Note: Descriptions are shown in the official language in which they were submitted.
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
.....
-
- 20 1 2470
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
20 1 2470
-
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)).
20 1 2470
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
20 1 2470
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
:
2 0 1 2 470
~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
20 1 2470
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.
20 1 2470
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
20 1 2470
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
20 1 2470
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.
20 1 2470
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.
20 1 2470
TABLE 1
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.
TABLE 2 2 0 1 2 4 7 0
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
16
. ,
:,,.
~, .. ~
