CA2012470C - Method for silicon reduction with dimercaptosuccinic acid (dmsa) - Google Patents
Method for silicon reduction with dimercaptosuccinic acid (dmsa)Info
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- CA2012470C CA2012470C CA002012470A CA2012470A CA2012470C CA 2012470 C CA2012470 C CA 2012470C CA 002012470 A CA002012470 A CA 002012470A CA 2012470 A CA2012470 A CA 2012470A CA 2012470 C CA2012470 C CA 2012470C
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- silicon
- dmsa
- dimercaptosuccinic acid
- blood
- composition
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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
Abstract
A method for silicon reduction with Dimercaptosuccinic Acid (DMSA) is described. DMSA is administered to reduce levels of silicon in blood and tissue thereby reducing blood pressure, improving kidney function, preventing or retarding the progression of chronic renal failure, treating the accumulation of silicon in advanced kidney disease, and/or preventing the onset or improving the current status of dementia and Alzheimer's Disease.
Description
20 1 247~
METHOD FOR SILICON REDUCTION
WITH DIMERCAPTOSUCCINIC ACID (DMSA) This invention relates generally to a method for reduction of silicon levels with Dimel~iap~succinic Acid (DMSA). More particularly, this invention relates to a method for reduction of silicon levels in human blood and tissue with DMSA, in order to reduce blood pl~ s~ r, impra~e kidney function, prevent or retard the pl~glession of chronic renal failure, treat the ~rcum~ tion of silicon in advanced kidney disease, and/or prevent the onset, or improve the current status of dP-mPnti~
and ~ hPimPr's Disease.
Silicon, next to oxygen, is the most prevalent elemPnt on earth, and is the most abundant miner~l in the earth's crust. It occurs in nature as silica oxides (SiO2) or colles~onding silicic acids. Silicon is present in plants, and is widespread in foodstuffs, particularly monocotyledons such as grain, in clay (aluminum silicate), in sand, and in glass. In medicine, silicon is used therapeutir~lly as m~nesium tri~ilir~tP~, and as organic compounds used as deru~ g agents. Silicones are used in various cosmetic surgical implant procedures. Due most probably to dietary intake, at least small amounts of silicon may be found in most animal tissues and fluids (~t Med J. 27:17-19 (1982)). Silicon is a trace PlPmPnt, comprising less than 0.01% of the human body. Silicon has been demon~tr~tP~ as an essenti~l elemPnt, i.e.
one that is required for m~intPn~nce of life, and when deficient, consiQ~ntly results in an illlpaillllent of a function from optimal to suboptimal (Science 213:1332 (1981)).
Proof of the essenti~lity of silicon was independently established by two investigators. Carlisle established a silicon deficiency state incolllpa~ible with normal X
20 1 ~47a -growth in chicks (Science 178:619 (1972)), and Schwartz and Milne showed similar results with rats (Nature 239:33 (1972)). Using comparable methods, both studies showed that the ~nim~lc responded to suppl~mPnt~tion with sodium meP~ te with a 30 to 50 percent stim~ tion in growth. Subsequent eY~min~tion of the ~nim~ls raised on silicon-deficient diets revealed deplcss~ bone growth and severe bone d~rvlmilies, particularly of the skull.
Although silicon has been known as a regular constit~1Pnt of biolc~ic~l m~t.ori~l~ since the be~innill~ of the century, little is known about its metabolism. It is known that silicon specifically conce~ dt~s in the mitochondri~ of osteoblasts, and that it plays a role in bone and cartilage formation (Science 213:1332 (1981)). In addition, since silicon is present in high concentrations in colla~on, it has been su~ested that silicon plays a role in cross-linking connective tissues at the level of mucopolysaccharides (Fed. Proc. 33: 1748 (1974)). It has therefore been postlll~t~d that apart from bone form~tion, silicon particir~tps in growth and ",~int~n~nce of conn~live tissue, as in embryonic development and wound healing and in regulation of ions, metabolites and water in connective tissue. (Fed. Proc. 33:1758-1766 (1974)).
Silica in foods and beverages is readily absoll.ed across the int~ al wall. Studies have shown that there is a narrow range of silicon concentration in the serum of healthy adults, and with the exception of urine, the conce"t.dtions of silicon in all other body fiuids is similar to that of normal serum. Higher and wider ranges of silicon levels in the urine show that the kidney is the main excretory organ for silicon absorbed from the ~limPnt~ry canal (Scot Med J. 27:17-19 (1982)).
`A
.....
-The level of silicon in the blood and tissues has been shown to be affected by age, as well as sex, castration, adrenalectomy and thyroidectomy (~n Endocrinol 32:397 (1971)). The silicon content of the aorta, skin and thymus in the rabbit, rat, chic~n and pig was found to signific~ntly decline with age, whereas other tissues such as the heart, kidney, muscle and te~don show little or no change (Fed.
Proc. 33:1758-1766 (1974)). In addition, the silicon content of the dermis of human skin has been shown to ~limini~h with age (J. Biol. Chem. 75:789-794 (1927)). In contrast, Leslie et al. showed an increase in rat brain, liver, spleen, lung and femur silicon with age (Proc. Soc. Explt. Bio. Med. 110:218 (1962)). And Kworning et al.
described elevated silicon deposition in the human aorta wall during aging (J. Geront.
5:23-25 (1960)). In addition, it has been demon~t~t~ that silicon was elevated in the aorta with focal atherosclerosis, as well as in the atherosclerotic focus itself (Folia Morph 25:353-356 (1977)). Further, it has been lC~?Ollt;d that with advancing age, the SiO2 level of human peribronchial lymph glands gr~d~l~lly increasçs even in those who have no history of ~A~S-Ilc to dust (J. Pathol. 51:269-275 (1940)). Our own work, moreover, has demon~tr~t~d an increase of kidney silicon levels in normal rats with aging.
Although silicon is an e~Pnti~l trace çlem~nt for human growth and is necc~ for bone form~til n, silicon intoxication has been shown to cause various e~es. In addition to cases of acute toxicity, there is justifiable suspicion that the pathogenesis of some chronic di~e~es may be relat~d to prolonged exposure to concentrations of toxins in~ufflci~nt to producç conspicuous m~nif~st~tic~ns (J. Chron.
Dis. 27: 135-161 )1974)). For eY~mpl~., a substantial portion of patients with terminal renal failure have no clearly definable etiology of their renal ~ e It may be -speculated lh~rolc~ that some renal flice~cçs may be associated with chronic exposure to certain toxins incl~l~ling silicon.
Much information is known about the toxic effects of silicon in the lung. Varying amounts of silica norm~lly enter the ~ illdLol,~ tract across the lung barrier as silicic acid and are eventually elil"in~l~ Prolonged inh~l~tinn and accl-mlJl~tion of fine particulate silica in the lung however, produces a pulmonary infl~mm~tnry response, granuloma form~tion and chronic fibrosis (silicosis) (Prin Int.
Med, 9th Ed., TccPlb~hPr et al. (eds), McGraw-Hill Book Co., N.Y. 1980). In silicosis, the injury seems to be related to both the crystal structure of the silicon and the host response. Workers in stone quarries, or in other indllctries where sand or other silicate dusts are prevalent, are prone to contract this ~liCP~CP~
It is commonly believed that ingesl~d sili(~tPs are both inert and nonabsorbable, but there has long been a suspicion that cili~tP,s are nephrotoxic in humans (Scot Med. J. 27: 10-17 (1982). In 1922, Gye and Purdy investig~t~d the toxicity of parel tel~lly ~-iminiQt~red colloidal silica in rabbits which resulted in in~l~liLial nephritis, hepatic fibrosis and splenomegaly within a period of weeks to several months (Br. J. Exp. Path 3:75-85 (1922)). These fin-lin~c were later confirmP~I by Sc~-P.pers et al. (AMA Arch. Industr. Hlth. 15:599 (1957)). In 1970, Newberne and Wlson showed that oral ~flminiQt~tion of certain cili~tP5 produced significant renal tubular damage and chronic interstitial infl~mm~tion in dogs (Proc.
Nat. Acad. Sci. 65:872-875 (1970)). And in 1982, Dobbie and Smith showed that oral ingestion of m~nPcillm tricilic~e resulted in renal damage in guinea pigs in four months (Scot. Med. J. 27: 10 (1982)).
In humans, chronic exposure to silica has been associated with mild renal functional abnorm~litiys and minor hi~tologic ch~nges in kidneys. Bolton et al.
d four p~tiPnt~ with a history of intense silica e~Jult; and rapidly pr~gl~ssi-/e renal failure, and concl~e~ that silicon app~ed to be ~ onsible for the nephlu~Aic chatlges (Am. J. Med. 71:823 (1981)). Silicon has also been shown to have a dir_ct dose-dependent toxic effect on the kidney (J. Pathol. 103:35-40 (1970)), and silicon particles are cytotoxic, as shown by studies demon~tr~ting damage to macrophages ingeSting silicon (Am. Rev. Respir. Dis. 113:643-665 (1976)).
Since it is known that the prin~ir~l organ of silicon elimin~tion is the kidney, it is not surprising that an increase in plasma silicon levels (Biom-P-licinP
33:228-230 (1980)), as well as an increase in certain tissue silicon levels have been c;~oll~d in studies of p~tient~ suffering from chronic renal failure and in p~ti~Pnt~ on hemodialysis (J. Chron. Dis 27:135-161 (1974)). The aCcllm~ tion of increased qu~ntities of silicon in renal failure results from its decreased renal clP~r~nce (~
Chron. Dis. 27:135-161 (1974)). The high serum silicon levels demon~t~ted in hemodialysis patients have been ~soci~t-P~ with osteitis fibrosa (Xth Intl. Con~. of Nephr. June 26-31, 1987), and elevated cerebral spinal fluid (CSF) silicon levels have been observed in patients with chronic renal in~llfflciency where CSF silicon levels increased as renal function declined. (Neurolo~y: 86-789 (1983)). It has been hypothe~i7~1 th~lcrolt;, that since silicon is n~hrotl,Aic and accumulates in blood and body tissues of patients with renal failure, silicon may contribute to the steady progression of renal failure once initi~tP~ ~
In ~-lition to silicon, aluminum has been found to accumulate in advanced kidney disease patients on chronic hemodialysis. Cullelllly, the most effective means of increased removal of ~ minllm during hemodialysis, is by chelation with de~fiP~rioxarnine (DFO). (Clin. Nephr. 24:594-597 (1985)). At the end of a dialysis tre~tment, the chelator is ~minict~red to the patient, whelcu~n at the next dialysis session, the ~ ;n~ ,-DFO complex is removed. Various dialysis related mo~lities may be used to remove the aluminum-DFO complex inclllrlin~
h~ lysis, peritoneal dialysis, hemofiltration or charcoal (or resin) hemoperfusion.
(Kid. Int. 33 suppl. 24:5-171 (1988)). Known side effects of DFO l~ include anaphylactic reactions, abdominal pain, posterior ~t~ ts, visual i~p~i""ent~ and predisposition to dcvelopment of fungal infections. In addition, DFO has not yet been inve~ti~t~l for its ability to form stable complexes with silicon (Clin. Neph. 24 at Table 1 p. 595). A need continues to exist therefore, for a çhel~tor that would help promote the remaval of silicon accumulation in patients with advanced kidney disease on chronic hemodialysis.
Silicon may also be a ncululu~ul. Silicon, together with aluminum, are significantly elevated in ~l7heim~r's disease in the neurofibrillary tangles, and in senile demPnti~ ther~ is a diffuse increase in silicon levels in the brain (Science 208:297-298 (1980)). Nikaido et al. demon~tr~d that patients with ~17.h~imer's disease showed a substantial increase of silicon in the cores and rims of the senile plaques (Arch. Neurol. 27:549-554 (1922)).
Meso-2, 3-Dimel.;a~los~ccinic acid (DMSA) is a water soluble compound analogous to 2,3-dimel~;ap~lupanol (BAL). In contrast to BAL however, DMSA is less toxic, has greater water solubility, limited lipid solubility, and is effective when given orally (Fund. Appl. Tox 11:715-722 (1988)). DMSA may be :
METHOD FOR SILICON REDUCTION
WITH DIMERCAPTOSUCCINIC ACID (DMSA) This invention relates generally to a method for reduction of silicon levels with Dimel~iap~succinic Acid (DMSA). More particularly, this invention relates to a method for reduction of silicon levels in human blood and tissue with DMSA, in order to reduce blood pl~ s~ r, impra~e kidney function, prevent or retard the pl~glession of chronic renal failure, treat the ~rcum~ tion of silicon in advanced kidney disease, and/or prevent the onset, or improve the current status of dP-mPnti~
and ~ hPimPr's Disease.
Silicon, next to oxygen, is the most prevalent elemPnt on earth, and is the most abundant miner~l in the earth's crust. It occurs in nature as silica oxides (SiO2) or colles~onding silicic acids. Silicon is present in plants, and is widespread in foodstuffs, particularly monocotyledons such as grain, in clay (aluminum silicate), in sand, and in glass. In medicine, silicon is used therapeutir~lly as m~nesium tri~ilir~tP~, and as organic compounds used as deru~ g agents. Silicones are used in various cosmetic surgical implant procedures. Due most probably to dietary intake, at least small amounts of silicon may be found in most animal tissues and fluids (~t Med J. 27:17-19 (1982)). Silicon is a trace PlPmPnt, comprising less than 0.01% of the human body. Silicon has been demon~tr~tP~ as an essenti~l elemPnt, i.e.
one that is required for m~intPn~nce of life, and when deficient, consiQ~ntly results in an illlpaillllent of a function from optimal to suboptimal (Science 213:1332 (1981)).
Proof of the essenti~lity of silicon was independently established by two investigators. Carlisle established a silicon deficiency state incolllpa~ible with normal X
20 1 ~47a -growth in chicks (Science 178:619 (1972)), and Schwartz and Milne showed similar results with rats (Nature 239:33 (1972)). Using comparable methods, both studies showed that the ~nim~lc responded to suppl~mPnt~tion with sodium meP~ te with a 30 to 50 percent stim~ tion in growth. Subsequent eY~min~tion of the ~nim~ls raised on silicon-deficient diets revealed deplcss~ bone growth and severe bone d~rvlmilies, particularly of the skull.
Although silicon has been known as a regular constit~1Pnt of biolc~ic~l m~t.ori~l~ since the be~innill~ of the century, little is known about its metabolism. It is known that silicon specifically conce~ dt~s in the mitochondri~ of osteoblasts, and that it plays a role in bone and cartilage formation (Science 213:1332 (1981)). In addition, since silicon is present in high concentrations in colla~on, it has been su~ested that silicon plays a role in cross-linking connective tissues at the level of mucopolysaccharides (Fed. Proc. 33: 1748 (1974)). It has therefore been postlll~t~d that apart from bone form~tion, silicon particir~tps in growth and ",~int~n~nce of conn~live tissue, as in embryonic development and wound healing and in regulation of ions, metabolites and water in connective tissue. (Fed. Proc. 33:1758-1766 (1974)).
Silica in foods and beverages is readily absoll.ed across the int~ al wall. Studies have shown that there is a narrow range of silicon concentration in the serum of healthy adults, and with the exception of urine, the conce"t.dtions of silicon in all other body fiuids is similar to that of normal serum. Higher and wider ranges of silicon levels in the urine show that the kidney is the main excretory organ for silicon absorbed from the ~limPnt~ry canal (Scot Med J. 27:17-19 (1982)).
`A
.....
-The level of silicon in the blood and tissues has been shown to be affected by age, as well as sex, castration, adrenalectomy and thyroidectomy (~n Endocrinol 32:397 (1971)). The silicon content of the aorta, skin and thymus in the rabbit, rat, chic~n and pig was found to signific~ntly decline with age, whereas other tissues such as the heart, kidney, muscle and te~don show little or no change (Fed.
Proc. 33:1758-1766 (1974)). In addition, the silicon content of the dermis of human skin has been shown to ~limini~h with age (J. Biol. Chem. 75:789-794 (1927)). In contrast, Leslie et al. showed an increase in rat brain, liver, spleen, lung and femur silicon with age (Proc. Soc. Explt. Bio. Med. 110:218 (1962)). And Kworning et al.
described elevated silicon deposition in the human aorta wall during aging (J. Geront.
5:23-25 (1960)). In addition, it has been demon~t~t~ that silicon was elevated in the aorta with focal atherosclerosis, as well as in the atherosclerotic focus itself (Folia Morph 25:353-356 (1977)). Further, it has been lC~?Ollt;d that with advancing age, the SiO2 level of human peribronchial lymph glands gr~d~l~lly increasçs even in those who have no history of ~A~S-Ilc to dust (J. Pathol. 51:269-275 (1940)). Our own work, moreover, has demon~tr~t~d an increase of kidney silicon levels in normal rats with aging.
Although silicon is an e~Pnti~l trace çlem~nt for human growth and is necc~ for bone form~til n, silicon intoxication has been shown to cause various e~es. In addition to cases of acute toxicity, there is justifiable suspicion that the pathogenesis of some chronic di~e~es may be relat~d to prolonged exposure to concentrations of toxins in~ufflci~nt to producç conspicuous m~nif~st~tic~ns (J. Chron.
Dis. 27: 135-161 )1974)). For eY~mpl~., a substantial portion of patients with terminal renal failure have no clearly definable etiology of their renal ~ e It may be -speculated lh~rolc~ that some renal flice~cçs may be associated with chronic exposure to certain toxins incl~l~ling silicon.
Much information is known about the toxic effects of silicon in the lung. Varying amounts of silica norm~lly enter the ~ illdLol,~ tract across the lung barrier as silicic acid and are eventually elil"in~l~ Prolonged inh~l~tinn and accl-mlJl~tion of fine particulate silica in the lung however, produces a pulmonary infl~mm~tnry response, granuloma form~tion and chronic fibrosis (silicosis) (Prin Int.
Med, 9th Ed., TccPlb~hPr et al. (eds), McGraw-Hill Book Co., N.Y. 1980). In silicosis, the injury seems to be related to both the crystal structure of the silicon and the host response. Workers in stone quarries, or in other indllctries where sand or other silicate dusts are prevalent, are prone to contract this ~liCP~CP~
It is commonly believed that ingesl~d sili(~tPs are both inert and nonabsorbable, but there has long been a suspicion that cili~tP,s are nephrotoxic in humans (Scot Med. J. 27: 10-17 (1982). In 1922, Gye and Purdy investig~t~d the toxicity of parel tel~lly ~-iminiQt~red colloidal silica in rabbits which resulted in in~l~liLial nephritis, hepatic fibrosis and splenomegaly within a period of weeks to several months (Br. J. Exp. Path 3:75-85 (1922)). These fin-lin~c were later confirmP~I by Sc~-P.pers et al. (AMA Arch. Industr. Hlth. 15:599 (1957)). In 1970, Newberne and Wlson showed that oral ~flminiQt~tion of certain cili~tP5 produced significant renal tubular damage and chronic interstitial infl~mm~tion in dogs (Proc.
Nat. Acad. Sci. 65:872-875 (1970)). And in 1982, Dobbie and Smith showed that oral ingestion of m~nPcillm tricilic~e resulted in renal damage in guinea pigs in four months (Scot. Med. J. 27: 10 (1982)).
In humans, chronic exposure to silica has been associated with mild renal functional abnorm~litiys and minor hi~tologic ch~nges in kidneys. Bolton et al.
d four p~tiPnt~ with a history of intense silica e~Jult; and rapidly pr~gl~ssi-/e renal failure, and concl~e~ that silicon app~ed to be ~ onsible for the nephlu~Aic chatlges (Am. J. Med. 71:823 (1981)). Silicon has also been shown to have a dir_ct dose-dependent toxic effect on the kidney (J. Pathol. 103:35-40 (1970)), and silicon particles are cytotoxic, as shown by studies demon~tr~ting damage to macrophages ingeSting silicon (Am. Rev. Respir. Dis. 113:643-665 (1976)).
Since it is known that the prin~ir~l organ of silicon elimin~tion is the kidney, it is not surprising that an increase in plasma silicon levels (Biom-P-licinP
33:228-230 (1980)), as well as an increase in certain tissue silicon levels have been c;~oll~d in studies of p~tient~ suffering from chronic renal failure and in p~ti~Pnt~ on hemodialysis (J. Chron. Dis 27:135-161 (1974)). The aCcllm~ tion of increased qu~ntities of silicon in renal failure results from its decreased renal clP~r~nce (~
Chron. Dis. 27:135-161 (1974)). The high serum silicon levels demon~t~ted in hemodialysis patients have been ~soci~t-P~ with osteitis fibrosa (Xth Intl. Con~. of Nephr. June 26-31, 1987), and elevated cerebral spinal fluid (CSF) silicon levels have been observed in patients with chronic renal in~llfflciency where CSF silicon levels increased as renal function declined. (Neurolo~y: 86-789 (1983)). It has been hypothe~i7~1 th~lcrolt;, that since silicon is n~hrotl,Aic and accumulates in blood and body tissues of patients with renal failure, silicon may contribute to the steady progression of renal failure once initi~tP~ ~
In ~-lition to silicon, aluminum has been found to accumulate in advanced kidney disease patients on chronic hemodialysis. Cullelllly, the most effective means of increased removal of ~ minllm during hemodialysis, is by chelation with de~fiP~rioxarnine (DFO). (Clin. Nephr. 24:594-597 (1985)). At the end of a dialysis tre~tment, the chelator is ~minict~red to the patient, whelcu~n at the next dialysis session, the ~ ;n~ ,-DFO complex is removed. Various dialysis related mo~lities may be used to remove the aluminum-DFO complex inclllrlin~
h~ lysis, peritoneal dialysis, hemofiltration or charcoal (or resin) hemoperfusion.
(Kid. Int. 33 suppl. 24:5-171 (1988)). Known side effects of DFO l~ include anaphylactic reactions, abdominal pain, posterior ~t~ ts, visual i~p~i""ent~ and predisposition to dcvelopment of fungal infections. In addition, DFO has not yet been inve~ti~t~l for its ability to form stable complexes with silicon (Clin. Neph. 24 at Table 1 p. 595). A need continues to exist therefore, for a çhel~tor that would help promote the remaval of silicon accumulation in patients with advanced kidney disease on chronic hemodialysis.
Silicon may also be a ncululu~ul. Silicon, together with aluminum, are significantly elevated in ~l7heim~r's disease in the neurofibrillary tangles, and in senile demPnti~ ther~ is a diffuse increase in silicon levels in the brain (Science 208:297-298 (1980)). Nikaido et al. demon~tr~d that patients with ~17.h~imer's disease showed a substantial increase of silicon in the cores and rims of the senile plaques (Arch. Neurol. 27:549-554 (1922)).
Meso-2, 3-Dimel.;a~los~ccinic acid (DMSA) is a water soluble compound analogous to 2,3-dimel~;ap~lupanol (BAL). In contrast to BAL however, DMSA is less toxic, has greater water solubility, limited lipid solubility, and is effective when given orally (Fund. Appl. Tox 11:715-722 (1988)). DMSA may be :
~mini~t~ored orally or pa,ent~l~lly. A p~;rt;llcd dosage of DMSA for hum~n~ is 10-30 mg/kg daily.
DMSA is available as a white crystalline powder and exists in two forms, the meso form and the DL form. ~ use Meso-DMSA is easier to synthe~i7 and purify, it is more readily available, and has been used in most published investi~tions. Meso-DMSA (m.p. 210-211C) is sp~ringly soluble and must be titrated to appr~)Yim~tloly pH 5.5 to go into solution, or dissolved in 5% NaHCO3.
The DL form (m.p. 124-125) on the other hand, is readily soluble in distilled water.
(Ann. Rev. Ph~rm~col. Toxicol. 23:193-215 (1983)). As used herein, DMSA
includes but is not limited to the meso, r~mic and D and L isomers whether derived from isomeric resolution of the racemic form or derived from st~.eo~l~ific synthesis.
DMSA is available from a variety of biochemi~l specialty firms.
DMSA has been shown to remove toxic forms of lead, mercury and arsenic from the body via urinary excretion, p~ull-ably by f~ rming water-soluble metal comrl~oY~-s or ch~ t~-s (Anal. Biochem. 160:217-226 (1987)).
DMSA has been shown to have variable success as an antidote for other toYicitiPs. DMSA was lt;l~olt~ to be effective at r~ducing the concentration of aluminum in the liver, spleen and kidney (Res. Com. Chem. Pathol. Pharm. 53:93-104 (1986)), reducing the con~Rntration of cobalt in the liver, brain, heart and blood (Arch. Toxicol. 58:278-281 (1986)), and as an antagonist for acute oral c~llmi~lm chloride int~Yi~tion by increasing the urinary elimin~tion of ~rlmium (l~x. Appl.
Pharm. 66:361-367 (1982)). DMSA however, did not increase urinary and fecal excretion of cobalt (Arch. Toxicol. 58:278-281 (1986)), and showed lower efficacy than other chel~tin~ agents as an antidote for zinc poisoning (Arch. Toxicol. 61:321-., .
2~1 2470323 (1988)). (See Ann. Rev. Pharm. Toxicol. 23:193-215 (1983) for a review of the success and failure of DMSA in treating toxicities).
DMSA has also been labelled with 99Tc for use in renal sc~llnine ~
Nucl. Med. 16:28-32 (1973), tumor detection (Clin. Otalanr 12:405-411 (1987); Clin.
Nucl. Med. 13:159-165 (1988)) and for im~ing ~ ~dial infarcts (Clin. Nucl.
Med. 12:514-518 (1987)).
DMSA has been reported as an e~eclive and relatively nontoxic agent for treatment of metal poi~onine Other chPl~ting agents have also been used as antidotes for metal toxicitiPs, but these drugs have been shown to have many side effects. BAL is ~mini~tered by a painful intramuscular injection and can cause nausea, -vullliling and severe he~dAf~he CAlcillm disodium ethylen~diAmin~otPtrAA-~ti-~acid (CaNa2 El TA) must be ~rlmini~red palc;n~l~lly, either intravenously or intr~mll~cularly. It is painful when given intr~mllscularly and when given in excessive dosage, can cause nephlut~icity. PenicillAmine is ~flmini~t~red orally but is not as e~eclive as BAL or CaNa2 El~TA. AMitic-n~lly, it can çause reactions resembling penicillin sensitivity, is potentially nephlut~ic and çauses neutlùpel~ia (Clinic~l Tox.
25:39-51 (1987).
To date, there are no know çhPl~ting agents effective for silicon remaval, as well as no previously demon~tr~t~ effects of silicon remaval. A need exists therefore, for a method to remove silicon from the body, thereby illlL~luving blood p~cs~ure and kidney function, reducing neurological toxicities, and lcll~lllin~
silicon to youthful levels.
Human exposure to silicon compounds is widespread, either in food, beverages, ~rinkin~ water, meAicine or the eYt~-rnAl environment. Many foods and X
bt;v~l~es contain n~tllr~lly oCcurring plant ~ilic~tes, and there is an increasing use of silicon co~ ?ounds in the food m~nul~tllring industries where they are extremely useful in prc~~ ;on and stabilization. Amorphous ~ilic~tes are widely used as ~nti~king agents in m~n~ ctllred food powers, extracts and con~im~nh. Silicon is present in beverages largely due to the natural silicate content of the m~tf-ri~l~ used in their production, as is the case with some beers made from grains. Silicates are frequently inco,~l~led into me~icinPs such as ~n~lg~$ic powders, ~ u~ s and tablets. Collodial silicas are used in the pharmaceuti~l industry as desiccants since they have a large surface area and highly polar silanol surface favorable for water vapor absorption. Silicon present in silicate dusts or sand, and silicon used in the co~ ulel industry in semiconducting devices, f~p,csent yet other sources of silicon exposure.
Long term silicon in~stion and accumulation, as well as silicon intoxication from in-lustri~l sources, creates the potential for nephlv~icity, n~uf~icity and other disease states. In addition, increased silicon levels in cases of renal failure or hemodialysis may further aggravate these conditions. Since silicon is a known collll?onent of scar tissue, elevated silicon levels could contribute to progressive sc~rring Thus, it is the object of the present invention to pravide a method of redu~ing silicon levels in the body.
It is the second object of the invention to provide a method of reducing kidney silicon in various types of kidney ~ es~ thereby lctdldillg plOg~ s,i~e renal sc~rring and failure.
~;
20 1 247~
It is another object of the present invention to pravide a method of reducin~ ~ccumulAt~d silicon thereby improving blood p~ssu,e and lcllllllinp kidney function to normal levels.
It is another object of the present invention to provide a method of c~ting ~ccumlllAtion of silicon in advanced kidney ~li~.
It is yet a further object of the present invention to provide a method of redu~ in~ brain silicon levels thereby preventing the onset of d~m~ntiA and ~l~heim~r's Disease or il~lplvving a current r~ A~ed status.
Wlth reference to the accolllp~l~ g dldwings:
Figure 1 is a graph showing the effect of DMSA on the Glomerular FiltrAtion Rate (GFR). The DMSA group is colll;~a,cd to normal controls (CD6) and to ~nim~l~ treated with lead for six months, then sacrificed at twelve months (ED6).
Figure 2 is a graph showing the effect of DMSA on mean blood pl~ssure.
In the course of an experim~-nt desipn~ to eY~mine the effect of lead on kidney function and blood pl~,S~Ulc, as well as the effect of DMSA on remaval of lead, we have unexpectedly found that DMSA reduces kidney silicon to levels seen in young normal control Anim~ and far bel~w the aged normal controls. In addition, DMSA-treated AnimAl~ had lc~ lion of glomerular filtration rates (GFR) and blood plc;S~u~c to the same level as young Anim~l~ due to reduction in silicon. Although DMSA also reduced kidney lead contP-nt, the reduction in lead was less than that seen in lead-treated Anim~l~ where lead was discontinued at six months (ED6) and where no improvement in GFR or blood plCS~UlC was seen. Thus the red~lction in silicon levels was more likely to be related to these favorable effects than reduction in lead.
FY~mr~le 1: Rat-Kidney F.mi~sion Sl)e.;L.osco~y Results Male Sprague-Dawley rats were fed begil-~-in~ at eight weeks of age and sacrificed acco~ g to the following sç~edl-le:
(1) Controls (C): fed only a semi-purified diet Cl - sacrificed at one month after initi~tion of the experimP-nt C6 - sacrificed at six months C12 - sacrificed at twelve months CD6 - sacrificed at twelve months (2) F.YrerimPnt~l continuous (EC): fed semi-purified diet and 0.5% lead acetate in ~lrinking water throughout the exp-PrimPnt ECl - sacrificed at one month EC12 - sacrificed at twelve months (3) ED6 - ExperimPnt~l discontinuous: fed semi-purified diet and 0.5%
lead acetate in drinking water for six months, no lead in ~lrinking water for the subsequent months; sacrificed at twelve months.
DMSA is available as a white crystalline powder and exists in two forms, the meso form and the DL form. ~ use Meso-DMSA is easier to synthe~i7 and purify, it is more readily available, and has been used in most published investi~tions. Meso-DMSA (m.p. 210-211C) is sp~ringly soluble and must be titrated to appr~)Yim~tloly pH 5.5 to go into solution, or dissolved in 5% NaHCO3.
The DL form (m.p. 124-125) on the other hand, is readily soluble in distilled water.
(Ann. Rev. Ph~rm~col. Toxicol. 23:193-215 (1983)). As used herein, DMSA
includes but is not limited to the meso, r~mic and D and L isomers whether derived from isomeric resolution of the racemic form or derived from st~.eo~l~ific synthesis.
DMSA is available from a variety of biochemi~l specialty firms.
DMSA has been shown to remove toxic forms of lead, mercury and arsenic from the body via urinary excretion, p~ull-ably by f~ rming water-soluble metal comrl~oY~-s or ch~ t~-s (Anal. Biochem. 160:217-226 (1987)).
DMSA has been shown to have variable success as an antidote for other toYicitiPs. DMSA was lt;l~olt~ to be effective at r~ducing the concentration of aluminum in the liver, spleen and kidney (Res. Com. Chem. Pathol. Pharm. 53:93-104 (1986)), reducing the con~Rntration of cobalt in the liver, brain, heart and blood (Arch. Toxicol. 58:278-281 (1986)), and as an antagonist for acute oral c~llmi~lm chloride int~Yi~tion by increasing the urinary elimin~tion of ~rlmium (l~x. Appl.
Pharm. 66:361-367 (1982)). DMSA however, did not increase urinary and fecal excretion of cobalt (Arch. Toxicol. 58:278-281 (1986)), and showed lower efficacy than other chel~tin~ agents as an antidote for zinc poisoning (Arch. Toxicol. 61:321-., .
2~1 2470323 (1988)). (See Ann. Rev. Pharm. Toxicol. 23:193-215 (1983) for a review of the success and failure of DMSA in treating toxicities).
DMSA has also been labelled with 99Tc for use in renal sc~llnine ~
Nucl. Med. 16:28-32 (1973), tumor detection (Clin. Otalanr 12:405-411 (1987); Clin.
Nucl. Med. 13:159-165 (1988)) and for im~ing ~ ~dial infarcts (Clin. Nucl.
Med. 12:514-518 (1987)).
DMSA has been reported as an e~eclive and relatively nontoxic agent for treatment of metal poi~onine Other chPl~ting agents have also been used as antidotes for metal toxicitiPs, but these drugs have been shown to have many side effects. BAL is ~mini~tered by a painful intramuscular injection and can cause nausea, -vullliling and severe he~dAf~he CAlcillm disodium ethylen~diAmin~otPtrAA-~ti-~acid (CaNa2 El TA) must be ~rlmini~red palc;n~l~lly, either intravenously or intr~mll~cularly. It is painful when given intr~mllscularly and when given in excessive dosage, can cause nephlut~icity. PenicillAmine is ~flmini~t~red orally but is not as e~eclive as BAL or CaNa2 El~TA. AMitic-n~lly, it can çause reactions resembling penicillin sensitivity, is potentially nephlut~ic and çauses neutlùpel~ia (Clinic~l Tox.
25:39-51 (1987).
To date, there are no know çhPl~ting agents effective for silicon remaval, as well as no previously demon~tr~t~ effects of silicon remaval. A need exists therefore, for a method to remove silicon from the body, thereby illlL~luving blood p~cs~ure and kidney function, reducing neurological toxicities, and lcll~lllin~
silicon to youthful levels.
Human exposure to silicon compounds is widespread, either in food, beverages, ~rinkin~ water, meAicine or the eYt~-rnAl environment. Many foods and X
bt;v~l~es contain n~tllr~lly oCcurring plant ~ilic~tes, and there is an increasing use of silicon co~ ?ounds in the food m~nul~tllring industries where they are extremely useful in prc~~ ;on and stabilization. Amorphous ~ilic~tes are widely used as ~nti~king agents in m~n~ ctllred food powers, extracts and con~im~nh. Silicon is present in beverages largely due to the natural silicate content of the m~tf-ri~l~ used in their production, as is the case with some beers made from grains. Silicates are frequently inco,~l~led into me~icinPs such as ~n~lg~$ic powders, ~ u~ s and tablets. Collodial silicas are used in the pharmaceuti~l industry as desiccants since they have a large surface area and highly polar silanol surface favorable for water vapor absorption. Silicon present in silicate dusts or sand, and silicon used in the co~ ulel industry in semiconducting devices, f~p,csent yet other sources of silicon exposure.
Long term silicon in~stion and accumulation, as well as silicon intoxication from in-lustri~l sources, creates the potential for nephlv~icity, n~uf~icity and other disease states. In addition, increased silicon levels in cases of renal failure or hemodialysis may further aggravate these conditions. Since silicon is a known collll?onent of scar tissue, elevated silicon levels could contribute to progressive sc~rring Thus, it is the object of the present invention to pravide a method of redu~ing silicon levels in the body.
It is the second object of the invention to provide a method of reducing kidney silicon in various types of kidney ~ es~ thereby lctdldillg plOg~ s,i~e renal sc~rring and failure.
~;
20 1 247~
It is another object of the present invention to pravide a method of reducin~ ~ccumulAt~d silicon thereby improving blood p~ssu,e and lcllllllinp kidney function to normal levels.
It is another object of the present invention to provide a method of c~ting ~ccumlllAtion of silicon in advanced kidney ~li~.
It is yet a further object of the present invention to provide a method of redu~ in~ brain silicon levels thereby preventing the onset of d~m~ntiA and ~l~heim~r's Disease or il~lplvving a current r~ A~ed status.
Wlth reference to the accolllp~l~ g dldwings:
Figure 1 is a graph showing the effect of DMSA on the Glomerular FiltrAtion Rate (GFR). The DMSA group is colll;~a,cd to normal controls (CD6) and to ~nim~l~ treated with lead for six months, then sacrificed at twelve months (ED6).
Figure 2 is a graph showing the effect of DMSA on mean blood pl~ssure.
In the course of an experim~-nt desipn~ to eY~mine the effect of lead on kidney function and blood pl~,S~Ulc, as well as the effect of DMSA on remaval of lead, we have unexpectedly found that DMSA reduces kidney silicon to levels seen in young normal control Anim~ and far bel~w the aged normal controls. In addition, DMSA-treated AnimAl~ had lc~ lion of glomerular filtration rates (GFR) and blood plc;S~u~c to the same level as young Anim~l~ due to reduction in silicon. Although DMSA also reduced kidney lead contP-nt, the reduction in lead was less than that seen in lead-treated Anim~l~ where lead was discontinued at six months (ED6) and where no improvement in GFR or blood plCS~UlC was seen. Thus the red~lction in silicon levels was more likely to be related to these favorable effects than reduction in lead.
FY~mr~le 1: Rat-Kidney F.mi~sion Sl)e.;L.osco~y Results Male Sprague-Dawley rats were fed begil-~-in~ at eight weeks of age and sacrificed acco~ g to the following sç~edl-le:
(1) Controls (C): fed only a semi-purified diet Cl - sacrificed at one month after initi~tion of the experimP-nt C6 - sacrificed at six months C12 - sacrificed at twelve months CD6 - sacrificed at twelve months (2) F.YrerimPnt~l continuous (EC): fed semi-purified diet and 0.5% lead acetate in ~lrinking water throughout the exp-PrimPnt ECl - sacrificed at one month EC12 - sacrificed at twelve months (3) ED6 - ExperimPnt~l discontinuous: fed semi-purified diet and 0.5%
lead acetate in drinking water for six months, no lead in ~lrinking water for the subsequent months; sacrificed at twelve months.
(4) DMSA: fed semi-purified diet and 0.5% lead acetate in drinkin~ water for six months, no lead for the subsequent siY~ months while treating with 0.5% DMSA in ~lrinkin~ water for five days every two months;
~-~rific~ at twelve months.
After sacrifice, kidneys were eYci~ .ii~s~, and analyzed using an emission spectrometer procedure known in the art for ~e~e. ",i ~ -g elPmPnt~ frequently found in biological tissues. SpecificaUy, in this study, the sample elements were vol~tili7-P~ and excited in a 12 a D.C. arc. The various elemPnt signals were sorted and recorded with an ARL l.Sm grating spectrometer. The signal data, which were autom~ti~lly tran~f~rred to IBM punched cards, were plocRssed to con~Rntr~tions in ppm dry weight with an IBM 360-91 co.llpul~r. The following ~lem~ont~ were d~ nined: sodium, poP~ium, c~lci~lm, phosphorus, m~ne~ m, c~lmi--m, zinc, copper, lead, iron, m~n~nese, ~lumimlm, silicon, boron, tin, cobalt, nickel, molyl~d~ ll;ll.ll, cl~,l,-iulll, SlI~JnI;~ b~ril-m, lithillm, silver and v~n~-lium.
Results are as shown in Table 1. Only silicon and lead are listed as the other elem~nt~ did not show major changes.
As can be seRn in Table 1, C12 and CD6 silicon levels increased ~ignific~ntly with age when compared to C1 and C6. The rats fed DMSA however, showed significantly decreased levels of silicon as compared to the older controls (C12 and CD6) and to experim~nt~l ~nim~l~ (EC12 and ED6).
FY~ml~le 2: De~ ",in~ion of GFR
Measurement of the glomerular filtration rate (GFR) provides a sensitive and commonly employed index of overall renal excretory function. GFR can be ~ssed indirectly by measurement of plasma cle~ e or serum urea nitl~en levels, and directly by clearance of inulin (C36 H62 31) or by clearance of various r~dio~ctive substances handled by the kidney in the same way as inulin (i.e.
ioth~l~m~te-Il25). When renal excretory function is i~llpailed, either acutely or chronically, one or more of the GFR determin~nt.~ is altered unfavorably so that total GFR declines. In this study GFR was measured by blood turnover rate of Ioth~l~m~t~
Il25 (J. Lab Clin. Med., 89:845-856 (1972)), as well as by plasma ~ ine and serum urea ni~gen. Results are shown in Table 2, and Figure 1. Figure 1 shows the effect of DMSA tre~tment on GFR. The DMSA group is co",l~ared to normal controls (CD6) and to Anim~ treated with lead for six months, then ~r~ifice~ at twelve months (ED6). As can be seen in Figure 1, ~nim?~l~ given DMSA showed ~,ignifit~ntly increased GFR, confirm~ by lower SUN and serum c c~ e levels than those in the ~nim~l~ without DMSA.
FY~mple 3: Blood Pl~si,ule Levels Mean blood lJNs~,u~c lccol-lings were obtdined using an autull~led tail blood p~ rc device. Results are shown in Figure 2. Blood ~ lrC iS shown to increase with age in both control ~nim~l~ and lead treated ~nim~l~ DMSA tlc~t~ t ~..t~ll~ blood pn,S~llc to levels seen in young ~nim~l~ (Cl) and significantly reduces blood pl~ rc below ED6 and CD6 controls.
FY~mple 4: Human ~(lmini~t~tion of DMSA
R~P1in~ levels of blood silicon, blood pl~7s~llc and GFR are measured for a 70 kg human accolding to standard techniques and those described in the pre~e~ing examples. Three gelatin c~ps--les each containing 270 mg of meso-2,3-dilllclca~lo3.~c-inic acid are taken daily by mouth for five days. Silicon blood levels, blood pressure and GFR are measured daily during tre~tmp-nt and for two days subsequent to tre~tment These measures are lc~ ed at two and seven weeks after lcl...in~l;( n of l,c~..ent~ and below baseline levels of blood silicon, blood ~ ss.~rc and GFR are measured.
By providing a method according to the above invention, several beneficial effects will be realized. First, reduction of silicon levels in the blood and tissue will reduce blood pl-,S~-Ilc and imp~ve kidney function. Second, reduction of silicon by this method will prevent or retard the p~ ssion of chronic renal failure.
Furthermore, remaval of silicon will prevent the onset, or improve the current status of ~em.o.nti~ and ~ htqim~.r's Disease.
Other and further embo~limP-nt~ of the invention are readily a~pa~nt from the aba~e de~,i~tion of the invention, and these elllbc ~ enl~ are believed to be within the scope of the invention.
TRACE ELEMENTS IN KIDNEY
Cl C6 C12 CD6 ECl EC12 ED6DMSA
Elements Si 9.42+ 12.32+ 98.00+ 299.00+ 8.31+ 137.00+ 124.22+ 5.31+u (ppm) 8.64 6.05 38.74 209.7414.10 98.01 118.898.08 Pb 5.00+ 1.97+ 1.57+ 0.75+ 70.33+ 291.78+ 54.22+ 132.29+
(ppm) 2.96 1.53 1.46 1.3923.67 187.18 24.94 127.96 ECl = ~ e~ al group (fed 0.5% lead in drinking water);
~ iGced at 1 month.
Cl = controls for ECl.
C6 = controls sacrificed at 6 months.
EC12 = experimental group (fed 0.5% lead in drinking water);
sacrificed at 12 months.
C12 = controls for EC12.
ED6 = experimental ~ U~ U1~Q group (fed 0.5% lead in drinking water for 6 months, no lead for the Q~lhseqm 6 months);
sacrificed at 12 months.
CD6 = controls for EDG.
DMSA = DMSA-treated rats (fed 0.5% lead in drinking water for 6 months, no lead for the sllbseql~nt 6 months while treated with 0.5% DMSA in drinking water for S days every 2 months);
sacrificed at 12 months.
GFR SERUM SUN
(ml/min/ CREAT. (mg/dl) 100 g) (mg/dl) Cl 0.59+ 0.46+ 19.3+
0.27 0.04 4.0 C6 1.09+ 1.08 + 12.8 +
0.13 0.14 2.4 CD6 0.96+ 1.59+ 14.4 +
0.05 0. 14 2.0 ED6 0.82 + ~ 1.96+~ 20.8 +
0.14 0.28 7.2 DMSA 1.16+~ 1.00+~ 11.1+~
0.13 0.10 2.2 * P ~ 0.05 when compared to ED6 and CD6 ** P < 0.05 when compared to CD6 . , :,,.
~, .. ~
~-~rific~ at twelve months.
After sacrifice, kidneys were eYci~ .ii~s~, and analyzed using an emission spectrometer procedure known in the art for ~e~e. ",i ~ -g elPmPnt~ frequently found in biological tissues. SpecificaUy, in this study, the sample elements were vol~tili7-P~ and excited in a 12 a D.C. arc. The various elemPnt signals were sorted and recorded with an ARL l.Sm grating spectrometer. The signal data, which were autom~ti~lly tran~f~rred to IBM punched cards, were plocRssed to con~Rntr~tions in ppm dry weight with an IBM 360-91 co.llpul~r. The following ~lem~ont~ were d~ nined: sodium, poP~ium, c~lci~lm, phosphorus, m~ne~ m, c~lmi--m, zinc, copper, lead, iron, m~n~nese, ~lumimlm, silicon, boron, tin, cobalt, nickel, molyl~d~ ll;ll.ll, cl~,l,-iulll, SlI~JnI;~ b~ril-m, lithillm, silver and v~n~-lium.
Results are as shown in Table 1. Only silicon and lead are listed as the other elem~nt~ did not show major changes.
As can be seRn in Table 1, C12 and CD6 silicon levels increased ~ignific~ntly with age when compared to C1 and C6. The rats fed DMSA however, showed significantly decreased levels of silicon as compared to the older controls (C12 and CD6) and to experim~nt~l ~nim~l~ (EC12 and ED6).
FY~ml~le 2: De~ ",in~ion of GFR
Measurement of the glomerular filtration rate (GFR) provides a sensitive and commonly employed index of overall renal excretory function. GFR can be ~ssed indirectly by measurement of plasma cle~ e or serum urea nitl~en levels, and directly by clearance of inulin (C36 H62 31) or by clearance of various r~dio~ctive substances handled by the kidney in the same way as inulin (i.e.
ioth~l~m~te-Il25). When renal excretory function is i~llpailed, either acutely or chronically, one or more of the GFR determin~nt.~ is altered unfavorably so that total GFR declines. In this study GFR was measured by blood turnover rate of Ioth~l~m~t~
Il25 (J. Lab Clin. Med., 89:845-856 (1972)), as well as by plasma ~ ine and serum urea ni~gen. Results are shown in Table 2, and Figure 1. Figure 1 shows the effect of DMSA tre~tment on GFR. The DMSA group is co",l~ared to normal controls (CD6) and to Anim~ treated with lead for six months, then ~r~ifice~ at twelve months (ED6). As can be seen in Figure 1, ~nim?~l~ given DMSA showed ~,ignifit~ntly increased GFR, confirm~ by lower SUN and serum c c~ e levels than those in the ~nim~l~ without DMSA.
FY~mple 3: Blood Pl~si,ule Levels Mean blood lJNs~,u~c lccol-lings were obtdined using an autull~led tail blood p~ rc device. Results are shown in Figure 2. Blood ~ lrC iS shown to increase with age in both control ~nim~l~ and lead treated ~nim~l~ DMSA tlc~t~ t ~..t~ll~ blood pn,S~llc to levels seen in young ~nim~l~ (Cl) and significantly reduces blood pl~ rc below ED6 and CD6 controls.
FY~mple 4: Human ~(lmini~t~tion of DMSA
R~P1in~ levels of blood silicon, blood pl~7s~llc and GFR are measured for a 70 kg human accolding to standard techniques and those described in the pre~e~ing examples. Three gelatin c~ps--les each containing 270 mg of meso-2,3-dilllclca~lo3.~c-inic acid are taken daily by mouth for five days. Silicon blood levels, blood pressure and GFR are measured daily during tre~tmp-nt and for two days subsequent to tre~tment These measures are lc~ ed at two and seven weeks after lcl...in~l;( n of l,c~..ent~ and below baseline levels of blood silicon, blood ~ ss.~rc and GFR are measured.
By providing a method according to the above invention, several beneficial effects will be realized. First, reduction of silicon levels in the blood and tissue will reduce blood pl-,S~-Ilc and imp~ve kidney function. Second, reduction of silicon by this method will prevent or retard the p~ ssion of chronic renal failure.
Furthermore, remaval of silicon will prevent the onset, or improve the current status of ~em.o.nti~ and ~ htqim~.r's Disease.
Other and further embo~limP-nt~ of the invention are readily a~pa~nt from the aba~e de~,i~tion of the invention, and these elllbc ~ enl~ are believed to be within the scope of the invention.
TRACE ELEMENTS IN KIDNEY
Cl C6 C12 CD6 ECl EC12 ED6DMSA
Elements Si 9.42+ 12.32+ 98.00+ 299.00+ 8.31+ 137.00+ 124.22+ 5.31+u (ppm) 8.64 6.05 38.74 209.7414.10 98.01 118.898.08 Pb 5.00+ 1.97+ 1.57+ 0.75+ 70.33+ 291.78+ 54.22+ 132.29+
(ppm) 2.96 1.53 1.46 1.3923.67 187.18 24.94 127.96 ECl = ~ e~ al group (fed 0.5% lead in drinking water);
~ iGced at 1 month.
Cl = controls for ECl.
C6 = controls sacrificed at 6 months.
EC12 = experimental group (fed 0.5% lead in drinking water);
sacrificed at 12 months.
C12 = controls for EC12.
ED6 = experimental ~ U~ U1~Q group (fed 0.5% lead in drinking water for 6 months, no lead for the Q~lhseqm 6 months);
sacrificed at 12 months.
CD6 = controls for EDG.
DMSA = DMSA-treated rats (fed 0.5% lead in drinking water for 6 months, no lead for the sllbseql~nt 6 months while treated with 0.5% DMSA in drinking water for S days every 2 months);
sacrificed at 12 months.
GFR SERUM SUN
(ml/min/ CREAT. (mg/dl) 100 g) (mg/dl) Cl 0.59+ 0.46+ 19.3+
0.27 0.04 4.0 C6 1.09+ 1.08 + 12.8 +
0.13 0.14 2.4 CD6 0.96+ 1.59+ 14.4 +
0.05 0. 14 2.0 ED6 0.82 + ~ 1.96+~ 20.8 +
0.14 0.28 7.2 DMSA 1.16+~ 1.00+~ 11.1+~
0.13 0.10 2.2 * P ~ 0.05 when compared to ED6 and CD6 ** P < 0.05 when compared to CD6 . , :,,.
~, .. ~
Claims (16)
1. A blood silicon regulant composition comprising of dimercaptosuccinic acid, together with a carrier therefor.
2. The composition defined in claim 1, wherein the blood is human or other animal.
3. The composition defined in claim 1, adapted for oral or parenteral administration.
4. A tissue silicon regulant composition comprising of dimercaptosuccinic acid, together with a carrier therefor.
5. The composition defined in claim 4, wherein the tissue is human or other animal.
6. The composition defined in claim 4, adapt for oral or parenteral administration.
7. A human tissue silicon regulant composition comprising of dimercaptosuccinic acid, together with a carrier therefor.
8. A human blood silicon regulant composition comprising of dimercaptosuccinic acid, together with a carrier therefor.
9. A blood pressure regulant composition comprising of dimercaptosuccinic acid, together with a carrier therefor.
10. A chronic renal failure regulant composition comprising of dimercaptosuccinic acid, together with a carrier therefor.
11. An Alzheimer's disease regulant composition comprising of dimercaptosuccinic acid, together with a carrier therefor.
12. A senile dementia composition comprising of dimercaptosuccinic acid, together with a carrier therefor.
13. A renal function improvement composition comprising of dimercaptosuccinic acid, together with a carrier therefor.
14. Use of dimercaptosuccinic acid for reducing silicon levels in the blood of human animals.
15. Use of dimercaptosuccinic acid for reducing silicon levels in tissue of mammalian animals.
16. Use of dimercaptosuccinic acid in the preparation of pharmaceutical composition for reducing silicon levels in mammalian blood and mammalian tissues.
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|---|---|---|---|
| CA002012470A CA2012470C (en) | 1989-03-17 | 1990-03-19 | Method for silicon reduction with dimercaptosuccinic acid (dmsa) |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/325,297 US4962127A (en) | 1989-03-17 | 1989-03-17 | Method for silicon reduction with dimercaptosuccinic acid (DMSA) |
| CA002012470A CA2012470C (en) | 1989-03-17 | 1990-03-19 | Method for silicon reduction with dimercaptosuccinic acid (dmsa) |
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| CA2012470C true CA2012470C (en) | 1995-11-07 |
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1990
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