United States Patent |
5,366,723 |
Tulok |
November 22, 1994 |
Method of alleviating toxicity originating from treatment with
anticancer platinum compounds
Abstract
The present invention concerns a method of administering the amino acids
L-glutamic acid, L-aspartic acid and L-cysteine for alleviating the toxicity
associated with the administration of anticancer platinum compounds such as
cisplatin and its derivatives.
Inventors: |
Tulok; Istvan (1525 Budapest PF. 21.
XII,, Rath GY. U. 7/9, HU) |
Appl. No.: |
027135 |
Filed: |
March 5, 1993 |
Current U.S. Class: |
424/649; 514/492; 514/561;
514/562 |
Intern'l Class: |
A61K 049/00; A61K 033/24; A61K
031/28; A61K 031/195 |
Field of Search: |
514/561,562,492 424/10,649
|
References Cited [Referenced
By]
U.S. Patent Documents
4547377 |
Oct., 1985 |
Ogawa et al. |
426/268. |
5039704 |
Aug., 1991 |
Smith et al. |
514/563. |
Foreign Patent Documents |
1-020128 |
Apr., 1989 |
JP. |
|
Primary
Examiner: Henley, III; Raymond J.
Attorney, Agent or Firm:
Pravel, Hewitt, Kimball & Krieger
Claims
What is claimed is:
1. A method of alleviating toxicity
originating from treatment with anticancer platinum compound(s), comprising
administering an effective amount of the amino acids L-glutamic acid, L-aspartic
acid and L-cysteine to a patient subject to the treatment with the anticancer
compound(s).
2. The method according to claim 1 wherein the amino acids
are present in a pharmaceutical composition in the following molar ratios:
______________________________________
L-glutamic acid:
L-cysteine from 4:1 to 1:1
L-aspartic acid:
L-cysteine from 2:1 to 1:2
L-glutamic acid:
L-aspartic acid from 3:1 to 1:3.
______________________________________
3. The method according to claim 1 wherein the amino acids are
administered contemporaneously and in connection with the anticancer platinum
compound(s).
4. The method according to claim 1 wherein the anticancer
compound is cisplatin, carboplatin or iproplatin.
5. The method of claim
1 wherein the amino acids are present in the following amounts (w/w):
______________________________________
50-60% L-glutamic acid
25-30% L-aspartic acid
15-20% L-cysteine.
______________________________________
6. The method of claim 2 wherein the pharmaceutical composition is
administered in tablet form.
7. A method of (i) increasing the
regeneration of bone marrow or intestinal mucosa in a patient whose bone marrow
or intestinal mucosa has been damaged or (ii) reducing renal or liver toxicity
caused by the administration of an anti-cancer platinum compound, wherein the
method comprises subjecting to the patient a therapeutically effective amount of
a pharmaceutical composition comprising L-glutamic acid, L-aspartic acid and
L-cysteine having the following molar ratios:
______________________________________
L-glutamic acid:
L-cysteine from 4:1 to 1:1
L-aspartic acid:
L-cysteine from 2:1 to 1:2
L-glutamic acid:
L-aspartic acid from 3:1 to 1:3.
______________________________________
8. The method according claim 7 wherein the amino acids are
administered contemporaneously and in connection with the anticancer platinum
compound(s).
9. The method according to claim 7 wherein the anticancer
compound is cisplatin, carboplatin or iproplatin.
10. The method
according to claim 7 wherein the pharmaceutical composition is in the form of a
tablet for oral administration.
11. The method according to claim 8
wherein the amino acids are present in the following amounts (w/w):
______________________________________
50-60% L-glutamic acid
25-30% L-aspartic acid
15-20% L-cysteine.
______________________________________
Description
SPECIFICATION
The present invention concerns a new biochemical modulator which mitigates
or eliminates the toxic side effects of cytotoxic agents.
In recent years intensive clinical and experimental studies have pointed
out that metabolic changes and disorders accompanying different antitumor
treatment modalities are to be corrected.
Damaged renal and liver functions and toxicity of bone marrow and
intestinal mucosa as well as immune and vitamin deficient states and other
pathological conditions without adequate compensation lead to the
exhaustion of the physiological reserves of the organism and to long term
or even irreversible damages of organs or organ systems.
Clinical practice has evidenced that chemotherapy and other antitumor
treatments are not really effective without metabolic compensation since
the malignant disease involves complex biochemical disorders. The tumor
processes and antitumor interventions are associated with several
"nonspecific" changes as well, which, influence the outcome of the
disease.
Due to the extended screenings and results of early tumor detection, the
number of patients receiving antitumor treatments keeps increasing.
Nonetheless, the "molecular dietetic" correction, i.e. application of
physiological substrates of metabolic disorders accompanying not only the
disease itself but its treatment too, is still a pressing necessity to be
solved.
Worldwide efforts are experienced to find biologically active agents able
to protect the organism against the consequences of intermediary metabolic
disturbances, overthrow of acid-base equilibrium and able to enhance at
the same time the defensive capacity of the organism. In fact, it is a
very difficult task to discover and produce such agents.
It is an object of the present invention to provide a biochemical modulator
which meets these criteria.
The biochemical modulator according to the present invention consists of a
composition of the amino acids L-glutamic acid, L-aspartic acid and
L-cysteine. Preferably the composition is administered in the form of a
tablet comprising the amino acids in the following molar ratios:
L-glutamic acid: L-cysteine from 4:1 to 1:1
L-aspartic acid: L-cysteine from 2:1 to 1:2
L-glutamic acid: L-aspartic acid from 3:1 to 1:3
or a composition containing the following components in the designated
amounts (w/w):
______________________________________
50-60% L-glutamic acid
25-30% L-aspartic acid
15-20% L-cysteine.
______________________________________
Specifically it has been found that beneficial effect of a composition
according to the invention occur in connection with the cytostatic agent
Cisplatin. The fact that cisplatin and its derivatives are really potent
antitumor agents is confirmed by their wide spread use in the therapy of
human germ cell testicular tumors, ovarian cancers, small and non-small
cell lung cancers, malignant melanoma, bladder carcinoma and certain
cancers of the head and neck. It is, however, widely recognized that
advances in the biochemical modulation of cisplatin toxicity should
provide significant therapeutic gain for this drug in the future.
Furthermore, it is believed that the side effects of other anticancer
platinum derivatives having similar mode of action as cisplatin, such as
carboplatin, i.e. cis-diamine-1-1-cyclobutane dicarboxylate platinum
(II)-CBDCA-, and iproplatin, i.e.
cis-diisopropylamine-trans-dihydroxy-dichloro platinum (IV), -CHIP-, would
be eliminated or mitigated by the composition, according to the present
invention.
The amino acids glutamic acid, aspartic acid and cystein have been used
previously in connection with cancer treatment. It is thus disclosed in
the Japanese patent publication 89020128B that the toxicity of the
anticancer agent 5-FU could be decreased if its use is combined with
certain carboxylic acids or derivatives thereof. The carboxylic acids
include i.a. the amino acids L-glutamic acid, L-aspartic acid and
L-cysteine. It is also know that these amino acids in combination with
other amino acids could be included in pharmaceutical anticancer
compositions which improve the nutritional conditions, cf the Japanese
Patent Publication J0 1301619. It has also been suggested that these amino
acids also in combination with other amino acids can be used for
transfusion in combination with cancer treatment cf. Japanese Patent
Publication J 62135420-A. Thus the prior art teaches that the amino acids
L-glutamic acid, L-aspartic acid and L-cysteine in combination with
various other amino acids might be useful in cancer treatment. It has
however never been suggested and disclosed that the combination and
selection of the three amino acids according to the present invention have
given good results in combination with the treatment of the anticancer
agent cisplatin. The observation that the amino acid combination
alleviates the side effects of cisplatin is interesting not only because
of the fact that the side-effects will be less painful. It is also
probable that the cisplatin dose could be increased and consequently more
effective. An interesting finding contrary to what could be expected from
the Japanese patent publication 89020128 is that the present combination
of amino acids has not proven to be effective against 5-FU.
Our experiments were aimed at investigating the effect of Cystergin, a new
chemoprotector on the bone marrow, and intestinal mucosal and kidney
toxicity of cytostatics. It has been observed that the modulators of this
invention, such as Cystergin, significantly reduce the kidney toxicity as
proven by the significant decrease of serum creatinine, urea and
gammaglutamyltranspeptidase values, which are pathologically increased
during treatment of anticancer derivatives. In addition, the modulators of
this invention reduce renal and liver toxicity as well as toxicity of bone
marrow and intestinal mucosa. The damaging effects of cytostatics on
different organs.
The damaging effects of cytostatics on different organs are well detectable
under both clinical and experimental conditions. Signs, suggestive of
impaired renal functions are: protein (enzymuria and elevated serum urea
and creatinine) concentrations. Disturbed liver functions are reflected by
elevated enzyme activity in the serum:
______________________________________
GOT (aspartate transferase, AST)
GPT (alanine transferase, ALT)
GGT (.gamma.-glutamyl transpeptidase)
ALP (alkaline phosphatase)
______________________________________
The affected bone cells and intestinal mucosal cell show, for instance,
higher alkaline phosphatase activity in the serum. Bone marrow damage is
indicated by more and more anaemic state of the patient.
The following series of experiments was performed to determine the
modifying effect of Cystergin on the toxicity of Cisplatin, on renal,
liver and intestinal functions and on different hepatobiliary disorders.
Experimental Methods
1. Animals
Experiments were performed on H-Riop: Wistar non-inbred male rats of our
own breeding. Housing conditions: Room temperature 23.degree.-26.degree.
C.; relative humidity 40-50%; food: LATI standard rat chew, sterilized
under steam, autoclaved wood shavings; 12-hour light and dark periods; no
starvation before treatments; drinking water; tap water ad libitum.
Body weight of rats ranged from 180 to 200 g before the treatment.
Intraperitoneal (i.p.) and oral (p.o.) treatments were given. With doses
expressed in mg/kg the concentration of the active agent (i.i. Cystergin,
which is an amino acid composition according to the invention) was
adjusted so that the ratio of the injected volume and the animal's body
weight be 1.0 ml/100 g. To the control group corresponding volumes of
isotonic NaCl solution were given. Each experimental group consisted of 4
animals.
2. Treatment
2.1 Cytostatics
Cisplatin (Cis-Pt) (Platidiam, Lachema, o.p. Brno).
Cyclophosphamide (CPA) (Endoxan, Ebewe),
5-Fluorouracil (5-FU) (Hoffman La Rouche)
Animals were treated i.p. with the cytostatics dissolved in isotonic NaCl
solution.
The experimental animals were killed 48 hours after the cytostatic
treatment when the biochemical parameters, indicating the side effects,
reached their nadir. Experiments to renal regeneration are exceptions. In
this case the animals were killed at 24, 48, 74 and 96 hours after
treatment respectively.
2.2 Cystergin (CR) - Composition According to the Present Invention
Preparation of the stock solution: (Active agent content of 100 tablets in
100 ml solution.) 13.3 g of 1-glutamic acid, 6.6 g of L-aspartic acid were
suspended in approximately 50,0 ml volume of (deionized) water. To this
solution the following were added slowly: 7.8 g of NaHCO.sub.3 (after
bubbling) and 2.0 g of KHCO.sub.3 (after bubbling) and 0.4 g of MgO. The
active agents in the mixture were solved by cautious warming. Then the
mixture was cooled down and after the addition of 0.45 g of NaCl its
volume was adjusted to 100 ml with deionized water.
Prior to treatment L-cysteine was added to the solution in 40 mg/ml
concentration. After complete dissolution 1 ml of the solution
corresponded to the planned active agent content of 1 tablet (i.e. 0.133 g
L-glutamic acid, 0.066 g L-aspartic acid and 0.040 g L-cysteine) which was
adjusted to the desired concentration in isotonic NaCl. In the first
experiment CR was administered orally but further on we changed it for
intraperitoneal treatment because of technical reasons (repeated
administration to high number of animals).
The moderation of toxicity was tested in a model elaborated by us. It is
suitable for the determination of changes in the biochemical parameters
induced by cytostatics.
The biochemical and morphological characterization of bone marrow toxicity
necessitated the study of protein and DNA content, thymidine kinase
activity and changes in nucleated cell number. Intestinal damages were
studied in cells isolated from the intestinal mucosa of rats treated with
the test agents in vivo. Changes in the activity of disaccharidases
(sucrase and maltase) and alkaline phosphatase, as markers of intestinal
function, were determined. Kidney toxicity was assessed by the
determination of the creatinine and urea concentrations in the serum of
the treated animals.
In order to reveal the mechanism of action of Cystergin, experiments were
carried out on the effect of Cystergin, as an adjuvant to Cytostatic
treatment, on the glutathione reductase and glutathione-S-transferase
activity.
Results:
1) Cystergin itself did not affect significantly the biochemical parameters
of either the bone marrow or the intestine or the kidney.
2) When working out the optimum conditions of Cystergin administration, its
reducing effect on toxicity was found to be dependent on its dose and time
of administration related to the time of cytostatic treatment. Most
pronounced effect of Cystergin was observed with application of
3.times.240 mg/kg dose i.p. (30 minutes before, simultaneously with and 30
minutes after the administration of cis-Pt).
3) Experiments aimed at reducing the toxicity of cytostatics showed that:
3.1 Cystergin treatment in a dosage schedule outlined in point 2 above,
reduced the toxic side effects caused by Cisplatin. Small intestinal
toxicity was reduced significantly, the seriousness of bone marrow
toxicity was mitigated and the significantly elevated values of serum
markers of kidney toxicity were normalized. In case of 5-FU however, the
adjuvant therapy in the applied dose (3.times.240 mg/kg i.p.) and schedule
(30 minutes before, simultaneously with and 30 minutes after the
cytostatics) remained ineffective and similarly the adverse effect of CPA
was only slightly modified.
3.2 In addition to mitigating the toxicity of cis-Pt, Cystergin accelerated
the completion of regeneration after cytostatic treatment both in the bone
marrow and intestinal mucosa.
3.3 According to the values of the dose modifying factors (bone marrow:
1.3-2.0 and intestinal mucosa: 2.5-3.1) there is a possibility, in
principle, to raise the dose of cis-Pt without increasing its toxicity on
the bone marrow and intestinal mucosa that would finally lead to higher
antitumor activity.
4. Studies on the mechanism of action of Cystergin have revealed that
decreased toxicity due to the administration of Cystergin is closely
related in effect on the activity of the intestinal detoxifying enzymes.
Specific studies are set forth below wherein blood samples were obtained
from the left ventricle while the animals were bled to death. Blood was
centrifuged at 5000 rpm for 15 minutes at 4.degree. C. The clinical
chemical determination were made from the serum samples. Determination of
glucose, urea, creatinine, cholesterol and triglyceride concentration as
well as the activity of GGT, GOT, GPT and alkaline phosphatase (ALP) in
the serum were made with a Beckmann-700 type analyzer. Mathematical
statistical analysis was applied to evaluate the results. We used the
paired "t"-test and the linear regression analysis.
This study further recognizes that the most severe side effects after a
single (8 mg/kg) dose of cisplatin developed 48 hours after the treatment
and further that Cystergin is most potent in reducing the side effects
when administered three times i.e. 30 minutes before, simultaneously with
and 30 minutes after(-30; 0; +30) Cisplatin treatment.
______________________________________
Treatment Groups:
______________________________________
I. = untreated control group, 8 animals
II. = 8 mg/kg Cisplatin (i.p.) + 3 .times. 80 mg/kg
Cystergin (i.p.), (-30; 0; +30), 8 animals
III. = 8 mg/kg Cisplatin (i.p.) + 3 .times. 160 mg/kg
Cystergin (i.p.), (-30; 0; +30), 8 animals
IV. = 8 mg/kg Cisplatin (i.p.) + 3 .times. 240 mg/kg
Cystergin (i.p.), (-30; 0; +30), 8 animals
V. = 8 mg/kg Cisplatin (i.p.), 8 animals
______________________________________
Serum determinations were made 24 hours (Table I) and 48 hours (Table II)
after the cytostatic treatment.
TABLE I
__________________________________________________________________________
THE EFFECT OF COMBINED TREATMENT WITH CISPLATIN (8 mg/kg, i.p.)
and CYSTERGIN (3 .times. 80, 3 .times. 160, 3 .times. 240 mg/kg i.p.) ON
THE
CHANGE OF CLINICAL CHEMICAL PARAMETERS
IN THE SERUM. (Results obtained 24 hours after Cisplatin treatment.)
Experimental Groups
II. III. IV. V.
TREATMENT I. - x .+-. SD
- x .+-. SD
- x .+-. SD
- x .+-. SD
Cis-Pt ip. (mg/kg) +
-x .+-. SD
8 + 8 + 8 + 8
CR ip. (mg/kg)
Control*
3 .times. 80
3 .times. 160
3 .times. 240
--
__________________________________________________________________________
Parameters:
glucose (a)
7.25 .+-. 0.33
6.95 .+-. 0.41
7.34 .+-. 0.23
7.41 .+-. 0.21
7.67 .+-. 0.41
urea (a) 4.75 .+-. 0.76
6.35 .+-. 0.34
5.87 .+-. 0.49
5.10 .+-. 0.85
9.45 .+-. 0.76
creatinine (b)
65.5 .+-. 5.12
71.2 .+-. 4.16
68.8 .+-. 8.10
63.8 .+-. 3.21
146.4 .+-. 2.72
cholesterol (a)
1.9 .+-. 0.11
2.2 .+-. 0.08
2.2 .+-. 0.07
2.0 .+-. 0.13
2.9 .+-. 0.14
triglyceride (a)
0.6 .+-. 0.08
1.6 .+-. 0.11
1.4 .+-. 0.09
0.8 .+-. 0.10
1.9 .+-. 0.11
GOT (d) 86 .+-. 4.56
97 .+-. 2.31
90 .+-. 4.43
76 .+-. 3.32
100.7 .+-. 5.67
GPT (d) 18 .+-. 2.34
31 .+-. 1.89
26 .+-. 3.34
20 .+-. 3.45
45 .+-. 4.35
GGT (d) 29.5 .+-. 5.34
44.3 .+-. 6.12
30.7 .+-. 4.32
15.1 .+-. 2.38
61.6 .+-. 4.53
ALP (d) 142 .+-. 11.6
276 .+-. 14.8
200 .+-. 13.4
117 .+-. 16.7
325 .+-. 14.5
__________________________________________________________________________
a = mmol/1, b = .mu.mol/l, c = g/l, d = U/l. -x = mean, .+-.SD = standard
deviations
*The control animals received isotonic NaCl solution in identical volume
instead of cisPt and CR treatment.
Evaluation of Table I
Mathematical statistical analysis:
a.) Linear regression analysis. (Dose dependence study of Cystergin based
on values measured in groups II, III and IV.)
______________________________________
Urea A = 610 B = -78.25 r = -0.7818
Creatinine A = 574 B = -6.12 r = -0.5284
Cholesterol A = 913 B = -354 r = -0.6311
Triglyceride A = 0.301 B = -174 r = -0.9340
GOT A = 783 B = -6.77 r = -0.9401
GPT A = 460 B = -11.7 r = -0.8945
GGT A = 2355 B = -5.69 r = -0.9431
Alkaline phosphatase
A = 353 B = -0.97 r = -0.9845
______________________________________
On the basis of experiments it can be concluded that there has been an
inverse correlation between the rise in Cystergin dose and decrease in the
concentration of the clinical chemical parameters and enzyme activities.
Raising of the Cystergin dose resulted in decreasing urea, creatinine,
cholesterol and triglyceride concentrations as well as it reduced the GGT,
GOT, GPT and alkaline phosphatase activities in the serum.
b.) The paired "t" test.
Cisplatin treatment alone and in combination with smaller dose of Cystergin
(groups II-III) significantly elevated the concentration of urea,
creatinine, cholesterol and triglyceride and the activity of GGT, GOT, GPT
and alkaline phosphatase in the serum as compared with the results of the
untreated control animals. The pathologically high values of clinical
chemical parameters were significantly lowered by Cystergin administration
as compared to the results obtained in animals treated with Cisplatin
alone. The measure of decrease was most pronounced in animals given
3.times.240 mg/kg Cystergin. Changes were highly dependent on the doses
applied.
TABLE II
__________________________________________________________________________
THE EFFECT OF COMBINED TREATMENT WITH CISPLATIN (8 mg/kg, i.p.)
and CYSTERGIN (3 .times. 80, 3 .times. 160, 3 .times. 240 mg/kg i.p.) ON
THE
CHANGE OF CLINICAL CHEMICAL PARAMETERS
IN THE SERUM. (Results obtained 48 hours after Cisplatin treatment.)
Experimental Groups
II. III. IV. V.
TREATMENT I. - x .+-. SD
- x .+-. SD
- x .+-. SD
- x .+-. SD
Cis-Pt ip. (mg/kg) +
-x .+-. SD
8 + 8 + 8 + 8
CR ip. (mg/kg)
Control*
3 .times. 80
3 .times. 160
3 .times. 240
--
__________________________________________________________________________
Parameters:
glucose (a)
7.34 .+-. 0.19
7.00 .+-. 0.33
6.96 .+-. 0.21
6.11 .+-. 0.32
8.38 .+-. 0.21
urea (a) 4.28 .+-. 0.69
7.76 .+-. 0.44
7.01 .+-. 0.44
6.06 .+-. 0.27
13.45 .+-. 0.43
creatinine (b)
66.8 .+-. 4.61
77.6 .+-. 6.16
71.5 .+-. 3.78
61.7 .+-. 5.48
102.7 .+-. 3.99
cholesterol (a)
2.01 .+-. 0.14
2.35 .+-. 0.21
2.11 .+-. 0.23
1.89 .+-. 0.19
3.05 .+-. 0.32
triglyceride (a)
0.68 .+-. 0.13
1.89 .+-. 0.16
1.64 .+-. 0.18
1.01 .+-. 0.14
2.26 .+-. 0.15
GOT (d) 82.8 .+-. 6.61
91.6 .+-. 4.56
80.1 .+-. 3.67
72.7 .+-. 4.35
115 .+-. 5.82
GPT (d) 20.5 .+-. 3.41
27.8 .+-. 2.35
20.1 .+-. 3.45
18.5 .+-. 4.52
46 .+-. 5.12
GGT (d) 27.8 .+-. 6.34
40.7 .+-. 6.66
26.9 .+-. 4.35
12.6 .+-. 4.82
64 .+-. 4.98
ALP (d) 147 .+-. 6.78
260 .+-. 7.59
160 .+-. 8.76
107 .+-. 7.76
343 .+-. 10.8
__________________________________________________________________________
a = mmol/1, b = .mu.mol/l, c = g/l, d = U/l. -x = mean, .+-.SD = standard
deviations
*The control animals received isotonic NaCl solution in identical volume
instead of cisPt and CR treatment.
Mathematical statistical analysis:
a.) Linear regression analysis. (Dose dependence study of intraperitoneally
administered Cystergin based on values obtained in groups II, III and IV.)
______________________________________
Urea A = 634 B = -68.4 r = -0.8702
Creatinine A = 707 B = -5.83 r = -0.7204
Cholesterol A = 194 B = -15 r = -0.061
Triglyceride A = 276 B = -97.8 r = -0.8076
GOT A = 750 B = -6.72 r = -0.9136
GPT A = 347 B = -6.63 r = -0.9329
GGT A = 320 B = -5.88 r = -0.9197
Alkaline phosphatase
A = 449 B = -1.75 r = -0.9139
______________________________________
Results show an inverse correlation between the rise in Cystergin dose and
decrease in the concentration of the clinical chemical parameters and
enzyme activities (negative correlation). Raising of the Cystergin dose
results in a linear fall of the concentration of urea, creatinine,
cholesterol and triglyceride concentration as well as in a decrease of
GGT, GOT, GPT and alkaline phosphatase activity in the serum.
b.) The paired "t" test
Cisplatin by itself (group V) and Cisplatin+Cystergin treatment (groups
II-III) significantly increased the concentration of urea, creatinine,
cholesterol and triglyceride as well as the activity of GGT, GOT and GPT
and alkaline phosphatase in the serum as compared to the results obtained
in untreated controls.
Comparison of the values of the untreated controls and those of animals in
group IV treated with the combination of 3.times.240 mg/kg Cystergin and 8
mg/kg Cisplatin makes it clear that Cystergin was able to normalize the
pathologically high concentration and activity values if administered in
3.times.240 mg/kg doses.
Clinical chemical parameters of animals treated with Cisplatin combined
with Cystergin were significantly lower than those of animals treated with
Cisplatin alone. Decrease and normalization of the parameters were in
correlation with the Cystergin dose applied.
These studies indicate that Cisplatin in the 8 mg/kg dose resulted in a
significant rise in serum urea, creatinine, cholesterol and triglyceride
concentration as well as in GGT, GOT, GPT and alkaline phosphatase
activity compared to those of the untreated controls.
The pathologically high values of the above parameters were reduced by
Cystergin in a dose dependent manner. Except carbamide and triglyceride
concentrations all parameters reached the values found in the untreated
controls.
Increased serum urea and creatinine levels are considered as indicators of
nephrotoxicity, therefore it can be concluded that Cisplatin treatment in
itself caused disturbances in renal functions. Cystergin administered, in
adequate doses is able to moderate the renal toxicity of Cisplatin. The
simultaneous rise of serum GGT, GOT and GPT activities are reliable
diagnostic signs of disturbed hepatic functions. These toxic effects of
the cisplatin, however, are moderated by Cystergin in a dose dependent
fashion.
Increased cholesterol and triglyceride levels indicate disorders in the
equilibrium of intermediary metabolism; since under unchanged dietary
conditions the endogenous lipid mobilization is likely to have set off.
Cystergin moderates the rise of cholesterol and triglyceride levels induced
by Cisplatin, though the measure of mitigation in case of triglyceride is
less pronounced.
Elevated alkaline phosphatase activity suggests hepatobiliary disturbances,
disorders in Ca homeostasis and damages to the intestinal mucosa.
Cisplatin in itself increases the alkaline phosphatase activity that can
be mitigated by adequate doses of Cystergin.
In view of our results Cystergin seems to be a potent agent in moderating
or even in eliminating the harmful effects of Cisplatin on the kidneys,
liver and intestinal mucosa.
* * * * *