LU86414A1 - PHARMACEUTICAL FORMULATION AND METHOD FOR PROTECTING SICK PERSONS FROM THE SIDE EFFECTS OF CIS-PLATINUM - Google Patents

Description

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The present invention relates to a pharmaceutical formulation intended in particular for use in dispensaries and hospitals, characterized by a high dose of reduced glutathione. More particularly, an object of the invention consists of a pharmaceutical formulation, intended in particular for use in dispensaries or hospitals containing, for each unit dose, at least 2.5 g of reduced glutathione, and preferably 5 g of reduced glutathione 10, to be used as a protective agent against side effects (in particular nephrotoxicity) caused by "cis-platinum".

The use of cis-diamino-dichloro-platin (CDDP) or "cis-platinum" is known in antiblasti-15 chemotherapy. We also know the significant nephrotoxicity caused by cisplatin in the renal tubules.

The administration of CDDP is also carried out concomitantly with intense hydration of the patients intravenously, hydration which precedes and follows the injection of the drug and is often accompanied by the initiation of forced diuresis by association with diuretics. However, neither massive hydration nor such massive forced diuresis succeed in avoiding tubular disorders of serious gravity following treatment with the cis-platinum.

It has been demonstrated in animals treated with cis-platinum (F. Zunino, 0. Tofanetti et al.,

Tumori 69, 105-111, 1983) a certain nephroprotective action on the part of reduced glutathione (GSH), noted on the basis of a few parameters (azotemia, creatinine level, change in body weight, ratio between the weight of the kidney and body weight). However, it has been found that even the administration of relatively large doses of GSH (1 g / kg body weight) does not completely avoid tubular disorders in rats or mice.

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On the other hand, it has now been unexpectedly discovered that GSH, administered to humans in high doses (above a determined value threshold and clearly higher than those used for other indications) but much weaker than those theoretically deductible from (still insufficient) experiments carried out on animals, is able not only to protect almost completely tubular disorders caused by cis-platinum, but to maintain at the same time unaltered the therapeutic effects of cisplatin itself .

The above surprising observation was furthermore carried out on the basis of parameters much more sensitive and precise than those adopted in animal experiments, and this by determining in the urine of the patients, the level of two microenzymes , Alanine-aminopeptidase

(AAP) and N-acetyl-β-glucosamirtidase (NAG), which undergo very high increases (approximately 8 to 10 times the normal values) in the specific case of tubular disorders. 20 The importance and credibility of the PAA and NAG rates

as indices of nephrotoxicity have been highlighted by many authors: see for example B.R. Jones et al., "Comparison of methods of evaluating nephrotoxicity of cis-platinum", Clin. Pharmacol. Ther., 1980. 557; 25 R.L. Sherman et al. "N-Acetyl - ^? - Glucosaminidase and f2-Microglobulin - Their Urinary Excretion in Patients with Renal Parenchimal Disease", Arch. Intern. Med. 145, 1185 (1985); B.R. Mayer et al. "Increased Urinary Enzyme Excretion in Worders Exposed to Nephrotoxic Chemicals", 50 Amer. Daily Med. 76. 989 (1984). Protection against tubular disorders induced by cisplatin, therefore, by means of the administration of GSH has been established by systematic dosing of AAP and NAG in the urine of patients, as reported below.

55 Female subjects with ovarian neoplasia have been taken into account for various cycles of treatment with cis-diamino-dichloro-platinum.

p (CDDP) at a rather high dosage (90 mg / m intravenously). AAP and NAG were assayed in the urine of patients in the absence of treatment with GHS 5 and in the presence of such treatment, carried out before and / or after injection of CDDP. (Administration of GSH was done intravenously anyway).

The assay for the microenzyme alanine-aminopeptidase (AAP) was carried out by determining by colorimetry the 10 p-nitroaniline released by the enzyme in question, by catalyzing the hydrolysis of alalanine-p-nitroanilide (see JE Peters et al. , Clin.Chim. Acta 37. 213 (1972); K, Jung et al., Clin. Chem. 26. 1251 (1980)). Also, N-acetyl-O-glucosaminidase (NAG) was assayed by colorimetry, by determining, in an alkaline medium, the p-nitrophenol which the microenzyme releases from p-nitrophenyl-N-acetyl. - ^ 3 "D-glucosaminide (see D. Marhun, Clin. Chim. Acta 73. 453 (1976); TD Lockwood et al., Tox. Appl. Pharmacol. 49. 323 (1979); AM Gressner et 20 coll. , Clin, Chim, Acta 124. 315 (1982)).

A total of 50 cycles of therapy were analyzed with - CDDP, with the results summarized below: A. Hydration alone, without treatment with GSH ï 1ΆΑΡ undergoes an average increase of approximately eight times 25 compared to normal values at NAG undergoes an average increase of about ten times compared to normal values.

B. Hydration + 1 gram (total) of GSH administered 15 minutes before or after the cis-platinum injection: 30 no protective action is observed; the level of urinary enzymes AAP and NAG is practically identical to that presented by group A.

C. Hydration + 2 grams (total) of GSH administered at a rate of 1 gram 15 minutes before and 1 gram 35 15 minutes after the injection of cis-platinum; a fairly obvious protective action is observed. · 4 * since the assay of the two microenzymes reveals an average increase in APA of five times compared to the normal level, and of NAG of seven times compared with the normal level.

5 D. Hydration + 2.5 grams (total) of GSH, also administered in this case for half 15 minutes before and for half 15 minutes after the injection of cis-platinum · the protection is greater than in the case of C), the APA and NAG levels increased by an average of three times and three and four times respectively compared to normal values. E. Hydration + 5 grams (total) of GSH, administered according to the above criteria: the average level of the two microenzymes is approximately double compared to normal, which demonstrates almost comolete protection sick people.

It is appropriate to emphasize, as has already been said previously, that even in group E (and a fortiori in the previous ones), the therapeutic effects of the administration of cis-platinum remain unaltered.

In view of the above, the following conclusions can be drawn: "a) the administration of 1 gram of GSH is substantially ineffective; b) passing from 2 grams to 2.5 grams of GSH, a critical dose threshold, since with a 25% increase in GSH, a 40% reduction in the level of APA is obtained, and directly of approximately 50% in the level of NAG; 50 c) the dose of GSH effective in protecting the cis-platinum-induced nephrotoxicity is significantly higher than the doses of GSH used for other therapeutic indications; at the same time, it is at least an order of magnitude lower than that compared to that in animals, also provides protection that is still unsatisfactory.

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An essential aspect of the invention therefore consists of pharmaceutical compositions, intended in particular for use in dispensaries and hospitals, suitable for protection against side effects induced by cis-platinum (in particular nephrotoxicity), containing a reduced amount of glutathione not less than 2.5 grams per unit dose, preferably 5 grams per unit dose, optionally in admixture with excipients commonly used in the pharmaceutical industry and / or with other active ingredients. Non-limiting examples of such pharmaceutical compositions are as follows.

EXAMPLE 1 a) Lyophilized vials each containing: 15 - reduced glutathione 2.50 g - ethylenediamine 0.20 ml - polyvinylpyrrolidone 40,000 (Codex quality) 0.125 gb) Vials of solvent each containing 20 - water for injections (Codex ) 15 ml EXAMPLE 2 a) Lyophilized vials each containing: - reduced glutathione 5.00 g 25 - ethylenediamine 0.40 ml - polyvinylpyrrolidone 40,000 (Codex) 0.25 gb) Vials of solvent each containing: - water for 2Q preparations injectables (Codex) 30 ml

Claims (3)

1. Pharmaceutical formulation with protective activity against the side effects caused by cisplatin, characterized in that it contains as active principle at least 2.5 grams of glutathione - 5 reduced per unit dose, optionally mixed with excipients commonly used in pharmaceutical technology and / or with other active ingredients. 2. Formulation according to claim 1, characterized in that it exerts a protective activity 10. against the nephrotoxicity caused by cisplatin. 5. Formulation according to claims 1 and 2, characterized in that it contains 5 grams of reduced glutathione per unit dose.