GB2174905A - Compositions containing reduced glutathione - Google Patents
Compositions containing reduced glutathione Download PDFInfo
- Publication number
- GB2174905A GB2174905A GB08610970A GB8610970A GB2174905A GB 2174905 A GB2174905 A GB 2174905A GB 08610970 A GB08610970 A GB 08610970A GB 8610970 A GB8610970 A GB 8610970A GB 2174905 A GB2174905 A GB 2174905A
- Authority
- GB
- United Kingdom
- Prior art keywords
- platinum
- reduced glutathione
- cis
- grams
- induced
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
- A61K38/063—Glutathione
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Inorganic Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Compositions containing, per unit dose, at least 2.5 g of reduced glutathione have protective action against side effects (namely nephrotoxicity) induced by cis-platinum compounds.
Description
SPECIFICATION
Pharmaceutical compositions containing reduced glutathione
The invention concerns a pharmaceutical composition, particularly for out-patient or hospital use, characterized by an high dosage of reduced glutathione. More precisely, the invention concerns a pharmaceutical composition, particularly for out-patient or hospital use, containing, per unit dose, at least 2.5 g of reduced glutathione, and preferably 5 g of reduced glutathione, for use as protecting agent against the side-effects (particularly the nephrotoxicity) induced by platinum coordination compounds, particularly "cis-platinum".
The use of cis-diamine-dichloroplatinum (CDDP), or "cis-platinum" in antiblastic chemioterapy is known.
The remarkable nephrotoxicity induced by cis-platinum at the level of the renal tubuli is also known. The
CDDP administration is therefore carried out contemporaneously with a marked hydratation of the patient by the intravenous route, both before and after the drug infusion and it is often coupled with the induction of forced diuresis by means of the combination with diuretics. Nevertheless, neither a strong hydratation nor a similarly strong forced diuresis succeed in avoiding tubular damages of remarkable seriousness following the cis-platinum treatment.
A certain degree of nephroprotective action of reduced glutathione (GSH), detected according to some parameters (azotemia, creatininemia, changes in body weight, weight ratio of the kidney to the body weight) has been previously shown in the cis-platinum treated animals (F. Zunino, O. Tofanetti et al., Tumori 69, 105-111, 1983). It was however noticed that even the administration of relatively enormous doses (1 g/kg body weight) of GSH did not allow to completely eliminate tubular damages both in the rat and in the mouse.
On the contrary, it has now been surprisingly found that GSH, administered to men in high doses (higher than a determined threshold value, and remarkably higher than those used for other indications) but that are much lower than those deducible from the experiences (although unsatisfactory) carried out on the animals, is able to protect not only to an almost complete extent from the cis-platinum induced tubular damages but to keep contemporaneously unchanged the therapeutic effects of cis-platinum itself.
The surprising remark above reported has been moreover made according to parameters which are much more sensitive and precise than those used in the animal tests, and particularly determining in the patients'urine the level of two microenzymes, alanine-aminopeptidase (AAP) and N-acetyl-ss- glucosaminidase (NAG), which dramatically increase (about 8-10 times the normal values) in the case of tubular damages.
The importance and the significance of the AAP and NAG levels as nephrotoxicity index have been shown by different authors: see, for instance, B.R. Jones et al., "Comparison of methods of evaluating nephrotoxicity of cis-platinum", Clin. Pharmacol. Ther. 1980, 557; R.L. Sherman et al., "N-Acetyl-ss- Glucosaminidase and 2-Microglobulin - Their Urinary Excretion in Patients with Renal Parenchimal Disease",Arch. lntern. Med. 143, 1 183 (1983); B.R. Mayer et al., "lncreased Urinary Enzyme Excretion in Workers Exposed to Nephrotoxic Chemicals", Amer. Mourn. Med. 76,989 (1984).
Therefore, the protection from tubular damages, induced by cis-platinum, by GSH administration has been documented by the systematic dosage of AAP and NAG in the patients'urine, as hereinafter reported.
Female patients, affected by ovarian neoplasias, have been taken into account, during different cycles of cis-diamine-dichloro-platinum (CDDP) treatment at rather high doses (90 mg/m2, by intravenous route). The
AAP and NAG dosage in the patients'urine has been carried out in the absence and in the presence of the
GSH treatment, carried out before and/or after the CDDP infusion (the GSH was always administered by slow infusion).
The dosage of the microenzyme alanine-aminopeptidase (AAP) has been carried out measuring by colorimetric assay the p-nitro-alanine released by said enzyme from the catalytic hydrolysis of alanine-pnitroenilide (see J.E. Peters et al., Clin. Chim. Acta 37,213(1972); K. Jung et al., Clin. Chem. 26, 1251(1980)).
Also N-acetyl-ss-glucosaminidase (NAG) has been determined by colorimetric assay, by measuring, in alkaline medium, the p-nitrophenol released by the microenzyme from p-nitrophenyl-N-acetyl-f3- glucosaminide (see D. Marhun, Clin. Chim. Acta 73, 453 (1976); T.D. Lockwood et al., Tox. Apt!. Pharmacol.
49,323(1979); A. M. Gressner et al., Clin. Chim. Acta 124,315(1982)).
50 CDDP therapeutic cycles have been altogether examined, with the results hereinafter summarized:
A. Onlyhydratation, without GSH treatment. AAP undergoes a mean increase of about 8 times the normal value; NAG undergoes a mean increase of about 10 times the normal value.
B. Hydratation + 1 gram rin total) of GSH administered 15 minutes before or after the cis-platinum infusion; no protective action is noticed; the level of urinary enzymes AAP and NAG is substantially comparable to that determined forthe group A.
C. Hydratation +2grams (in total) ofGSHadministered at the rate of 1 gram 15 minutes before and 1 fram 15 minutes after the cis-platinum infusion: a sufficiently evident protective action is noticed since the dosage of the two enzymes reveals a means increase of 5 times for AAP and of 7 times for NAG, with respect to the normal values.
D. Hydratation + 2.5 grams (in total) of GSH, administered also in this case half 15 minutes before and half 15 minutes after the cis-platinum infusion: the protection is higher than in the case of C, the AAP and NAG mean levels being three times and three-four times the normal values, respectively.
E. Hydratation + Sgrams (in total) of GSH, administered with the above mentioned criteria: the mean level of the two enzymes is about twice the normal value, with an almost complete patients' protection.
It should be pointed out that, as already mentioned, even in group E (and consequently even in the previous groups) the therapeutic results of the cis-platinum administration remain unchanged.
The above results allow to draw the following conclusions:
a) administration of 1 g of GSH is substantially devoid of efficacy;
b) changing the dosage from 2 to 2.5 grams of GSH, a critical dosage is found since by increasing GSH of 25%, a 40% decrease in AAP level and even about a 50% decrease in NAG level, is obtained;
c) the effective dose of GSH in the protection from the cis-platinum induced nephrotoxicity is remarkably higher than the GSH dosages used for other therapeutic indications; at the same time, it is at least one order of magnitude lower in comparison with that exerting in the animal a protection which is moreover yet unsatisfactory.
An essential aspect of the invention is therefore provided by pharmaceutical compositions, particularly for out-patient or hospital use, suited for the protection from platinum compound induced side-effects (particularly nephrotoxicity), containing amounts of reduced glutathione not lower than 2.5 grams per unit dose, preferably 5 grams per unit dose, optionally in admixture with excipients commonly used in pharmaceutical technique and/or with other active principles.
Non limitative examples of said pharmaceutical compositions are hereinafter reported:
Example 1
a) Lyophilized bottles each containing:
- reduced glutathione 2.50 g
- ethylendiamine 0.20 ml
- polyvinylpyrrolidone 40,000 0.125 g
b) Solvent vials each containing: -waterforinjectable preparations 15 ml.
Example 2
a) Lyophilized bottles each containing
- reduced glutathione 5.00 g
- ethylendiamine 0.40 ml
- polyvinylpyrrolidone 40,000 0.25 g
b) Solvent vials each containing: -waterforinjectable preparations 30 ml.
Claims (6)
1. Pharmaceutical compositions having protective activity from the platinum compound, particularly cis-platinum, induced side effects, containing as an active ingredient at least 2.5 grams of reduced glutathione per unit dose, optionally in admixture with excipients commonly used in pharmaceutical technique and/or with other active ingredients.
2. Compositions according to claim 1, having protective activity from the cis-platinum induced nephrotoxicity.
3. Compositions according to claim 1 or 2, containing 5 grams of reduced glutathione per unit dose.
4. Method for the protection of patients from the side effects induced by platinum compounds, particularly by cis-platinum, characterized in that doses of at least 2.5 grams of reduced glutathione are administered to the patients shortly before and/or after from the platinum compound infusion.
5. Method according to claim 4, characterized in that the administered dose is of 5 grams of reduced glutathione.
6. Method according to claims 4 and 5, characterized in that the administration is divided in two equal portions, one being administered shortly before and the other shortly after the platinum compound infusion.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT20591/85A IT1200467B (en) | 1985-05-06 | 1985-05-06 | PHARMACEUTICAL FORMULATION |
Publications (3)
Publication Number | Publication Date |
---|---|
GB8610970D0 GB8610970D0 (en) | 1986-06-11 |
GB2174905A true GB2174905A (en) | 1986-11-19 |
GB2174905B GB2174905B (en) | 1989-09-20 |
Family
ID=11169266
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB8610970A Expired GB2174905B (en) | 1985-05-06 | 1986-05-06 | Pharmaceutical compositions containing reduced glutathione |
Country Status (11)
Country | Link |
---|---|
BE (1) | BE904717A (en) |
CH (1) | CH672988A5 (en) |
DE (1) | DE3615313A1 (en) |
FR (1) | FR2581312B1 (en) |
GB (1) | GB2174905B (en) |
HK (1) | HK69890A (en) |
IT (1) | IT1200467B (en) |
LU (1) | LU86414A1 (en) |
NL (1) | NL8601157A (en) |
SE (1) | SE8602060L (en) |
SG (1) | SG62190G (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0327999A1 (en) * | 1988-02-08 | 1989-08-16 | Mochida Pharmaceutical Co., Ltd. | A pharmaceutical composition for relieving side effects of platinum-containing drugs |
US8426625B2 (en) | 2005-12-22 | 2013-04-23 | Cell Therapeutics, Inc. | Bis-platinum complexes with antitumor activity |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HUT63565A (en) * | 1990-08-20 | 1993-09-28 | Ohlenschlaeger Gerhard | Process for producing curqtive mixture consisting of glutathione and anthocyan compounds |
US5925620A (en) * | 1990-08-20 | 1999-07-20 | Ohlenschlaeger; Gerhard | Therapeutically active mixture of glutathione and anthocyanin compounds |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0087865A2 (en) * | 1982-03-01 | 1983-09-07 | Efamol Limited | Pharmaceutical composition |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR3866M (en) * | 1964-07-08 | 1966-01-24 | Rocal | Medicinal product based on pyrocatechol derivative. |
GB1110392A (en) * | 1964-09-28 | 1968-04-18 | Yamanouchi Pharma Co Ltd | Composition containing glutathione and an amino acid or amino acids, and salts thereof |
-
1985
- 1985-05-06 IT IT20591/85A patent/IT1200467B/en active
-
1986
- 1986-04-30 FR FR868606269A patent/FR2581312B1/en not_active Expired - Lifetime
- 1986-04-30 CH CH1766/86A patent/CH672988A5/it not_active IP Right Cessation
- 1986-04-30 LU LU86414A patent/LU86414A1/en unknown
- 1986-05-05 SE SE8602060A patent/SE8602060L/en not_active Application Discontinuation
- 1986-05-05 BE BE2/60978A patent/BE904717A/en not_active IP Right Cessation
- 1986-05-06 NL NL8601157A patent/NL8601157A/en not_active Application Discontinuation
- 1986-05-06 DE DE19863615313 patent/DE3615313A1/en not_active Ceased
- 1986-05-06 GB GB8610970A patent/GB2174905B/en not_active Expired
-
1990
- 1990-07-26 SG SG621/90A patent/SG62190G/en unknown
- 1990-09-06 HK HK698/90A patent/HK69890A/en not_active IP Right Cessation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0087865A2 (en) * | 1982-03-01 | 1983-09-07 | Efamol Limited | Pharmaceutical composition |
Non-Patent Citations (2)
Title |
---|
EXTRA PHARMACOPOEIA, MARTINDALE, 28TH EDITION, PAGE 53 UNDER GLUTATHIONE * |
TUMORI 69, 1983, PAGES 105-111, F. ZUNINO ET. AL. * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0327999A1 (en) * | 1988-02-08 | 1989-08-16 | Mochida Pharmaceutical Co., Ltd. | A pharmaceutical composition for relieving side effects of platinum-containing drugs |
US4950465A (en) * | 1988-02-08 | 1990-08-21 | Mochida Pharmaceutical Co., Ltd. | Pharmaceutical composition for relieving side effects of platinum-containing drugs |
US8426625B2 (en) | 2005-12-22 | 2013-04-23 | Cell Therapeutics, Inc. | Bis-platinum complexes with antitumor activity |
Also Published As
Publication number | Publication date |
---|---|
SE8602060D0 (en) | 1986-05-05 |
SG62190G (en) | 1990-09-07 |
LU86414A1 (en) | 1986-09-02 |
HK69890A (en) | 1990-09-14 |
FR2581312A1 (en) | 1986-11-07 |
NL8601157A (en) | 1986-12-01 |
BE904717A (en) | 1986-09-01 |
FR2581312B1 (en) | 1992-05-29 |
CH672988A5 (en) | 1990-01-31 |
DE3615313A1 (en) | 1986-11-20 |
IT1200467B (en) | 1989-01-18 |
SE8602060L (en) | 1986-11-07 |
GB8610970D0 (en) | 1986-06-11 |
IT8520591A0 (en) | 1985-05-06 |
GB2174905B (en) | 1989-09-20 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19990506 |