster).


SOLUTION
A clear, homogeneous liquid1 dosage form that



contains one or more chemical substances



dissolved in a solvent or mixture of mutually



miscible solvents.


SOLUTION,
A liquid preparation (i.e., a substance that flows


CONCENTRATE
readily in its natural state) that contains a drug



dissolved in a suitable solvent or mixture of



mutually miscible solvents; the drug has been



strengthened by the evaporation of its nonactive



parts.


SOLUTION, FOR
A solution for the preparation of an iced saline


SLUSH
slush, which is administered by irrigation and used



to induce regional hypothermia (in conditions



such as certain open heart and kidney surgical



procedures) by its direct application.


SOLUTION, GEL
A solution, which after usually being administered


FORMING/
in a drop-wise fashion, forms a gel.


DROPS



SOLUTION, GEL
A solution that forms a gel when it comes in


FORMING, 
contact with ocular fluid, and which allows at least


EXTENDED 
a reduction in dosing frequency.


RELEASE



SOLUTION/
A solution which is usually administered in a


DROPS
drop-wise fashion.


SUPPOSITORY
A solid body of various weights and shapes,



adapted for introduction into the rectal orifice of



the human body; they usually melt, soften, or



dissolve at body temperature.


SUPPOSITORY,
A drug delivery system in the form of a


EXTENDED 
suppository that allows for a reduction in dosing


RELEASE
frequency.


SUSPENSION
A liquid1 dosage form that contains solid particles



dispersed in a liquid vehicle.


SUSPENSION,
A liquid preparation consisting of solid particles


EXTENDED 
dispersed throughout a liquid phase in which the


RELEASE
particles are not soluble; the suspension has been



formulated in a manner to allow at least a



reduction in dosing frequency as compared to that



drug presented as a conventional dosage form



(e.g., as a solution or a prompt drug-releasing,



conventional solid dosage form).


SUSPENSION/ 
A suspension which is usually administered in a


DROPS
dropwise fashion.


SYRUP
An oral solution containing high concentrations of



sucrose or other sugars; the term has also been



used to include any other liquid dosage form



prepared in a sweet and viscid vehicle, including



oral suspensions.


TABLET
A solid dosage form containing medicinal



substances with or without suitable diluents.


TABLET, 
A solid dosage form containing medicinal


CHEWABLE
substances with or without suitable diluents that is



intended to be chewed, producing a pleasant



tasting residue in the oral cavity that is easily



swallowed and does not leave a bitter or



unpleasant after-taste.


TABLET, 
A solid dosage form that contains medicinal


COATED
substances with or without suitable diluents and is



covered with a designated coating.


TABLET,
A solid dosage form containing a conglomerate of


COATED 
medicinal particles that have each been covered


PARTICLES
with a coating.


TABLET, 
A solid dosage form which releases a drug (or


DELAYED
drugs) at a time other than promptly after


RELEASE
administration. Enteric-coated articles are delayed



release dosage forms.


TABLET, 
A solid dosage form containing a conglomerate of


DELAYED
medicinal particles that have been covered with a


RELEASE 
coating which releases a drug (or drugs) at a time


PARTICLES
other than promptly after administration. Enteric-



coated articles are delayed release dosage forms.


TABLET, 
A tablet that, prior to administration, is intended to


DISPERSIBLE
be placed in liquid, where its contents will be



distributed evenly throughout that liquid. Note:



The term ‘tablet, dispersible’ is no longer used for



approved drug products, and it has been replaced



by the term ‘tablet, for suspension’.


TABLET,
A solid dosage form containing mixtures of acids


EFFERVESCENT
(e.g., citric acid, tartaric acid) and sodium



bicarbonate, which release carbon dioxide when



dissolved in water; it is intended to be dissolved or



dispersed in water before administration.


TABLET, 
A solid dosage form containing a drug which


EXTENDED
allows at least a reduction in dosing frequency as


RELEASE
compared to that drug presented in conventional



dosage form.


TABLET, FILM
A solid dosage form that contains medicinal


COATED
substances with or without suitable diluents and is



coated with a thin layer of a water-insoluble or



water-soluble polymer.


TABLET, FILM
A solid dosage form that contains medicinal


COATED, 
substances with or without suitable diluents and is


EXTENDED
coated with a thin layer of a water-insoluble or


RELEASE
water-soluble polymer; the tablet is formulated in



such manner as to make the contained medicament



available over an extended period of time



following ingestion.


TABLET, FOR
A tablet that forms a solution when placed in a


SOLUTION
liquid.


TABLET, FOR
A tablet that forms a suspension when placed in a


SUSPENSION
liquid (formerly referred to as a ‘dispersible



tablet’).


TABLET,
A solid dosage form containing medicinal


MULTILAYER
substances that have been compressed to form a



multiple-layered tablet or a tablet-within-a-tablet,



the inner tablet being the core and the outer



portion being the shell.


TABLET,
A solid dosage form containing medicinal


MULTILAYER,
substances that have been compressed to form a


EXTENDED 
multiple-layered tablet or a tablet-within-a-tablet,


RELEASE
the inner tablet being the core and the outer



portion being the shell, which, additionally, is



covered in a designated coating; the tablet is



formulated in such manner as to allow at least a



reduction in dosing frequency as compared to that



drug presented as a conventional dosage form.


TABLET,
A solid dosage form containing medicinal


ORALLY DIS-
substances which disintegrates rapidly, usually


INTEGRATING
within a matter of seconds, when placed upon the



tongue.


TABLET, 
A solid dosage form containing medicinal


ORALLY DIS-
substances which disintegrates rapidly, usually


INTEGRATING,
within a matter of seconds, when placed upon the


DELAYED 
tongue, but which releases a drug (or drugs) at a


RELEASE
time other than promptly after administration.


TABLET, 
A solid dosage form that contains medicinal


SOLUBLE
substances with or without suitable diluents and



possesses the ability to dissolve in fluids.


TABLET, 
A solid dosage form that contains medicinal


SUGAR
substances with or without suitable diluents and is


COATED
coated with a colored or an uncolored water-



soluble sugar.





Footnotes:


1A liquid s pourable; it flows and conforms to its container at room temperature. It displays Newtonian or pseudoplastic flow behavior.


2Previously the definition of a lotion was “The term lotion has been used to categorize many topical suspensions, solutions, and emulsions intended for application to the skin.” The current definition of a lotion is restricted to an emulsion.


3A semisolid is not pourable; it does not flow or conform to its container at room temperature. It does not flow at low shear stress and generally exhibits plastic flow behavior.


4A colloidal dispersion is a system in which particles of colloidal dimension (i.e., typically between 1 nm and 1 μm) are distributed uniformly throughout a liquid.


5Percent water and volatiles are measured by a loss on drying test in which the sample is heated at 105° C. until constant weight is achieved.






Example 13
Route of administration. A suitable route of administration for a dosage form containing OSR may be chosen from among those listed in Table 13-1.







TABLE 13-1







Routes of administration








NAME
DEFINITION





BUCCAL
Administration directed toward the cheek,



generally from within the mouth.


CONJUNCTIVAL
Administration to the conjunctiva, the



delicate membrane that lines the eyelids



and covers the exposed surface of the



eyeball.


CUTANEOUS
Administration to the skin.


ENDOSINUSIAL
Administration within the nasal sinuses of



the head.


ENTERAL
Administration directly into the intestines.


EPIDURAL
Administration upon or over the dura



mater.


EXTRACORPOREAL
Administration outside of the body.


HEMODIALYSIS
Administration through hemodialysate



fluid.


INFILTRATION
Administration that results in substances



passing into tissue spaces or into cells.


INTERSTITIAL
Administration to or in the interstices of a



tissue.


INTRA-ABDOMINAL
Administration within the abdomen.


INTRA-ARTERIAL
Administration within an artery or arteries.


INTRA-ARTICULAR
Administration within a joint.


INTRACARTILAGINOUS
Administration within a cartilage;



endochondral.


INTRACAUDAL
Administration within the cauda equina.


INTRACORONARY
Administration within the coronary



arteries.


INTRADERMAL
Administration within the dermis.


INTRADUCTAL
Administration within the duct of a gland.


INTRADUODENAL
Administration within the duodenum.


INTRADURAL
Administration within or beneath the dura.


INTRAEPIDERMAL
Administration within the epidermis.


INTRAESOPHAGEAL
Administration within the esophagus.


INTRAGASTRIC
Administration within the stomach.


INTRAGINGIVAL
Administration within the gingivae.


INTRALYMPHATIC
Administration within the lymph.


INTRAMEDULLARY
Administration within the marrow cavity



of a bone.


INTRAMENINGEAL
Administration within the meninges (the



three membranes that envelope the brain



and spinal cord).


INTRAMUSCULAR
Administration within a muscle.


INTRAOCULAR
Administration within the eye.


INTRAOVARIAN
Administration within the ovary.


INTRAPERICARDIAL
Administration within the pericardium.


INTRAPERITONEAL
Administration within the peritoneal



cavity.


INTRAPLEURAL
Administration within the pleura.


INTRAPULMONARY
Administration within the lungs or its



bronchi.


INTRASINAL
Administration within the nasal or



periorbital sinuses.


INTRASPINAL
Administration within the vertebral



column.


INTRASYNOVIAL
Administration within the synovial cavity



of a joint.


INTRATENDINOUS
Administration within a tendon.


INTRATHECAL
Administration within the cerebrospinal



fluid at any level of the cerebrospinal axis,



including injection into the cerebral



ventricles.


INTRATHORACIC
Administration within the thorax (internal



to the ribs); synonymous with the term



endothoracic.


INTRATUMOR
Administration within a tumor.


INTRAUTERINE
Administration within the uterus.


INTRAVASCULAR
Administration within a vessel or vessels.


INTRAVENOUS
Administration within or into a vein or



veins.


INTRAVENOUS BOLUS
Administration within or into a vein or



veins all at once.


INTRAVENOUS DRIP
Administration within or into a vein or



veins over a sustained period of time.


INTRAVENTRICULAR
Administration within a ventricle.


INTRAVESICAL
Administration within the bladder.


INTRAVITREAL
Administration within the vitreous body of



the eye.


NASAL
Administration to the nose; administered



by way of the nose.


OPHTHALMIC
Administration to the external eye.


ORAL
Administration to or by way of the mouth.


OROPHARYNGEAL
Administration directly to the mouth and



pharynx.


OTHER
Administration is different from others on



this list.


PARENTERAL
Administration by injection, infusion, or



implantation.


PERCUTANEOUS
Administration through the skin.


PERIARTICULAR
Administration around a joint.


PERIDURAL
Administration to the outside of the dura



mater of the spinal cord..


PERINEURAL
Administration surrounding a nerve or



nerves.


PERIODONTAL
Administration around a tooth.


RECTAL
Administration to the rectum.


RESPIRATORY 
Administration within the respiratory tract


(INHALATION)
by inhaling orally or nasally for local or



systemic effect.


SOFT TISSUE 
Administration into any soft tissue.


SUBCONJUNCTIVAL
Administration beneath the conjunctiva.


SUBCUTANEOUS
Administration beneath the skin;



hypodermic. Synonymous with the term



SUBDERMAL.


SUBLINGUAL
Administration beneath the tongue.


SUBMUCOSAL
Administration beneath the mucous



membrane.


TOPICAL
Administration to a particular spot on the



outer surface of the body. The E2B term



TRANSMAMMARY is a subset of the



term TOPICAL.


TRANSDERMAL
Administration through the dermal layer



of the skin to the systemic circulation by



diffusion.


TRANSMUCOSAL
Administration across the mucosa.









The foregoing description of the preferred embodiments of the present invention have been presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise form disclosed. Obvious modifications or variations are possible in light of the above teachings. The embodiments were chosen and described to provide the best illustration of the principles of the invention and its practical application to thereby enable one of ordinary skill in the art to utilize the invention in various embodiments and with various modifications as are suited to the particular use contemplated. All such modifications and variations are within the scope of the invention as determined by the appended claims when interpreted in accordance with the breadth to which they are fairly, legally and equitably entitled. The drawings and preferred embodiments do not and are not intended to limit the ordinary meaning of the claims in their fair and broad interpretation in any way.

## Claims

1. A method of supplementing a diet of a mammal, comprising:
administering to said mammal a pharmaceutically effective amount of a compound having a chemical formula:




where n=1-4 and X is selected from the group consisting of hydrogen, lithium sodium, potassium, rubidium, cesium and francium.

2. The method of claim 1, including using oral administration.

3. The method of claim 1, including administering between about 0.5 and about 40 milligrams of said compound per kilogram of said mammal's total body weight per day.

4. The method of claim 1, including using transdermal administration.

5. The method of claim 1, including using nasal administration.

6. The method of claim 1, including using administration by suppository.

7. The method of claim 1, including using intravenous administration.

8. The method of claim 1, including administering said compound with antioxidant.

9. The method of claim 8, including selecting said antioxidant from a list of antioxidants consisting of vitamin-E, vitamin-D, cysteine, glutathione, lipoic acid and combinations thereof.

10. The method of claim 1, wherein said compound has the chemical formula:

11. The method of claim 10, including using oral administration.

12. The method of claim 10, including administering between about 0.5 and about 40 milligrams of said compound per kilogram of said mammal's total body weight per day.