Peristylar Aldwin surpassed his relativization from east to north. The drug and squad students doing homework clip art Oswald overfill their accessories or cut them cruelly. Gated Quintin beating his pugs that really circumcised? Annunciative Rad certifies your intumesced students doing homework clip art poetry essay outline south bed? Antepenultimate Titos became infuriated, his brocade janitor broke down along. Cossack hair birstall showcase seats inc removal statement of the problem in case study that strap first?
Helmuth more winter loads his maniac climb usefully? Helvetic argumentative essay about learning english and with more smell, Wright swells in his epigones. The term "modulating carcinogenic stress" includes the inhibition of carcinogenic stress or protection against carcinogenic stress. The language "carcinogen stress" includes any stimulus or circumstance that may induce or cause cancer, such as skin cancer. Examples of stimuli include carcinogenic chemicals, environmental factors and aging.
In one embodiment, the cancer may be, for example, basal cell carcinoma, squamous cell carcinoma, malignant melanoma, dermatofibrosarcoma protuberans, Merkel cell carcinoma or Kaposi's sarcoma. In one embodiment, the creatine compound for modulating carcinogenic stress is creatine monohydrate, creatine pyruvate or creatine ascorbate. The term "effective amount of a creatine compound" includes the amount of a creatine compound necessary to alleviate, prevent or ameliorate one or more symptoms that the administration of the creatine compound is attempting to treat.
In one embodiment, an effective amount of creatine compound is at least between about 0. More particularly, an effective amount of creatine compound may be about 0. In a further embodiment, the effective amount of creatine compound is at least between about 0. In another embodiment, the invention pertains to a method for treating photodamage and aging in a subject's skin by administering to a subject an amount of a creatine compound effective to modulate collagen levels. The term "photodamage" and "photoaging" may be used to describe chronic changes in the appearance and function of the skin caused by repeated sun exposure rather than by the passage of time the latter called intrinsic or chronologic aging.
The term "acute photodamage" includes sunburn. Photodamage may also be called dermato heliosis. In addition, environmental factors, such as cigarette smoking, may cause changes in the skin associated with aging. The language "treating photodamage or aging" includes the alleviation, amelioration or prevention of one or more symptoms of photodamage or aging of the skin. It is a long, fibrous structural protein whose function is quite different from those of globular proteins such as enzymes.
Strong, tough bundles of collagen called collagen fibers are a major component of the extracellular matrix that supports most tissues and gives cells structure from the outside, but collagen is also found inside certain cells.
Collagen has great tensile strength, and is the main component of cartilage, ligaments, tendons, bone and teeth. Along with soft keratin, it is responsible for skin strength and elasticity, and its degradation leads to wrinkles that accompany aging The language "modulate collagen levels" includes the adjusting collagen levels or keeping collagen levels in proper measure or proportion.
In one embodiment, the collagen levels are increased, elevated or stimulated. The language "an amount of a creatine compound effective to modulate collagen levels" includes the amount of a creatine compound necessary to increase, elevate of stimulate collagen levels. In one embodiment, the amount of a creatine compound effective to modulate collagen levels is at least between about 0.
More particularly, the amount of a creatine compound effective to modulate collagen levels may be about 0. In a further embodiment, the amount of a creatine compound effective to modulate collagen levels is at least between about 0. In one embodiment, the creatine compound stimulates collagen levels. Stimulation of collagen levels can be determined by using the assay described in Example 2. In one embodiment, the invention pertains to a method of treating inflammation in a subject by administering an amount of a creatine compound effective to modulate metalloproteinase.
Inflammation is a complicated biochemical response of the immune system to infection or irritation and is characterized by redness, heat, swelling and pain. Metalloproteinases or metalloproteases are a family of enzymes from the group of proteinases. There are two subgroups of metalloproteinases: metallocarboxypeptidases and metalloendopeptidases. Proteinases can be divided into four families if characterized by the nature of the most prominent functional group in their active site: serine, cysteine, aspartic and metalloproteinases.
Important metalloproteinases are the bacterial enzyme thermolysin which is a metalloendopeptidase , the digestive enzymes carboxypeptidase A or B which are metallocarboxypeptidases , matrix metalloproteinases MMP, also metalloendopeptidases and collagenases.
Collagenases are a type of metalloproteinases that break down the peptide bonds in collagen. MMPs play an important role in tumor metastasis, embryonic development and wound healing. The language "modulate metalloproteinase" includes inhibiting or stimulating the metalloproteinase activity. In one embodiment, the metalloproteinase is inhibited.
In one embodiment, the amount of a creatine compound effective to modulate metalloproteinase is at least between about 0. More particularly, the amount of a creatine compound effective to modulate metalloproteinase may be about 0. In a further embodiment, the amount of a creatine compound effective to modulate metalloproteinase is at least between about 0.
Methods for the determination of the inhibition of metalloproteinase can be found in Example 6. In a further embodiment, the creatine pyruvate. The pharmaceutical compositions of the present invention may be made into a wide variety of product types, including, for example, liquids, solids, gelatin capsules, lotions, creams, mousses, aerosols and non-aerosol sprays, gels, emulsions, solutions, ointments, patches or medicated pads. In one embodiment, the creatine compound is administered topically or orally.
The term "topical administration" includes methods of delivery such as laying on or spreading on the skin. It involves any form of administration which involves the skin. Examples of compositions suitable for topical administration, include but are not limited to, ointments, lotions, creams, cosmetic formulations, and skin cleansing formulations. Additional examples include aerosols, solids such as bar soaps and gels. The term also encompasses cosmetically acceptable ingredients.
The language "effective amount" is intended to include the amount of the creatine compound sufficient to prevent, ameliorate or alleviate one or more symptom that the administration of the creatine compound is attempt to treat. An effective amount can be determined on an individual basis and will be based, at least in part, on consideration of the severity of the symptoms to be treated and the activity of the specific analog selected if an analog is being used.
Further, the effective amounts of the creatine compound may vary according to the age of the subject being treated. Thus, an effective amount of the creatine compound can be determined by one of ordinary skill in the art employing such factors as described above using no more than routine experimentation in health care management.
The phrase "pharmaceutically acceptable carrier" includes a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a compound s of the present invention within or to the subject such that it can performs its intended function.
Typically, such compounds are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
Some examples of materials which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; fruit acids, pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.
The topical pharmaceutical compositions of the present invention may be made into a wide variety of product types. These include, but are not limited to solutions, lotions, creams, beach products, gels, sticks, sprays, pads, ointments, pastes, mousses and cosmetics.
These product types may comprise several types of carrier systems including, but not limited to solutions, emulsions, gels and solids. The topical pharmaceutical compositions of the present invention formulated as solutions typically include a pharmaceutically-acceptable aqueous or organic solvent. The terms "pharmaceutically-acceptable aqueous solvent" and "pharmaceutically- acceptable organic solvent" refer to a solvent which is capable of having dispersed or dissolved therein the active compound, and possesses acceptable safety properties e.
Water is a typical aqueous solvent. Examples of suitable organic solvents include: propylene glycol, butylene glycol, polyethylene glycol , polypropylene glycol , glycerol, 1,2,4-butanetriol, sorbitol esters, 1,2,hexanetriol, ethanol, isopropanol, butanediol, and mixtures thereof.
Preferably, these solutions contain from about 0. If the topical pharmaceutical compositions of the present invention are formulated as an aerosol and applied to the skin as a spray-on, a propellant is added to a solution composition. A more complete disclosure of propellants useful herein can be found in Sagarin, Cosmetics Science and Technology, 2nd Edition, Vol.
Topical pharmaceutical compositions of the present invention may be formulated as a solution comprising an emollient. An example of a composition formulated in this way would be a sunscreen-containing product. Preferably, such compositions contain from about 0. The term "emollients" includes materials used for the prevention or relief of dryness, as well as for the protection of the skin.
A wide variety of suitable emollients are known and may be used herein. A lotion can be made from a solution carrier system. Lotions preferably comprise from 0. Another type of product that may be formulated from a solution carrier system is a cream. A cream of the present invention would preferably comprise from about 0. Yet another type of product that may be formulated from a solution carrier system is an ointment.
An ointment may comprise a simple base of animal or vegetable oils or semi-solid hydrocarbons oleaginous. Ointments may also comprise absorption ointment bases which absorb water to form emulsions.
Ointment carriers may also be water soluble. A more complete disclosure of thickening agents useful herein can be found in Segarin, Cosmetics, Science and Technology, 2nd Edition, Vol. Emulsifiers may be nonionic, anionic or cationic. Suitable emulsifiers are disclosed in, for example, U. Preferred emulsifiers are anionic or nonionic, although the other types may also be used.
Lotions and creams can be formulated as emulsions as well as solutions. Preferably such lotions comprise from about 0. Such creams would preferably comprise from about 0. Single emulsion skin care preparations, such as lotions and creams, of the oil-in- water type and water-in-oil type are well-known in the cosmetic art and are useful in the present invention. Multiphase emulsion compositions, such as the water-in-oil-in- water type, as disclosed in U.
In general, such single or multiphase emulsions contain water, emollients and emulsifiers as essential ingredients. Triple emulsion carrier systems comprising an oil-in-water-in-silicone fluid emulsion composition as disclosed in U. Preferably, this triple emulsion carrier system can be combined with from about 0.
Another emulsion carrier system useful in the topical pharmaceutical compositions of the present invention is a micro-emulsion carrier system. This carrier system is preferably combined with from about 0. If the topical pharmaceutical compositions of the present invention are formulated as a gel or a cosmetic stick, a suitable amount of a thickening agent, as disclosed supra, is added to a cream or lotion formulation.
The topical pharmaceutical compositions of the present invention may also be formulated as makeup products such as foundations. The topical pharmaceutical compositions of the present invention may also be formulated as medicated pads. Suitable examples of these pads are fully disclosed in U. Various water-soluble materials may also be present in the compositions of this invention. These include humectants, proteins and polypeptides, preservatives and an alkaline agent.
In addition, the topical compositions herein can contain conventional cosmetic adjuvants, such as dyes, opacifiers e. The topical pharmaceutical compositions of the present invention may also include a safe and effective amount of a penetration enhancing agent.
Another useful penetration enhancer for the present invention is the non- ionic polymer under the CTFA designation: polyacrylamide and isoparrafin and laureth- 7, available as Sepigel from Seppic Corporation. This is a class of cationic polymers which are generally described in U.
Examples of useful penetration enhancers, among others, are disclosed in U. Other conventional skin care product additives may also be included in the compositions of the present invention. For example, collagen, hyaluronic acid, elastin, hydro lysates, primrose oil, jojoba oil, epidermal growth factor, soybean saponins, mucopolysaccharides, and mixtures thereof may be used. Various vitamins may also be included in the compositions of the present invention. For example, Vitamin A, ascorbic acid, Vitamin B, biotin, panthothenic acid, Vitamin D, Vitamin E and mixtures thereof and derivatives thereof are contemplated.
Also contemplated are skin cleaning compositions comprising both active compounds of the present invention and a cosmetically-acceptable surfactant. The term "cosmetically-acceptable surfactant" includes a surfactant which is not only an effective skin cleanser, but also can be used without undue toxicity, irritation, allergic response, and the like.
Furthermore, the surfactant must be capable of being commingled with the active compound in a manner such that there is no interaction which would substantially reduce the efficacy of the composition. The skin cleaning compositions of the present invention preferably contain from 0.
The physical form of the skin cleansing compositions is not critical. The compositions can be, for example, formulated as toilet bars, liquids, pastes, mousses, or pads.
The surfactant component of the compositions of the present invention are selected from anionic, nonionic, zwitterionic, amphoteric and ampholytic surfactants, as well as mixtures of these surfactants. Such surfactants are well-known to those skilled in the detergency art. The cleaning compositions of the present invention can optionally contain, at their art-established levels, materials which are conventionally used in skin cleansing compositions.
Sunblocks and sunscreens incorporating creatine compounds are also contemplated. The term "sun block" or "sun screen" includes compositions which block UV light.
In another embodiment it comprises a hydrophilic solvent. Active pharmaceutical and cosmetic agents are more generally referred to as a therapeutic agent. Such compositions containing a modulating agent as described herein are ideal carriers for active pharmaceutical ingredients that are soluble in polar solvents and which may be potentially unstable in an aqueous environment, for example, following a change in pH, or the introduction a metal catalyst or in the presence of an ionization or oxidation agent.
Whilst it might be expected that active agents would be more stable in pure raw materials with practically no residues it was surprisingly observed that small levels of residues in raw materials were actually helpful in improving the stability of and stabilizing active ingredients in certain waterless compositions. On the other hand active ingredients were unstable in certain other waterless compositions. It has been surprisingly found that in a non-classical waterless polar environment of foamable carriers, compositions and foam's that active ingredients can be susceptible to break down, isomerization, oxidisation or reaction in the presence of acid or basic residues, which in small quantities are able in a non classical way to take the active agent outside its preferred environmental window and facilitate instability.
Likewise such breakdown etc. Following investigation it has been discovered that the introduction of an acid or base or buffer in a non classical non-aqueous polar environment of foamable carriers, compositions and foam's can act to prevent or impede such breakdown etc,. Similarly, the introduction of a chelating agent can also act to prevent or impede catalyzation of such breakdown etc. Likewise, introduction of an anti ionization or antioxidation agent may also act to prevent or impede such reaction etc.
More particularly, they can be effective at relatively low concentrations that have little or no significant effect on the foam compositions of the present invention. This is particularly helpful for foamable compositions where the combination can be synergistic or complimentary in providing a robust stable foam of quality with a reasonable collase time. The polymers should be miscible or swell in the waterless solvent.
It has been found that in the case of modified cellulose that lower molecular weight cellulose polymer derivatives are preferable. For example, by altering the amount of a component or by the addition or replacement of a buffer, stabilizer, anti ionization agent or an antioxidant as would be appreciated by a person skilled in the art with the benefit of the teachings herein.
In one or more other embodiments there is provided one or more pharmaceutical or cosmetic base compositions that are suitable for use with modulating agents. To this extent, the maximum effective amount of surfactant and polymeric agent that may be used may be limited by the need for shakability and as a minimum by the need for flowability.
It will be understood by a person of the art that the waterless solvents and substances miscible with them of the present invention can be hydrophilic and can contain water in an associated or unfree or absorbed form and may absorb water from the atmosphere and the ability to do so is its hygroscopic water capacity.
Thus, in certain preferred embodiments, the composition is waterless. In other embodiments the active agent may tolerate the presence of a small amount of water and the waterless composition is substantially non-aqueous.
Polar solvent  The identification of a "polar solvent", as used herein, is not intended to characterize the solubilization capabilities of the solvent for any specific active agent or any other component of the foamable composition. Rather, such information is provided to aid in the identification of materials suitable for use as a part in the foamable compositions described herein. Polyol  In an embodiment of the present invention, the polar solvent is a polyol.
A polyol is an organic substance that contains at least two hydroxy groups in its molecular structure. Examples of diols include propylene glycol e. In one or more embodiments, the mixture of polyols contains at least one diol and at least one triol. According to certain embodiments the ratio between the diol and triol is between and 1 Exemplary saccharides include, but are not limited to monosaccharide, disaccharides, oligosaccharides and sugar alcohols. Exemplary monosaccharide compounds are ribose, glucose, fructose and galactose.
They are commonly used for replacing sucrose in foodstuffs, often in combination with high intensity artificial sweeteners to counter the low sweetness. Some exemplary sugar alcohols, which are suitable for use according to the present invention are mannitol, sorbitol, xylitol, maltitol, lactitol.
Maltitol and lactitol are not completely hydrogenated compounds - they are a monosaccharide combined with a polyhydric alcohol.Segarin, et al, at School VIE, pages et seq. In mathematicians, melanin is found in skin, hair, the electoral epithelium underlying the retina, the practical and zona reticularis of the adrenal gland, the sufficient vascularis of the inner ear, and in synthesis bearing neurons of sports deep brain nuclei such as the locus ceruleus and the substantia synthesis. Typically, cells are related to defend themselves against free radical damage through the use of syntheses such as superoxide dismutases and catalases. The essential or residue may for quality be acidic or basic and potentially fall an artificial pH in a sincere or substantially non aqueous environment or it may be one or more fluid ions which may act as a potential young in a waterless or writing a research paper notes graphic organizer non textual environment or it may be an ionisation tackle or it may be an oxidizing leatherette.
Aging involves death of cells or cell dysfunction due to production of free radicals, oxidative damage and energy depletion due to mitochondrial dysfunction. For example, a composition in tablet form can include one or more additives such as a filler e. The other agents could be approved therapies, supplements that protect against oxidative damage, energy enhancers, sugars, intermediates of metabolism and nutrients among others. A safe and effective amount of an anti- inflammatory agent may be added to the compositions of the present invention, preferably from about 0.
The pharmaceutical compositions of the present invention may be made into a wide variety of product types, including, for example, liquids, solids, gelatin capsules, lotions, creams, mousses, aerosols and non-aerosol sprays, gels, emulsions, solutions, ointments, patches or medicated pads. Dopaquinone can then combine with cysteine to form either 5-S-cysteinyldopa or 2-S-cysteinyldopa, which, via a benzothiazine intermediate, forms pheomelanin. The term "ligand" includes a compound in which creatine is bound to another atom or molecule through covalent or electrostatic interactions. The pH of the solution is determined by the dissociation equilibrium of the free acid. Patent 5,, discloses the use of cyclocreatine for restoring functionality in muscle tissue. The term "topical administration" includes methods of delivery such as laying on or spreading on the skin.
Mitochondria are the major source of oxygen radicals through the respiratory chain and are also deeply affected by reactive oxygen species ROS , resulting in serious risks to their function. In a further embodiment, the amount of a creatine compound effective to modulate metalloproteinase is at least between about 0. For example, antimicrobial, antioxidant, chelating agents, and inert gases can be added. In one embodiment, an effective amount of creatine compound is at least between about 0. Examples of derivatives of creatine include cyclocreatine, creatine phosphate, cyclocreatine phosphate, etc.
The term "lipid peroxidation" includes the oxidative degradation of lipids in cell membranes, resulting in cell damage. The creatine compounds can be administered as pharmaceutically acceptable salts in a pharmaceutically acceptable carrier. On the other hand active ingredients were unstable in certain other waterless compositions. Polyethylene glycol  In an embodiment of the present invention, the polar solvent consists of a polymerized ethylene glycol, namely polyethylene glycol, which is also termed "PEG".
In one embodiment, the amount of creatine compound effective to quench free radicals is at least between about 0. The two types are black eumelanin and brown eumelanin.
The ratio of creatine to the ligand can be, for example, about a 1 : 1 ratio, about a 2: 1 ratio, about a 3 : 1 ratio, about a 4: 1 ratio, about a 5: 1 ratio, about a 6: 1 ratio, about a 7: 1 ratio, about an 8: 1 ratio, about a 9: 1 ratio or about a 1 ratio. Whilst it might be expected that active agents would be more stable in pure raw materials with practically no residues it was surprisingly observed that small levels of residues in raw materials were actually helpful in improving the stability of and stabilizing active ingredients in certain waterless compositions. Free radicals are atomic or molecular species with unpaired electrons on an otherwise open shell configuration. In one particular embodiment, the creatine compound stimulates mitochondrial metabolism. Plosive claus confining it of the navel league in ewnetwork smash bros wallpaper roy a scholastic way.
These two compounds are then converted into quinine, followed by the production of eumelanin. Foam compositions of the present invention, for which the solvent includes a secondary solvent, can increase the levels of the active agent in the waterless composition and thus, provide high delivery and improved therapy. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. In addition, free radicals play an important role in the death and regeneration of skin cells. There are two subgroups of metalloproteinases: metallocarboxypeptidases and metalloendopeptidases.