WO1997017081A1 - Use of d-arginine and/or l-arginine to remove or block toxic carbonyls and/or dicarbonyls - Google Patents
Use of d-arginine and/or l-arginine to remove or block toxic carbonyls and/or dicarbonyls Download PDFInfo
- Publication number
- WO1997017081A1 WO1997017081A1 PCT/US1996/017821 US9617821W WO9717081A1 WO 1997017081 A1 WO1997017081 A1 WO 1997017081A1 US 9617821 W US9617821 W US 9617821W WO 9717081 A1 WO9717081 A1 WO 9717081A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- arginine
- dicarbonyls
- methylglyoxal
- toxic
- group
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
Definitions
- the present invention relates to a method for removing or blocking toxic dicarbonyls and carbonyls in vivo to prevent them from otherwise binding to and/or cross-linking proteins, forming protein adducts and/or cross-linked complexes, denaturing proteins, disrupting protein structure and/or function, and/or from causing disease states produced by or associated with carbonyl and/or dicarbonyl induced protein complexes. More particularly, the present invention relates to a method of using D-and/or L-arginine, or substituted or modified arginine, or arginine containing compounds to remove or block toxic carbonyls and/or dicarbonyls, for example in vivo.
- the present invention relates to a method of treating disease states which are associated with levels of toxic carbonyls and/or dicarbonyls in vivo, such as diabetes mellitus and acute chemical poisoning, by removing or blocking toxic carbonyls and/or dicarbonyls with the therapeutic administration of L- and/or D-arginine; for example, one embodiment of the present invention relates to the treatment of diabetes mellitus by reducing the in vivo level of toxic dicarbonyl containing methylgloxal and related toxic metabolites of sugar in a patient by administering L- and/or D-arginine to a patient.
- Reactive carbonyl groups for example in vivo are toxic by, inter alia , reacting with native proteins to form adducts and/or cross-linked complexes. This process can inactivate important proteins as well as form unwanted protein complexes in vivo . Indeed, a number of ailments are believed to be caused by the accumulation in vivo, and subsequent reaction of toxic carbonyls and/or dicarbonyls and toxic carbonyls and/or dicarbonyl containing compounds with native compounds such as proteins.
- diabetes mellitus such as, for example, cataracts and kidney problems
- toxic dicarbonyl containing compounds that are sugar-derived such as, for example, but not limited to, methylglyoxal, glyoxal, deosylucossone and chemicals of similar structure.
- high blood glucose levels can lead to high levels of methylglyoxal.
- the methylglyoxal can then, via its reactive dicarbonyl group, react with native proteins leading to, inter alia , unwanted protein-methylglyoxal adducts and cross-linked proteinaceous complexes. These complexes can then be responsible for such symptoms of diabetes mellitus as cataracts and kidney problems.
- the ocular structures of higher vertebrates vary structurally and chemically from those of humans.
- the human eye lacks the tapetum lucidum of many higher vertebrates, for example the deer.
- the human sclera contains no bones as in birds.
- Human aqueous humor does not coagulate as in the rabbit.
- the human retina contains color receptor pigments lacking in the dog.
- Prior to the publication of the inventor's exhaustive biochemical and enzymatic study of the human eye no one had isolated methylglyoxal, glyoxalase I and glyoxalase II from the human lens (Haik et al. 1994, which is incorporated herein by reference).
- methylglyoxal has the ability to produce solid yellow gel formation from liquid proteins. The inventor attributes this at least primarily, and not intending to be bound by theory, to imine bond formation and the cross-linking of proteins.
- the inventor has discovered that one can block methylglyoxal-induced gel formation of liquid bovine serum albumin by pretreatment with D-arginine or L-arginine in the free base or hydrochloride form.
- the inventor believes, but does not intend to be limited by any particular theory, that a process involving protein cross-linking by methylglyoxal (and perhaps to a lesser degree by glyoxal and other dicarbonyls) can produce rapid cataract formation in diabetics and relatively slower senile cataracts formation in non-diabetics over a period of years.
- methylglyoxal Larger amounts of methylglyoxal would be expected to be produced from higher concentrations of the substrate glucose, however, free methylglyoxal levels are rapidly diminished by attachment to available proteins and amino acids or detoxified via the glutathione-dependent glyoxalase system. This is especially important since levels of reduced glutathione diminish with oxidative stress and the aging of tissues.
- the present invention provides a method for removing toxic carbonyls and/or dicarbonyls from environments, for example in vivo environments, before they react with tissues to form adducts and/or detrimental cross-linked complexes, thereby providing a method for eliminating or reducing the detrimental effects caused, for example in vivo, by toxic dicarbonyls.
- the present invention recognizes that both L- and D-arginine are reactive with toxic carbonyls and dicarbonyls in such a manner that the presence of D- and/or L-arginine can react with toxic carbonyls and dicarbonyls in order to block and/or remove them before they can react with other compounds, such as native proteins.
- L- and/or D-arginine can, for example in vivo , effectively compete with native "target" compounds, such as proteins, for binding to any toxic dicarbonyls and carbonyls that might be present, thereby providing a method for blocking and/or removing toxic carbonyls and/or dicarbonyls from an environment before the dicarbonyls and/or carbonyls can react with native tissues and cause damage.
- native "target" compounds such as proteins
- the present invention further recognizes that in addition to physiologically active L-arginine, importantly one can also use non-naturally occurring D-arginine with the instant invention.
- D-arginine to block and/or remove toxic dicarbonyls and/or carbonyls from, for example in vivo environments provides a non-physiologically reactive substance with which to block and/or remove toxic dicarbonyls and/or carbonyls. This can be of great value as it provides a means of administering a water soluble and excretable scavenger that is not physiologically active other than to act in the blocking/scavenging manner of the present invention.
- the method of the present invention solves the problems confronted in the art in a simple and straightforward manner.
- the present invention recognizes that D- and L-arginine can, for example in vivo, reduce the level of toxic carbonyls and/or dicarbonyls and thereby reduce or prevent adduct formation and cross-linking with native tissues which would otherwise be caused by the presence of toxic dicarbonyls and/or carbonyls in a living body.
- What is provided therefore is a method which utilizes arginine, and/or substituted or modified arginine, to preferentially and chemically react with toxic carbonyls and dicarbonyls, preferably in vivo, to thereby remove them before they react with native tissues to form detrimental adducts and/or cross-linked complexes.
- This method can reduce the level, and/or block toxic carbonyls and dicarbonyls in a living body and thereby reduce the damaging effects caused by cross-linking and/or adduct formation of carbonyls with native tissues.
- D-arginine in addition to physiologically active L-arginine, importantly one can also use non-naturally occurring D-arginine to block and/or remove toxic dicarbonyls and/or carbonyls from, for example in vivo environments.
- D-arginine importantly provides a non-physiologically reactive substance with which to block and/or remove toxic dicarbonyls and/or carbonyls from a living system.
- Figure 1 shows the structure of arginine as well as numbered positions whereat arginine may be modified and/or substituted in keeping with the practice of the present invention
- Figure 2 shows the structure of methylglyoxal, a toxic dicarbonyl containing metabolite of glucose and target of the blocker of the instant invention, arginine, substituted or modified arginine, or arginine like molecules;
- Figure 3 shows the structure of one possible adduct, a dimer adduct of methylglyoxal-arginine, formed by a blocking reaction of the present invention, the reaction of arginine with methylgyloxal;
- Figure 4 shows the structure of one possible adduct, a methylglyoxal-arginine adduct, formed by a blocking reaction of the present invention, the reaction of arginine with methylgyloxal;
- Figure 5 shows the structure of one possible adduct, a methylglyoxal-arginine adduct, formed by a blocking reaction of the present invention, the reaction of arginine with methylgyloxal;
- Figure 6 shows the reactive pi electron clouds above or below the planes of carbonyl groups forming a reactive target site for the blocking arginine of the present invention.
- Table 1 shows a representative but not inclusive list of dicarbonyl structures that can act as "targets" for the arginine blockers of the present invention
- Table 2 shows an illustrative list of possible types of arginine, substituted arginine and/or modified arginine blockers of the present invention including complexes such as polypeptides;
- Table 3 shows biochemical pathways related to sugar metabolism, diabetes mellitus and the production of toxic dicarbonyl containing methylglyoxal including the role glyoxalase I and II enzymes;
- Table 7 shows the effect of pH changes on the reaction of methylglyoxal with bovine serum albumin.
- the present invention recognizes that both L- and D-arginine can be used to block and/or inactivate toxic carbonyls and/or dicarbonyls that would otherwise in vivo react with native tissues to form detrimental adducts and/or cross-linked complexes.
- the instant invention recognizes that both L- (levorotary) and D- (dextrorotary) stereoisomers of the amino acid arginine are active in this capacity. This means that both naturally occurring and physiologically active L-arginine and non-naturally occurring and physiologically inactive D-arginine can be used in the method of the present invention.
- D-arginine can be used as the blocker or "scavenger" of the present invention as many advantages may be presented by using D- over L-arginine.
- D-arginine has no other known use in living systems and is not recognized by known enzymes or other biologic machinery
- D-arginine is not biologically active, other than as a blocking agent in the practice of this invention, nonetheless it is water soluble and therefore excretatable.
- administration of the blocker is not toxic due either to biological activity or biological accumulation, for example.
- the present invention is demonstrated both in vitro and in vivo and it is shown that, in fact, both D- and L-arginine can act to block and inactivate toxic dicarbonyls before they can form physiologically detrimental complexes.
- At least one disease state, diabetes mellitus is studied in detail in order to provide one example of the beneficial use of the present invention.
- Arginine (2-amino-5-guanidovaleric acid) ( Figure 1) is a water soluble dibasic amino acid with a molecular weight of 174.20 containing a reactive guanidino grouping.
- the L form of arginine occurs in mammalian systems and is enzymatically reactive, whereas the D form of arginine does not occur naturally in mammalian systems and is not enzymatically reactive. Both are especially well suited as scavengers and protectants against the reactive dicarbonyls of methylglyoxal, glyoxal, deoxyglucosone and similar compounds of the following structures (and see Figure 2 and Table 1):
- arginine can react with any of the above-identified compounds forming, for example, the products shown in Figures 3-5.
- arginine or other toxic carbonyl and/or dicarbonyl blockers of the present invention can react with any chemical structure that is reactive with the group or with any compound containing any such reactive structure. This can include, for example but not limited to, the following groups and compounds containing the following groups: carbonyls, dicarbonyls, deoxyglucosone, methylglyoxal, glyoxal, malonic acid aldehyde, malonidialdehyde, formaldehyde, gluteraldehyde and other aldehydes (see also Table 1).
- the carbonyl and/or dicarbonyl blocker arginine may be present as free L- and/or D- arginine, or as free base forms or salts thereof, or may be present as part of a larger complex such as, for example, a peptide, or, for example, be administered as a prodrug form wherein the active arginine is specifically delivered or uncovered in vivo .
- the blocker may also be supplied in a precursor form such as, for example, by supplying precursors of L-arginine biosynthesis such that in vivo L-arginine is produced.
- Table 2 shows illustrative, but not limiting, types of arginine and arginine containing dicarbonyl blockers of the present invention.
- the present invention involves the use of any arginine, modified or substituted arginine or arginine-like molecule (such as, for example but not limited to those structures shown in Table 2) that is reactive with any appropriate target such as, for example, carbonyls and dicarbonyls.
- any appropriate target such as, for example, carbonyls and dicarbonyls.
- the reactive "target" group to be blocked by the arginine, modified or substituted arginine or arginine-like blocker of the present invention can include toxic dicarbonyl groups, dicarbonyl containing molecules, as well as simple aldehydes and the like such as formaldehyde and any other chemical group that is reactive with arginine and arginine like molecules.
- the toxic carbonyl and dicarbonyl blockers of the present invention can be used in cases such as, but not limited to the treatment of toxic exposure to, for example but not limited to, aldehydes, ketones and ketoaldehydes.
- the present invention can be used to treat metabolic medical conditions in which oxidative stress could deplete the body stores of "reduced glutathione" and thus compromise the ability of the glyoxalase enzyme system to detoxify dicarbonyls such as methylglyoxal including such medical condition as diabetic ketoacidoses, lactic acidosis, metabolic acidosis, respiratory acidosis, uremia, and localized tissue anoxia as produced by the narrowing of blood vessels to a target organ such as the heart, muscle, brain, kidney and so forth.
- Table 1 shows, for example, some representative types of dicarbonyl structures that can be blocked by the practice of the present invention.
- the following discussion concerns the administration of arginine as a blocker of toxic dicarbonyl-containing methylglyoxal, a toxic end product of sugar metabolism and, as discussed above, a problematic compound in diabetes mellitus.
- Methylglyoxal is found in elevated amounts in the blood of diabetics and lesser amounts in the blood of non-diabetics. Methylglyoxal is a toxic ketoaldehyde metabolite of glucose and other sugars formed in the Embden-Meyerhoff and Polyol pathways and via anaerobic glycolysis in normal and diabetic human tissues (Table 3).
- Glyoxal was produced by Harries in 1904 from benzene, and methylglyoxal was derived from o-xylene by ozonization by A. A. Levine and A. G. Cole in 1932. Glyoxal has been used by embalmers to plasticize tissues. Nobel Prize laureate, Dr. Albert Szent-Gyorgyi describes the high degree of toxicity of methylglyoxal in his text "The Living State” and postulated a role for it in cell proliferation and cancer. Ruth van Heyningen of Nuffield Laboratory at Oxford identified glyoxalase in the lens of rabbits with radiation-induced cataract in 1954.
- the substrate of the glyoxalase system is methylglyoxal, a toxic metabolite of glucose. It is a keto-aldehyde with 2 very reactive carbonyls. Methylglyoxal binds primarily in human proteins to lysine, cysteine, and arginine sites in the tissue protein. The reaction with lysine and cysteine is reversible, and that with arginine is irreversible.
- glyoxalase I Several inhibitors of glyoxalase I have been identified including compounds containing the tropolone structure, squaric acid derivatives, aflatoxin B1, and glutathione adducts of benzoquinone and naphthoquinone. These inhibitors have not been identified in the human body.
- the present invention proposes, but does not intend to be bound by any particular theory, that it is not a primary failure of the glyoxalase system which produces tissue damage and cataracts, but rather an excessive flux of glucose producing methylglyoxal and other dicarbonyls. In age-related cataracts, lens damage from methylglyoxal and other dicarbonyls may occur at lower concentrations over periods of decades.
- the present invention suggests that the process of protein cross-linking which is clinically visible as a cataract is analogous to the protein cross-linking in the vasculature and microvasculature of the circulatory system, kidney, retina, brain, nerve tissues and throughout the human body.
- Critical to this theory of imine type cross-linking is the fact that all human proteins irrespective of amino acid sequence contain amine groups capable of reacting with free carbonyls.
- Methylglyoxal can cross-link and denature protein and is present in elevated amounts in the blood of diabetics and also found in the human crystalline lens. Additionally, glyoxalase I and II are found ubiquitously in mammalian tissues including the human lens. It is reasonable to consider that an excessive methylglyoxal flux in diabetics can produce damage to structural and functional proteins in diabetes.
- methylglyoxal may damage the tissues of the non-diabetic. It is reasonable to consider that i) excessive flux of methylglyoxal and similar dicarbonyls such as glyoxal and 3-deoxyglucosone; and/or ii) failure of the glyoxalase system including, but not limited to diminished amounts of the essential coenzyme of glyoxalase I, reduced glutathione, can produce diabetic tissue damage by the dicarbonyl grouping.
- Methylglyoxal is a toxic ketoaldehyde by-product of sugar metabolism and is an important cause of cross-linking of human organ proteins via imine bonding to amino groups especially arginine, cystine, and lysine. The bonding to arginine is irreversible.
- Methylglyoxal can be detoxified by glyoxalase I and glyoxalase II in the presence of the antioxidant coenzyme "reduced" glutathione with the resulting product being lactic acid.
- the present inventor has demonstrated for the first time the presence of methylglyoxal and the presence of both glyoxalase I and glyoxalase II in human lens tissue in two separate studies.
- the amount of the essential antioxidant coenzyme glutathione decreases with age in human lens tissue, and this has been implicated in the development of age-related cataract.
- the present invention shows that L-arginine, as well as D-Arginine, is capable of blocking the binding of methylglyoxal to both egg albumin and bovine serum albumin.
- the levorotary form of most amino acids is the biologically active form.
- the dextrorotary form of arginine is also capable of scavenging methylglyoxal and preventing binding to bovine serum albumin and ovalbumin. There is no appreciable steric hindrance to this reaction.
- the sp 2 ⁇ bonding is present in both compounds (See Figure 6).
- the present invention comprises the use of L-arginine and/or D-arginine to prevent the linking of methylglyoxal, glyoxal, and all dicarbonyl metabolites to protein in human and mammalian tissues and to prevent the cross-linking of these proteins.
- the Examples presented herein show that a solution of liquid methylglyoxal reacts with liquid bovine serum albumin to form a gelatin at body temperature in a variety of strongly buffered and pH adjusted systems.
- the present invention demonstrates the ability of D-arginine to block the cross-linking reaction of methylglyoxal and protein in bovine serum albumin in vi tro and maintain the albumin in a liquid state.
- guanidine and aminoguanidine should block methylglyoxal and glyoxal from cross-linking protein albumin and that glycocyamine and any number of amino acids should work, including, sulfhydryl-containing amino acids.
- the present inventor has tested these compounds and they do not behave as good blockers of or protectant agents against the cross-linking of albumin by methylglyoxal or glyoxal.
- aminoguanidine is in early human trials as a preventative agent of the formation of advanced glycation end products (AGEs).
- Glycocyamine, ornithine, citrulline, aminoguanidine, diaminoguanidine, and guanidine are chemically similar to arginine but did not work. It is believed that they did not function as protectants and scavengers of methylglyoxal because they lack the appropriate side groupings.
- guanidine hydrochloride might also not function as effective scavengers, for example in vi vo, because of their tendency to unfold or disrupt protein structure (see, e.g., Smith J.S. and Schotz, J.M.; and Zhang, YL et al.). Indeed, the only agents which worked consistently were the hydrochloride salts and free base forms of D-arginine and L-arginine.
- the present invention has reacted methylglyoxal in both buffered and unbuffered systems at pH 6.4 to 11 and found that methylglyoxal binds albumin more effectively at acidic pH levels.
- acidic solution one millimole of methylglyoxal is capable of converting 2cc bovine serum albumin to gelatin at room temperature, but that one millimole of L-arginine or D-arginine can be used to pretreat the bovine serum albumin and will prevent gelatin formation when the methylglyoxal is added.
- one millimole of methylglyoxal is capable of converting 2cc of a liquid 30% solution of bovine serum albumin to gelatin at room temperature, 75, 80, 83, 90 and 98.6 degrees Fahrenheit.
- the liquid bovine serum albumin is pretreated with one millimole of either L-arginine or D-arginine prior to the addition of the one millimole of methylglyoxal to the bovine serum albumin, then, the methylglyoxal fails to convert the bovine serum albumin from liquid to gelatin and the albumin remains liquid.
- L-arginine is subject to enzymatic activity and is biologically active in diverse processes, e.g., (1) several isoforms of nitric oxide synthetase produce nitric oxide from L-arginine enzymatically but not D-arginine (Morikawa, E., et.al.); (2) nitric oxide plays an unclear role in septic shock (Wolfe, T.A., et.al.); (3) dietary L-arginine increases levels of interleukin 1 alpha in patients with diabetes mellitus (Hayde, M., et.al.); (4) paradoxically L-arginine and nitric oxide have beneficial effect in protecting against the neurotoxicity produced in the corpus striatum of rats by the 1-methyl-4-phenylpyridinium ion
- L-arginine when infused into the rat L-arginine induces the release of glucagon and insulin markedly and slightly increases levels of somatosatin (Takahashi, K., et.al.); (6) L-arginine can aggravate gastric injury produced by ethanol in rats through mechanisms both dependent on and independent of nitric oxide (Ferraz, J.G., et.al.); (7) L-arginine reduces heart collagen accumulation in the diabetic db/db mouse (Khaidar, A., et.al.). There is a plethora of beneficial and harmful effects attributed to L-arginine. It may, nevertheless, have a beneficial effect in diabetes and in the prevention of protein cross-linking.
- D-arginine is a good candidate for use as a scavenger of methylglyoxal, glyoxal and other glycation products which contain 2 adjacent carbonyl groupings as in the case of deoxyglucosone.
- the reaction between the guanidino group of D-arginine and the dicarbonyl grouping of, e.g., methylglyoxal is a straightforward, pH-dependent, non-enzymatic reaction.
- tissue acidosis which is an ideal condition for the reaction between dicarbonyls, e.g., methylglyoxal, and protein bound or free arginine to progress rapidly.
- serum albumins treated with methylglyoxal become visibly syrupy and viscous. This could aggravate local tissue anoxia in living systems, decrease the local tissue pH further, and accelerate protein cross-linking.
- subject can refer to a human patient or a non-human animal in need of treatment.
- the present invention comprises primarily the use of arginines (free base forms and hydrochloride salts thereof) and appropriate related chemicals to block cross-linking reactions of toxic dicarbonyls, such as methylglyoxal and glyoxal, with proteins in mammals.
- the medication of the present invention to be administered to a subject could comprise any compound containing an L-arginine or D-arginine structure in which a reactive site is sterically unhindered or can become sterically unhindered in the subject's body (as in the case of a pro-drug).
- the medication of the present invention to be administered to a subject could comprise any compound containing a structure functionally similar to an L-arginine or D-arginine structure in which a reactive site is sterically unhindered or can become sterically unhindered in the subject's body (as in the case of a pro-drug) such as, but not limited to, custom designed (engineered) carbohydrates and the like.
- the therapeutically effective daily amount of the medication of the present invention could comprise from about 400mg to about 1700mg of free base forms of D-arginine, from 500mg to 2000mg of hydrochloride salts of D-arginine, from about 400mg to about 1700mg of free base forms of L-arginine, or from 500mg to 2000mg of hydrochloride salts of L-arginine.
- one half of this amount could be administered 2 times per day, 15-30 minutes prior to meals, or one third of this amount could be administered 3 times per day, 15-30 minutes prior to meals.
- a therapeutically effective daily amount of the medication of the present invention could comprise racemic mixtures of L-arginine and D-arginine, either free base forms, hydrochloride salts, or both.
- a therapeutically effective daily amount of the medication of the present invention can be administered orally or parenterally (in which case about one fifth of the dose would be used).
- the medication could be administered chronically or in emergency situations. Implants or time-release forms could be used as well.
- Another method of treating a subject under the present invention could be to administer L-citrulline or another precursor of L-arginine in the urea cycle to produce the L-arginine in the subject's body.
- Yet another method of treating a subject could be to administer a compound containing a structure functionally similar to L-citrulline or another precursor of L-arginine in the urea cycle to produce the L-arginine in the subject's body.
- bovine serum albumin BSA
- 2 cc of 30% bovine serum albumin (BSA) was added by glass pipette (Kimax 1/100) to each of three glass 7 ml. test tubes numbered 1, 2, and 3.
- 0.4 ml. of 6 molar HEPES buffer was added to tube #1 by glass pipette.
- 0.5 ml. of 6 molar HEPES buffer was added to test tube #2.
- 0.3 ml. of 6 molar HEPES buffer was added to tube #3.
- HEPES salt, HEPES acid, and bovine serum albumin was obtained from Sigma.
- Tubes 1, 2 and 3 were placed in a warm water bath at 98.6 degrees Farenheit with PTFE-coated microflea magnetic stirrer bars on a magnetic stirrer at 217 RPM for 5 minutes.
- 0.18 ml. of 40% methylglyoxal (pH not adjusted) was added to test tube #1.
- 0.10 ml. of 40% methylglyoxal (buffered with 0.3 cc of 6 molar HEPES to pH 7.44 at 98.6 degrees Fahrenheit) was added to test tube #2.
- 0.20 ml. of 40% methylglyoxal (buffered with 0.3 cc of 6 molar HEPES to pH 7.36 at 98.6 degrees Fahrenheit) was added to test tube #3.
- test tube #7 Into test tube #7 was added 1 millimole of L-arginine hydrochloride, not pH adjusted. Into test tube #8 was added 1 millimole of D-arginine hydrochloride, not pH adjusted. To each of the tubes sample numbers 1 through 8 pH-adjusted methylglyoxal was added as described in column C. Again the pH was recorded for each sample and observations listed in the table. Sample numbers 1, 2, 3 and 4 formed a distinguishable gel. Sample numbers 5, 6, 7 and 8 remained liquid. After 3 hours the heating unit was turned off reducing the temperature to room temperature, 75 degrees Fahrenheit, to prevent the drying out of the sample and the reaction was allowed to proceed overnight. Sample #7 became slightly viscous overnight.
- EXAMPLE 4 As described in Table 7, 2 ml. of a 30% aqueous solution (0.85% NaCl) of bovine serum albumin was added to each glass test tube and placed in a 98.6 F warm water bath with a microflea magnetic stirrer bar in each tube. The magnetic stirrer was set to 217 rpm. The pH was checked at five minutes. The B.S.A. was buffered to the desired pH with 6 molar HEPES by slow addition of the buffer to the albumin at 98.6 F and 217 rpm until the pH was stable.
- the glass electrode of the pH meter (Hanna) was placed in the test tube with the buffered albumin and the buffered methylglyoxal was added slowly with a 25 gauge needle on a glass syringe.
- the pH was constantly monitored as were the color and fluid characteristics of the mixture.
- the mixing speed was constant at 217 rpm at a temperature of 98.6 F.
- the tubes were tilted periodically to determine fluidity, viscosity, color and gel formation.
- the end-point was recorded when a visible non-flowing gel formed in the tube and could not be caused to flow when the tube was inverted at 40 degrees below the horizontal for two minutes. At this point the gelatin was adherent to the glass pH electrode. Often the gelatin could be removed as a solid mass. At lower pH levels the gel had the consistency of firm rubber and at more neutral pH the consistency was that of soft gelatin.
- the albumin samples which were pretreated with 1 millimole of the D-arginine Hydrochloride or 1 millimole of L-arginine Hydrochloride did not gel at any time and remained liquid.
- Example 5 shows the in vivo use of both D- and L- arginine in the prevention or reduction of signs of diabetes in an animal model.
- 50 young adult male New Zealand White rabbits are divided into five groups of ten and fed standard veterinary rabbit pellet food. All rabbits are made diabetic by streptozotocin injection (65 mg/kg administered i.v. per the technique of R. Burcelin, (1993) J. Biochemistry 291:109, which is hereby incorporated by reference).
- the arginine protectant is administered concurrently in the diet or prior to the challenge with radiolabeled methylglyoxal per i.v.
- Group 1 Using a 25 gauge needle and i.v. apparatus, 1 millimole of radiolabeled methylglyoxal (e.g., tritiated or carbon 14 labeled) (or an appropriate dose, for example, but not limited to ranging from 1 nmole to a sublethal dose, such as the LD50 of methylglyoxal which is reported to be 252 mg/kg in rats; Ceskoslovenska Farmacie, (1966) 15:300, which is hereby incorporated by reference) in 10cc of normal saline is administered per day by ear vein over a 2 hour period. This is repeated daily for 30, 60, 90, 120 or some other appropriate number of days.
- radiolabeled methylglyoxal e.g., tritiated or carbon 14 labeled
- an appropriate dose for example, but not limited to ranging from 1 nmole to a sublethal dose, such as the LD50 of methylglyoxal which is reported to be 252
- Group 2 The rabbits of group 2 are fed a diet supplemented with oral D-arginine HCL 30mg/kg/day (or an appropriate dose which can range from, for example, but not limited to, 1 mg/kg/day to 100 mg/kg/day). As described above for Group 1, the rabbits in Group 2 are administered an identical regime of radiolabeled methylglyoxal as the control group, Group 1 (for example, 1 millimole of tritiated methylglyoxal in 10cc normal saline is administered by ear vein over a period of 2 hours per day for, for example, 30 days).
- Group 1 for example, 1 millimole of tritiated methylglyoxal in 10cc normal saline is administered by ear vein over a period of 2 hours per day for, for example, 30 days).
- Group 3 The rabbits of group 3 are fed a diet supplemented with oral L-arginine HCL 30mg/kg/day (or an appropriate dose which can range from, for example, but not limited to, 1 mg/kg/day to 100 mg/kg/day). As described above for Group 1, the rabbits in Group 3 are administered an identical regime of radiolabeled methylglyoxal as the control group.
- Group 4 The rabbits of group 4 receive L-arginine HCL by ear vein in 10cc normal saline at a dose of 10mg/kg/day (or an appropriate dose which can range from, for example, but not limited to, 1 mg/kg/day to 100 mg/kg/day) for the duration of the experiment.
- the rabbits in Group 4 are also administered an identical regime of radiolabeled methylglyoxal as the control group.
- the arginine protectant is administered i.v. for a 2 hour period immediately proceeding administration of the methylglyoxal.
- Group 5 The rabbits of group 5 receive D-arginine
- the rabbits in Group 5 are also administered an identical regime of radiolabeled methylglyoxal as the control group.
- the arginine protectant is administered i.v. for a 2 hour period immediately proceeding administration of the methylglyoxal.
- the experimental groups show that the administration of the dicarbonyl blocker arginine, both D- and L-, and both i.v. and by mouth, effectively blocks the detrimental effects of methylglyoxal in vivo . This is shown by the reduced or absent gross and microscopic changes in the kidney of the treated animals as compared to the control, and by the reduced or absent accumulation of radiolabeled methylglyoxal in the kidneys of the arginine treated animals as compared with the control.
- Example 6 shows the in vivo use of both D- and L-arginine in the prevention or reduction of symptoms of diabetes in an animal model.
- mice 50 young adult male New Zealand White rabbits are divided into five groups of ten and fed standard veterinary rabbit pellet food. All rabbits are made diabetic by streptozotocin injection (65 mg/kg administered i.v. per the technique of R. Burcelin, (1993) J. Biochemistry 291:109, which is hereby incorporated by reference). In all groups except Group 1, the arginine protectant is administered concurrently in the diet or prior to the challenge with radiolabeled glucose per i.v.
- Group 1 Using a 25 gauge needle and i.v. apparatus, a solution of radiolabeled glucose, for example, but not limited to a 10% solution of tritiated or carbon 14 labeled glucose, is administered by ear vein over, for example, a 2 hour period per day. This is repeated daily for 30, 60, 90, 120 or some other appropriate number of days.
- a solution of radiolabeled glucose for example, but not limited to a 10% solution of tritiated or carbon 14 labeled glucose
- Group 2 The rabbits of group 2 are fed a diet supplemented with oral D-arginine HCL 30mg/kg/day (or an appropriate dose which can range from, for example, but not limited to, 1 mg/kg/day to 100 mg/kg/day). As described above for Group 1, the rabbits in Group 2 are administered an identical regime of radiolabeled glucose as the control group, Group 1 (for example, a 10% solution of tritiated glucose administered by ear vein over a period of 2 hours per day for, for example, 30 days).
- Group 1 for example, a 10% solution of tritiated glucose administered by ear vein over a period of 2 hours per day for, for example, 30 days.
- Group 3 The rabbits of group 3 are fed a diet supplemented with oral L-arginine HCL 30mg/kg/day (or an appropriate dose which can range from, for example, but not limited to, 1 mg/kg/day to 100 mg/kg/day). As described above for Group 1, the rabbits in Group 3 are administered an identical regime of radiolabeled glucose as the control group.
- Group 4 The rabbits of group 4 receive L-arginine HCL by ear vein in 10cc normal saline at a dose of 10mg/kg/day (or an appropriate dose which can range from, for example, but not limited to, 1 mg/kg/day to 100 mg/kg/day) for the duration of the experiment. As described above for Group 1, the rabbits in Group 4 are also administered an identical regime of radiolabeled glucose as the control group.
- the arginine protectant is administered i.v. for a 2 hour period immediately proceeding administration of the methylglyoxal.
- Group 5 The rabbits of group 5 receive D-arginine HCL by ear vein in 10cc normal saline at a dose of 10mg/kg/day (or an appropriate dose which can range from, for example, but not limited to, 1 mg/kg/day to 100 mg/kg/day) for the duration of the experiment. As described above for Group 1, the rabbits in Group 5 are also administered an identical regime of radiolabeled glucose as the control group. The arginine protectant is administered i.v. for a 2 hour period immediately proceeding administration of the methylglyoxal.
- the experimental groups show that the administration of the dicarbonyl blocker arginine, both D- and L-, and both i.v. and by mouth, effectively blocks the detrimental effects of diabetes, at least on the kidney, in vivo . This is shown by the reduced or absent gross and microspopic changes in the kidney of the treated animals as compared to the control, and by the reduced or absent accumulation of radiolabeled glucose metabolites in the kidneys of the arginine treated animals as compared with the control.
- Example 7 is identical to Example 5 except that the animals are not made diabetic by streptozotocin. Also, the amount of radiolabeled methylglyoxal may be as high as a sub-lethal dose, the LD50 for methylglyoxal being reported as being 252 mg/kg (Ceskoslovenska Farmacie, (1966) Vol. 15, page 300).
- This example shows that arginine blocks changes caused by methylglyoxal even in a non-diabetic animal model.
- Example 8 shows the in vivo use of both D- and L-arginine in the reduction of the level of toxic methylglyoxal in an animal.
- methylglyoxal or an appropriate dose, for example, but not limited to ranging from 1 nmole to a sub-lethal dose
- 10cc of normal saline is administered per day by ear vein over a 2 hour period to all animals. This is repeated daily for 30, 60, 90, 120 or some other appropriate number of days.
- the arginine protectant is administered concurrently in the diet or prior to the challenge with radiolabeled methylglyoxal per i.v.
- Group 1 The rabbits of control group 1 are not administered any arginine but are administered methylglyoxal in a manner identical to the experimental groups (e.g., 1 millimole of methylglyoxal per day for 30 days).
- Group 2 The rabbits of group 2 are fed a diet supplemented with oral D-arginine HCL 30mg/kg/day (or an appropriate dose which can range from, for example, but not limited to, 1 mg/kg/day to 100 mg/kg/day). As described above for Group 1, the rabbits in Group 2 are administered an identical regime of methylglyoxal as the control group, Group 1.
- Group 3 The rabbits of group 3 are fed a diet supplemented with oral L-arginine HCL 30mg/kg/day (or an appropriate dose which can range from, for example, but not limited to, 1 mg/kg/day to 100 mg/kg/day). As described above for Group 1, the rabbits in Group 3 are administered an identical regime of methylglyoxal as the control group.
- Group 4 The rabbits of group 4 receive L-arginine HCL by ear vein in 10cc normal saline at a dose of 10mg/kg/day (or an appropriate dose which can range from, for example, but not limited to, 1 mg/kg/day to 100 mg/kg/day) for the duration of the experiment. As described above for Group 1, the rabbits in Group 4 are also administered an identical regime of methylglyoxal as the control group. The arginine protectant is administered i.v. for a 2 hour period immediately proceeding administration of the methylglyoxal.
- Group 5 The rabbits of group 5 receive D-arginine HCL by ear vein in 10cc normal saline at a dose of 10mg/kg/day (or an appropriate dose which can range from, for example, but not limited to, 1 mg/kg/day to 100 mg/kg/day) for the duration of the experiment. As described above for Group 1, the rabbits in Group 5 are also administered an identical regime of methylglyoxal as the control group. The arginine protectant is administered i.v. for a 2 hour period immediately proceeding administration of the methylglyoxal.
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Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
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AU10740/97A AU1074097A (en) | 1995-11-07 | 1996-11-07 | Use of d-arginine and/or l-arginine to remove or block toxic carbonyls and/or dicarbonyls |
GB9809878A GB2322800B (en) | 1995-11-07 | 1996-11-07 | Use of D-Arginine and/or L-Arginine to remove or block toxic carbonyls and/or dicarbonyls |
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US630495P | 1995-11-07 | 1995-11-07 | |
US60/006,304 | 1995-11-07 |
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PCT/US1996/017821 WO1997017081A1 (en) | 1995-11-07 | 1996-11-07 | Use of d-arginine and/or l-arginine to remove or block toxic carbonyls and/or dicarbonyls |
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AU (1) | AU1074097A (en) |
CA (1) | CA2236923A1 (en) |
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US4234570A (en) * | 1977-06-10 | 1980-11-18 | Kakenyaku Kako Kabushiki Kaisha | Proteinic active substances |
US5077313A (en) * | 1988-11-25 | 1991-12-31 | Gert Lubec | Process for inhibiting pathological collagen cross-linking in diabetes patients |
-
1996
- 1996-11-07 CA CA 2236923 patent/CA2236923A1/en not_active Abandoned
- 1996-11-07 AU AU10740/97A patent/AU1074097A/en not_active Abandoned
- 1996-11-07 WO PCT/US1996/017821 patent/WO1997017081A1/en active Application Filing
- 1996-11-07 GB GB9809878A patent/GB2322800B/en not_active Expired - Fee Related
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Publication number | Priority date | Publication date | Assignee | Title |
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US4234570A (en) * | 1977-06-10 | 1980-11-18 | Kakenyaku Kako Kabushiki Kaisha | Proteinic active substances |
US5077313A (en) * | 1988-11-25 | 1991-12-31 | Gert Lubec | Process for inhibiting pathological collagen cross-linking in diabetes patients |
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GB9809878D0 (en) | 1998-07-08 |
AU1074097A (en) | 1997-05-29 |
GB2322800B (en) | 1999-09-22 |
GB2322800A (en) | 1998-09-09 |
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