DE3615313A1 - REDUCED PHARMACEUTICAL COMPOSITIONS CONTAINING GLUTATHION AND THE USE THEREOF TO INHIBIT TUMOR GROWTH AND TO REDUCE THE SIDE EFFECTS Caused By Platinum Compounds - Google Patents

Description

T 55 468

Applicant: Boehringer Biochemia Robin SpA Via S. Uguzzone, 5
1-20122 Milano, Italy

10- Containing reduced glutathione

pharmaceutical compositions and their use for inhibiting the Tumor growth and to reduce those caused by platinum compounds Side effects

The invention relates to a pharmaceutical composition or preparation (pharmaceutical preparation), in particular is applicable to patients outside and inside a hospital who have a high dose of reduced glutathione contains; the invention particularly relates to a pharmaceutical composition for use in particular in patients outside and inside a hospital, the reduced rate of at least 2.5 g per unit dose Contains glutathione, preferably 5 g of reduced glutathione, which can be used as a protective agent against the side effects caused by platinum coordination compounds, in particular "cis-platinum" (in particular Nephrotoxicity).

The use of cis-diamine dichloroplatinum (CDDP) or "cis-platinum" in antiblastic chemotherapy is already known. The by cis-platinum in the area of the renal tubules induced remarkable nephrotoxicity is also known. The administration of CDDP is therefore carried out simultaneously with a pronounced hydration (water supply) of the patient by intravenous route both before

as well as after the drug has been infused, and is often coupled with the induction of forced diuresis by combination with diuretics. However, neither a strong hydration nor a corresponding one can do this severe forced diuresis the remarkably severe tubular damage after cis-platinum treatment be avoided.

A certain extent of the kidney protective effect of reduced glutathione (GSH), proven by some Parameters (azotemia, creatininemia, change in body weight and change in weight ratio of Kidney to body weight) could be proven earlier in animals treated with cis-platinum (f. Zunino, 0. Tofanetti et al., "Tumori" £ 9, 105-111, 1983). It however, it was found that the administration was also proportionate very large doses (1 g / kg body weight) of GSH did not completely eliminate the tubular damage allowed in both rats and mice.

On the other hand, it has now surprisingly been found that GSH, when used in high doses (higher than a set threshold and significantly higher than such. as used in other indications), but much lower are as those derived from the experiences (albeit unsatisfactory) that have been made with animals, administered to humans, is not only able to counteract them to an almost complete extent to protect the tubular damage caused by cis-platinum, but also the therapeutic ones at the same time To maintain the effects of the cis platinum itself unchanged.

The above surprising finding was also made using parameters that are much more sensitive and are more accurate than those as applied in the animal experiments, and especially below

-SBr-

Determination of the patient's urine content of the two Microenzymes alanine aminopeptidase (AAP) and N-acetyl-β-glucosaminidase (NAG), which increases dramatically (to about 8-10 times normal values in the case of tubular damage).

The importance and significance of the AAP and NAG levels as a nephrotoxicity index has been shown by various authors, see, for example, BR Jones et al., "Comparison of methods of evaluating nephrotoxicity of cis-platinum" in "Clin. Pharmacol. Ther . " 1980 , 557; RL Sherman et al., "N-Acetyl-β-Glucosaminidase and β ₂ -Microglobulin - Their Urinary Excretion in Patients with Renal Parenchimal Disease" in "Arch. Intern. Med" J_4_3, 1183 (1983); BR Mayer et al., "Increased Urinary Enzyme Excretion in Workers Exposed to Nephrotoxic Chemicals" in "Amer. Journ. Med.", £ 7, 989 (1984).

Protection against tubular damage caused by cis-platinum by administering GSH, systematic dosing of AAP and NAG in the patient's urine, documented as described below.

There were female patients with an ovarian neoplasm during different cycles of a cis-diamine-dichloroplatinum (CDDP) treatment in fairly high Do-

2
sen (90 mg / m, administered intravenously) was observed. The AAP and NAG dosing in the patient's urine took place in the absence and 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) was carried out by colorimetric measurement of this Enzyme b ^ i of the catalytic hydrosysis of alanine-p-nitroanilide released p-nitroaniline (cf. J.E. Peters et al., "Clin. Chim.Acta", 37, 213 (1972); K. Jung et al.,

■ 54 * -

"Clin. Chem.", 26_, 1251 (1980)). N-acetyl-ß-glucosaminidase (NAG) was also determined colorimetrically by measuring the p-nitrophenol released by the microenzyme from p-nitrophenyl-N-acetyl-ß-D-glucosaminide in an alkaline medium (cf. D. Marhun, " Clin. Chim. Acta ", 73 , (1976); TD Lockwood et al," Tox. Appl. Pharmacol. ", 49, 323 (1979); AM Gressner et al.," Clin. Chim. Acta ", 124 , 315 (1982)).

A total of 50 therapeutic CDDP cycles were investigated, the results summarized below were obtained:

(A) Hydration only , no GSH treatment: the AAP level gave a mean increase to about 8 times normal; the NAG content showed a mean increase to about 10 times the normal value.

(B) hydration + 1g (total) GSH administered 15 minutes before or after the infusion of cis-platinum: no protective effect was found; the content of the urine enzymes AAP and NAG was essentially comparable to that found for group A.

(C) hydration + 2g (total) GSH administered in

a rate of 1 g / 15 min prior to infusion of cis-platinum, and in a rate of 1 g / 15 min after the infusion of cis-platinum: An obvious QQ lent sufficient protective effect observed, as the dosing of the two Enzymes gave a mean increase of 5-fold for AAP and 7-fold for NAG, based on normal values.

ge (D) hydration + 2.5 g (total) GSH , administered in this case half 15 minutes before the infusion of cis-platinum and half 15 minutes after

* the infusion of cis-platinum: the protection was higher than in the case of C, the mean content of AAP and NAG were 3 times and 3 to 4 times respectively

Normal values.
5

(E) Hydration + 5g (total) GSH , administered according to the above criteria: the mean content of the two enzymes was about twice the normal value with almost complete patient protection.

It should be noted that, as already mentioned, even in group E (and consequently also in the previous groups) the therapeutic results of the administration of cis-platinum remained unchanged.

The above results allow the following conclusions:

(a) administration of 1 g GSH is essentially ineffective;

(b) when changing the dose from 2 g to 2.5 g GSH, a critical dose has been found, since it was increased from GSH by 25%, a decrease in the content of AAP by 40% and a decrease in the content of NAG by

even about 50% is achieved;

(c) is the effective dose of GSH to protect against cis-platinum induced nephrotoxicity significantly higher than the GSH doses used for other therapeutic indications; simultaneously

"^ it is at least an order of magnitude lower, compared with that which exerts a protective effect on animals, which is, moreover, still unsatisfactory is.

An essential aspect of the present invention are therefore pharmaceutical compositions or preparations, which are particularly applicable to patients outside

■ * ■ and within a hospital that are suitable as Protection against the side effects (especially nephrotoxicity) caused by a platinum compound, the reduced glutathione in amounts not less than

2.5 g, preferably 5 g per unit dose, optionally mixed with excipients such as are usually found on the pharmaceutical field, and / or contain with other active ingredients.

A common concentration or amount of platinum coordination compound ranges from about 5 to about 35 mg, preferably from 6.5 to 32.5 mg, calculated as Platinum metal. When using CDDP, the ampoules suitably contain 10 to 50, preferably 10 or 50 mg CDDP. These amounts are also preferred according to the present invention.

The invention is illustrated in more detail by the following examples, without, however, being restricted thereto. 20th

example 1

(a) Lyophilized bottles, each containing:

- reduced glutathione 2.50 g

- ethylenediamine 0.20 ml

Polyvinylpyrrolidone (MW 40,000) 0.125 g

(b) solvent vials, each containing:

- Water for injectables 15 ml

Example 2

(a) Lyophilized bottles, each containing:

- reduced glutathione 5.00 g

- ethylenediamine 0.40 ml

Polyvinylpyrrolidone (MW 40,000) 0.25 g

(b) solvent vials, each containing:

- Water for injectables 30 ml

Claims (1)

T 55 468 July 7, 1936 Applicant: Boehrirger Biochemia Robin SpA Via S. Uguzzone, 5
I-2O122 Milano, Italy Claims 1. Pharmaceutical compositions that provide a protective have effect on the side effects caused by a platinum compound, in particular cis-platinum, characterized in that they contain at least 2.5 g of reduced glutathione per unit dose as an active ingredient (active ingredient), possibly mixed with auxiliary substances such as they are usually twisted in the pharmaceutical field, and / or contain other active ingredients (active ingredients). 2. Compositions according to claim 1, characterized in that they have a protective effect against the nephrotoxicity caused by cis-platinum. Compositions according to Claim 1 or 2, characterized in that they contain 5 g of reduced glutathione per unit dose. BATH ORIGINAL 4 »Use of the pharmaceutical compositions according to one of claims 1 to .3, which contain at least 2.5 g .reduced GJ.uta-thi.Qn _{per unit dose;} jz, to combat the side effects caused by platinum compounds, especially cisplatin. 5. Use according to claim ' ¹ , characterized in that the pharmaceutical composition -per unit dose contains 5 g of reduced glutathione. f. Use of a pharmaceutical composition made up of two spatially separate phases, packaged in a packaging unit, of which one phase has at least one IPl; a t.in-rKppr donation compound, in particular cis-rDiamine ^ -Dichloroplatinum (CDDP) in an amount customary for antitumor chemotherapy and the other phase contains at least 2.5 g reduced glutathione, for successive use to inhibit tumor growth and to reduce the side effects caused by the platinum compound. 7th Use according to claim r, characterized in that the phase containing the reduced glutathione contains 5 g of reduced glutathione. 8 .. Use according to claim 6 or 7, characterized Γ that the pharjuazeutische .Mittel in the two separate phases in each case approximately the same amount contains reduced glutathione. ■ BATH ORIGINAL