WO2001036450A1 - S-allylmercaptoglutathione and uses thereof - Google Patents
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- WO2001036450A1 WO2001036450A1 PCT/IL2000/000761 IL0000761W WO0136450A1 WO 2001036450 A1 WO2001036450 A1 WO 2001036450A1 IL 0000761 W IL0000761 W IL 0000761W WO 0136450 A1 WO0136450 A1 WO 0136450A1
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- allicin
- gssa
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- allylmercaptoglutathione
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- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0215—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing natural amino acids, forming a peptide bond via their side chain functional group, e.g. epsilon-Lys, gamma-Glu
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- A61P9/12—Antihypertensives
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention relates to a new glutathione derivative, namely S- allylmercaptoglutathione, its preparation and pharmaceutical compositions comprising it.
- BAPNA N- ⁇ -benzoyl-DL-arginine p-nitroanilide
- Biradical bis (2,2,5,5- tetramethyl-3-imidazoline-l-oxyl-4-yl) disulfide
- CSSA S-allylmercapto cystein
- DAD diallyl disulfide
- DTT dithiothreitol
- DMPO 5,5'-dimethyl-l-pyrroline N- oxide
- DTNB 5,5'-dithio-bis (2-nitrobenzoic acid
- ESR electron spin resonance
- GSH reduced glutathione
- GSSA S-allylmercaptoglutathione
- GSSG oxidized glutathione
- LPO lipid peroxides production
- NTB 2-nitro-5-thiobenzoate
- PBS phosphate-buffered saline
- RBC red blood cell
- SUV small unilamellar phospholipid vesicles
- TBA TBA
- Allium sativum garlic sativum
- allicin diallyl thiosulfmate
- Allicin is produced during the crushing of garlic cloves by the interaction between the non-protein amino acid alliin (S-allyl-L-cysteine sulfoxide) and the enzyme alliinase.
- Allicin is a precursor of a number of secondary products formed in aged garlic and crushed garlic preparations. Allicin possesses various biological activities among which antibacterial, antifungal and antiparasitic effects are included [Ankri et a., 1997; Koch and Lawson, 1996; Feldberg et al., 1988; Cavallito et al., 1944). In addition to that it reduces serum cholesterol and triglycerides levels as well as atherosclerotic plaque formation and platelet aggregation, it inhibits cancer promotion and decreases ocular pressure [Koch and Lawson, 1996; Chu et al., 1993]. Allicin rapidly disappears after injection into the blood [Lawson and Wang, 1993; Freeman and Kodera, 1995].
- CSSA Recently antioxidant, antiproliferative, decreasing ocular pressure activities of CSSA have been demonstrated [Imai et al., 1994; Lee et al, 1994; Sigounas et al. , 1997a, 1997b; Pinto et al., 1997; Chu et al., 1999]. CSSA revealed antiproliferative effect on different cell lines whereas S-allylcysteine had no effect [Lee et aL, 1994] The concentration of GSH in the blood is about 100-fold higher than that of cysteine, therefore GSH remains as the main candidate for the interaction with allicin in vivo.
- GSSA S-allylmercaptoglutathione
- the present invention thus relates to the novel synthetic glutathione derivative, S-allylmercaptoglutathione, and to salts thereof, to its preparation by reaction of glutathione with allicin or with diallyl disulfide, and to pharmaceutical compositions comprising it.
- salts of GSSA are also included in the invention.
- salts refers both to salts of carboxyl groups and to acid addition salts of the amino group.
- Salts of a carboxyl group may be formed by methods known in the art and include inorganic salts such as salts with alkali metals, e.g. sodium or potassium, and salts with ammonia or with organic bases such as with amines.
- Acid addition salts include salts with mineral acids such as hydrochloric acid or sulfuric acid and salts with organic acids such as acetic acid.
- compositions comprising S-allylmercaptoglutathione are useful for the treatment of several disorders including atherosclerosis, coronary artery diseases, thrombosis, high levels of cholesterol and blood lipids, high blood pressure, control of weight, Alzheimer disease, glaucoma, cancer and inflammatory disorders such as colitis.
- Fig. 1 shows the kinetics of the reaction of allicin with GSH, monitored by appearance of S-allylmercaptoglutathione (GSSA) (white circles) and disappearance of allicin (black circles).
- GSSA S-allylmercaptoglutathione
- the initial concentration of GSH was 1 .2 mM and that of allicin 0.7 mM.
- the reaction was carried out at pH 7.0.
- Fig. 2 shows estimation of concentration of intracellular thiols under incubation, as a function of allicin added to a 1% RBC suspension. Concentration of SH-groups was estimated by ESR with Biradical.
- Fig. 3 shows the kinetics of appearance of GSSA in RBC at 37°iC after treatment with allicin. Allicin-treated RBC were washed with cysteine and PBS to remove external allicin, then treated with trichloroacetic acid. The concentration of GSSA was assayed in the supernatant.
- Fig. 4 shows GSSA formation rate in the allicin/GSH reaction mixture ( 1 mM GSH incubated with 0.7, 1.0 or 1.3 mM allicin at pH 5.0, at room temperature) as function of allicin concentration.
- the initial amount of GSSA produced was followed by HPLC analysis at different time intervals after dilution with HPLC acidic running buffer.
- Fig. 5 shows the kinetics of formation of GSSA in the allicin/GSH reaction mixture (0.25 mM GSH incubated with 1.068 mM allicin) at pH 6.0 and 7.0. At different time intervals, aliquots were diluted with 0.1% formic acid in 60% methanol, and assayed by HPLC.
- Fig. 6 shows GSSA formation rate in the allicin/GSH reaction mixture (0.25 mM GSH incubated with 1 mM allicin at room temperature) as a function of pET. Each column represents the mean ⁇ S.D. of three determinations done at the same pH.
- Fig. 7 shows papain inhibition by GSSA.
- the residual activity of the inhibited enzyme was assayed at pH 6.5.
- Activity is expressed as % of enzyme activity of non-inhibited papain.
- Figs. 8A-8B show ESR spectra of spin-adduct of DMPO with OH radical formed in the Fenton system, in the absence of an antioxidant (Fig. 8A) and in the presence of 1 mM GSSA (Fig. 8B).
- Fig. 9 shows that allicin, CSSA and GSSA inhibit the appearance of -OHradicals and thus decrease the formation of DMPO- -OH spin adduct.
- Fig. 10 shows lipid peroxides (LPO) production (%) in fetal rat brain slices during 30 min incubation in presence of 0.1 mM of alliin, allicin, GSSA, GSH or vitamin E, as determined by the thiobarbituric acid assay (production of thiobarbituric acid reactive substance - TBARS).
- Fig. 11 shows the antioxidant effect of alliin, allicin, GSSA and vitamin E on LPO production by fetal rat brain slices, determined as in Fig. 10 above, as function of reagent concentration.
- Fig. 12 shows the effect of concentrations of allicin (squares) and GSSA (diamonds) on the proliferation of MCF-7 human mammary cancer cells. Measurements were done after three days of treatment at various concentrations.
- Fig. 13 shows the effect of 32 ⁇ M of GSSA, 32 ⁇ M of allicin or medium only, on the proliferation of MCF-7 cells.
- GSSH was synthesized for the first time and its SH-modifying and antioxidant properties were demonstrated.
- GSSA is prepared by reaction between allicin and GSH. This reaction is rather fast with K of bimolecular reaction apparently 3.0 M' ⁇ sec - 1 . It is pH- dependent revealing strong dependence on real concentration of GS ⁇ , indicating that products of allicin transformation which include a thioallyl radical possess some of allicin activities due to its SH-modifying effect.
- the invention further includes pharmaceutical compositions comprising GSSA and a pharmaceutically acceptable carrier.
- GSSA can be incorporated in conventional, solid and liquid pharmaceutical formulations (e.g- tablets, capsules, caplets, injectable and orally administerable solutions) for use in treating mammals, including humans, suffering from several disorders including atherosclerosis, coronary artery diseases, thrombosis, high levels of cholesterol and blood lipids, high blood pressure, control of weight, Alzheimer disease, glaucoma, cancer and inflammatory disorders such as colitis.
- the GSSA compositions can be used for all uses known for allicin, excepting as antibacterial.
- the phannaceutical composition of the invention is in a form for oral administration, for example as an aqueous solution.
- DAD Diallyl disulfide
- Papain (EC 3.4.22.2) was obtained from Boehringer Mannheim (Germany). Alcohol dehydrogenase from. Thermoanaerobium brockii (TBAD) (EC 1.1.1.2) was the kind gift of Dr. M. Peretz and Dr. Y. Burstein, Weizmann Institute of Science, Rehovot, Israel. Egg phosphatidylcholine (PC) was purchased from Lipid Products (South Nutfield, UK). Cholesterol (extra pure) was from Merck (Darmstadt, Germany).
- Symmetrical stable nitroxyl biradical containing disulfide bond bis (2,2,5,5- tetramethyl-3-imidazoline-l-oxyl-4-yl) disulfide (Biradical) synthesized according to [Kitz and Wilson, 1962] was a kind gift of Dr.V. Martin (Lipitek Int. Inc, San Antonio, Texas, USA). All other reagents were of analytical grade.
- Alliin was synthesized as described in Rabinkov et al., 1998. Allicin was produced by applying synthetic alliin onto immobilized alliinase as described in published PCT Patent Application No. WO 97/39115. CSSA was synthesized from cysteine and allicin and isolated as described in Rabinkov et al., 1998. NTB was prepared according to Degani and Patchornik, 1971.
- Papain activation was carried out by dilution (1 : 10) of papain suspension with 50 mM Na acetate, 2 mM EDTA, pH 6.1 (Na acetate/EDTA buffer) in presence of 2.5 mM dithiothreitol (DTT) for 30 min at room temperature. Excess of DTT was removed by gel filtration on Sephadex G-25 pre-equilibrated with Na acetate/EDTA buffer. The activity of papain was determined at room temperature by following the hydrolysis of BAPNA at pH 6.1, in room temperature at 382 nm [Angelides and Fink, 1979]. (e) Assay of TB AD activity
- the rate constant for the reaction of allicin (0.7-1.3 mM) and GSH (1 mM) was obtained in 10 mM phosphate/citrate buffer (pH 5.0) or in 0.1 M NaCl, 0.01 M Na phosphate buffer (pH 7.0).
- the initial rate of GSSA appearance was monitored by HPLC. At various time intervals, samples were diluted with HPLC running buffer and analyzed by HPLC. For calculation the following equation was used: d[GSSA]/dt - [Allicin]x[GSH] where: d[GSSA]/dt is the initial rate of GSSA appearance; K is the bimolecular rate constant; [Allicin], [GSH] are the initial concentrations of allicin and GSH.
- Small unilamellar phospholipid vesicles were made either from egg phosphatidylcholine (PC) or dimyristoylphosphatidylcholine (DMPC) and cholesterol.
- PC egg phosphatidylcholine
- DMPC dimyristoylphosphatidylcholine
- cholesterol content was 25%.
- Cholesterol was dissolved in CHCl 3 /MeOH (2:1 v/v). The cholesterol solution was added to the dry lipid.
- a film of 2.5-5 mg lipid/glass vial was prepared by evaporating the solvents under a stream of nitrogen, followed by 3 h drying under high vacuum.
- SUV containing GSH were obtained by sonication according to Shin et al., 1996, as follows: GSH solution (0.2 M in 0.05 M NaCl, pH 7.0) was added to the dried film, mixed by vortex and sonicated for 10-30 min in a bath-type sonicator (G1125SP1, Laboratory Supplies Co. Inc., New York, NY). Final phospholipid concentration was either 5 or 10 mg/ml.
- Fresh human blood in the presence of heparin was washed three times with PBS. RBCs were collected after centrifugation (2000 rpm, 5 min) and resuspended in PBS. A 10% or 1% (vol/vol) suspension of RBC in PBS was used in the experiments.
- Measurements were performed in a flat cell of the Bruker ER-200 D-SRC spectrometer.
- the experimental conditions included the following: field, 3500 G; sweep width, 100 G; receiver gain, 2x10 ⁇ ; microwave power, 20 mW; modulation amplitude, 0.8 G.
- DMPO was purified as described in Buettner and Oberley, 1978.
- the sample contained H2O2 ( 1 mM), Fe ⁇ (EDTA)2 (0.8 mM ), DMPO (100 mM), in 20 mM sodium phosphate buffer (pH 7.4)) and NaCl (0.2 M), (final volume 0.2 ml)
- H2O2 1 mM
- Fe ⁇ (EDTA)2 0.8 mM
- DMPO 100 mM
- 20 mM sodium phosphate buffer (pH 7.4) mM sodium phosphate buffer (pH 7.4)
- NaCl 0.2 M
- NMR spectra were collected on a Bruker AMX-400 spectrometer. Analysis of allicin and CSSA structures was performed as described in Rabinkov et al., 1998. The product of the interaction between allicin and glutathione was isolated and dissolved in deuterated water and solutions of 10 mM were prepared. The pH was adjusted to 6.5 using KOD. ID *H (with water signal suppression) and 13 C spectra were collected at 25 ⁇ C. Structure analysis of the product obtained was performed as described previously (Miron et al., 1998; Rabinkov et al., 1998). Resonance multiplicities for * 3 C were established by acquiring DEPT spectra. For the DEPT sequence, the width of a 3 C 90° pulse was 7ms, that of a ⁇ H 90° was 12.8 ms, and the (2J)"1 delay was set to 3.45 ms.
- the 2D COSY45 H-1H shift-correlated spectra was recorded using a data size of 512 (tl)x 2048 (t2) with a spectral width of 1400 Hz.
- the HMQC spectra were recorded using a pulse sequence (invbtp in the Bruker software) which included the bilinear rotational decoupling (BIRD) pulse to invert the magnetization of protons not coupled to l ⁇ C.
- the spectra were collected with 2048 (t2) x 256 (tl) data points. Spectral widths of 1400 and 11000 Hz were used in the
- F2 (IK) and FI ( ⁇ C) domains were multiplied in both dimensions by a 90°- shifted sine bell or Gaussian transformation function and generally zero-filled to 512 in tl dimension prior to Fourier transformation.
- the delay Di was set to 3.4 ms while D2 was empirically optimized at 600ms.
- GSH Small unilamellar phospholipid vesicles (SUV) containing GSH were prepared in order to show allicin's propensity to permeate the lipid bilayer membrane.
- GSH the main intracellular thiol of mammalian cells, is highly hydrophilic and therefore cannot pass lipid membranes.
- Red blood cells are naturally occurring membrane vesicles in which GSH is present at a concentration of 1-2 mM.
- the amount of thiols in PBS-washed human RBC was measured either by the noninvasive ESR technique with Biradical developed earlier by Weiner (1995), or directly after trichloroacetic acid (TCA) precipitation of the RBC and assay with DTNB at pH 7.0 (Table 4).
- the total concentration of thiol-containing compounds estimated by the two independent methods were very similar (about 2 mM) and are in a good agreement with data reported by others (Vina et al., 1995).
- the advantage of the ESR method is that it enables monitoring of the decrease of thiol concentration in cells after short exposure to allicin.
- Allicin (up to 2.5 x 10 "5 M final concentration) was added to a 1% washed RBC suspension in an Eppendorf tube. After 1 -2 min at room temperature the Biradical was added (10 "4 M final concentration) and the content of residual thiol concentration was monitored. As shown in Fig. 2, allicin penetrates through the RBC membrane and reacts with intracellular thiols in a concentration dependent manner
- GSSA S-allylmercaptoglutathione
- GSH (1 mM) was incubated with allicin (0.7 mM to 1.3 mM) in 10 mM citrate phosphate buffer pH 5.0, at room temperature.
- the initial amount of GSSA produced was followed by HPLC analysis at different time intervals after dilution with HPLC acidic running buffer.
- the appearance of the product on HPLC during the reaction enabled us to follow the kinetic of interaction of allicin with GSH.
- the bimolecular kinetic constant of the reaction at pH 5 was determined at allicin concentrations of 0.7, 1.0 and 1.3 mM. The results are shown in Fig. 4 and in
- the SH-modifying activity of GSSA and CSSA was determined in the same enymatic systems as was described earlier for allicin (Rabinkov et al., 1998), namely, in SH-protease papain, where a SH-group (Cys25) J s located in the active site, and in alcohol dehydrogenase from the thermophylic bacteria Thermoanaerobium brockii (TBAD), where a SH-group (Cys20 ) ⁇ s located very close to the NADP + - binding site (Korkhin et al., 1998).
- the Cys25 of papain is located on the protein surface, on the groove between the two lobes of the protein, and therefore is available for chemical modification.
- Each TBAD subunit contains one free SH-group on the protein surface. Chemical modification of that group inhibits dramatically the enzymatic activity (Peretz et al., 1997; Rabinkov et al., 1998).
- DTT-activated and gel-filtered papain (papain-SH) was inactivated by GSSA (2.0 mM, 4.0 mM. 9.0 mM) in 50 mM Na acetate buffer pH 6.2 containing 2 mM EDTA.
- the residual activity of the inhibited enzyme was assayed at pH 6.5 and recorded as described in Material and Methods, section (d). Activity is expressed as % of enzyme activity of non- inhibited papain.
- incubation of activated papain with GSSA led to rapid loss of enzymatic activity.
- CSSA data not shown
- allicin Rosin et al, 1998
- the loss of activity was time dependent.
- the rates of enzyme inactivation depend on the initial disulfide's concentration. As follows from these experiments, CSSA and GSSA, the natural products of allicin transformation, show pronounced SH modifying activity.
- Example 7 Effect of GSSA on LPO production by fetal rat brain slices ex vivo
- the antioxidant activity of GSSA was investigated in tissues using fetal rat brain slices model ex vivo under iron-induced oxidative stress by determination of the lipid peroxides level as described in Materials and Methods, section (m).
- the effect of GSSA was compared with activities of alliin, allicin, GSH, GSSG, 2- deoxyribose and vitamin E.
- LPO production (%) in fetal rat brain slices was determined during 30 min incubation in presence of 0.1 mM of the various reagents by the TBA assay as described in Materials and Methods, section (m). As shown in Fig. 10, no significant antioxidant activity was observed after incubation of brain slices with alliin.
- MCF-7 human mammary cancer cells were grown in DMEM medium containing 0.6 ⁇ g/ml insulin. The medium was supplemented with penicillin (10O U/ml), streptomycin (0.1 mg/ml) nystatin (12.5 ⁇ g/ml), and 10% FCS. Cells were seeded into 6-multiwell plates (170,000 cells per well) or 96-multiwell plates (5,000 cells per well) or 100 mm dish (1,500,00 cells per dish) in medium containing 3% FCS. One day later the medium was changed to one containing either only medium or allicin or GSSA, and the media were replaced daily.
- Lipid peroxides are generated by the fetal rat brain after episodes of global ischemia in utero, Neurochemical Research, 22: 201-208.
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Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
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IL14963800A IL149638A0 (en) | 1999-11-16 | 2000-11-16 | S-allylmercaptoglutathione and uses thereof |
CA002391969A CA2391969A1 (en) | 1999-11-16 | 2000-11-16 | S-allylmercaptoglutathione and uses thereof |
JP2001538939A JP2003514830A (en) | 1999-11-16 | 2000-11-16 | S-allyl mercaptoglutathione and use thereof |
EP00976230A EP1230259A1 (en) | 1999-11-16 | 2000-11-16 | S-allylmercaptoglutathione and uses thereof |
AU14104/01A AU1410401A (en) | 1999-11-16 | 2000-11-16 | S-allylmercaptoglutathione and uses thereof |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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IL132971 | 1999-11-16 | ||
IL13297199A IL132971A0 (en) | 1999-11-16 | 1999-11-16 | Glutathione derivative its preparation and pharmaceutical compositions comprising it |
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WO2001036450A1 true WO2001036450A1 (en) | 2001-05-25 |
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PCT/IL2000/000761 WO2001036450A1 (en) | 1999-11-16 | 2000-11-16 | S-allylmercaptoglutathione and uses thereof |
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JP (1) | JP2003514830A (en) |
AU (1) | AU1410401A (en) |
CA (1) | CA2391969A1 (en) |
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Cited By (2)
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US8217084B2 (en) | 2004-05-24 | 2012-07-10 | Allium Vitalis Incorporated | Medicinal products incorporating bound organosulfur groups |
CZ308144B6 (en) * | 2014-05-09 | 2020-01-22 | Fakultní nemocnice Hradec Králové | Process for preparing S-allylthioglutathione, optionally in admixture with S-allyldithioglutathione, mixture of S-allylthioglutathione with S-allyldithioglutathione and S-allyldithioglutathione |
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JP2011078357A (en) * | 2009-10-07 | 2011-04-21 | Kochi Univ | Method for fractional determination of vitamin b6 and kit for fractional determination of vitamin b6 |
KR102464435B1 (en) * | 2020-09-22 | 2022-11-07 | 의료법인 성광의료재단 | Composition for preventing or treating inflammatory diseases comprising D-glutathione or derivatives thereof |
Citations (1)
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JPH0782144A (en) * | 1993-09-09 | 1995-03-28 | Fuji Sangyo Kk | Antiallergic agent |
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2000
- 2000-11-16 WO PCT/IL2000/000761 patent/WO2001036450A1/en not_active Application Discontinuation
- 2000-11-16 EP EP00976230A patent/EP1230259A1/en not_active Withdrawn
- 2000-11-16 JP JP2001538939A patent/JP2003514830A/en active Pending
- 2000-11-16 AU AU14104/01A patent/AU1410401A/en not_active Abandoned
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JPH0782144A (en) * | 1993-09-09 | 1995-03-28 | Fuji Sangyo Kk | Antiallergic agent |
Non-Patent Citations (4)
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DATABASE CHEMABS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002159575 * |
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Cited By (2)
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US8217084B2 (en) | 2004-05-24 | 2012-07-10 | Allium Vitalis Incorporated | Medicinal products incorporating bound organosulfur groups |
CZ308144B6 (en) * | 2014-05-09 | 2020-01-22 | Fakultní nemocnice Hradec Králové | Process for preparing S-allylthioglutathione, optionally in admixture with S-allyldithioglutathione, mixture of S-allylthioglutathione with S-allyldithioglutathione and S-allyldithioglutathione |
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IL132971A0 (en) | 2001-03-19 |
AU1410401A (en) | 2001-05-30 |
CA2391969A1 (en) | 2001-05-25 |
JP2003514830A (en) | 2003-04-22 |
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