Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1986-08-13
1990-12-18
Goldberg, Jerome D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
A61K 31165
Patent
active
049786830
DESCRIPTION:
BRIEF SUMMARY
The subject of the present invention is a new therapeutic use of D,L-4-benzamido-N,N-dipropyl-glutamic acid (proglumide) and its pharmaceutically-acceptable salts, for use in the treatment of neoplastic affections in which there is a pathological cell increase indirectly affected by gastrin, cholecystokinin (CCK), other bioactive peptides or by related mechanisms which are not yet well clarified.
The applicants have found that the said drug, already widely used in the treatment of gastric ulcers (see for example Merck Index No. 7680, 10th edition), in fact has an unexpected but extremely interesting therapeutic activity, which is that of significantly inhibiting the cell increase of tumour cells resulting from chemically induced pancreatic, colic or gastric cancer or of destroying such cells.
The invention is based on the discovery that the polypeptide hormone gastrin has a trophic effect on the digestive epithelium, just as the hormone CCK has a trophic action on pancreatic acini. Thus the chronic administration of gastrin to rats (or of pentagastrin which is the biologically active part of the physiological hormone) causes hyperplasia of the fundic and colic mucous membranes. Recently (Winsett et al--Surgical Forum, 33, 384 (1982)) it has been shown that gastrin stimulates the growth, in mice, of transplantable colic tumours obtained by chemical induction.
It has also been shown that the chronic treatment of rats with cerulein (a synthetic analog of CCK) causes hyperplasia of the pancreatic acinus cells (Solomon et. al.--An. J. Physiol 235, E714-719 (1978)).
On the basis of these theoretical premises, there has been a desire to experiment to see whether proglumide might behave as an antagonist to the growth of induced gastro-intestinal tumours and to evaluate whether this action could also affect the survival time of the animals.
This antitumoral activity of proglumide, which is the subject of the present invention, will thus be illustrated by a series of pharmacological experiments in vitro and in vivo arranged to show both the qualitative and quantitative aspects of the antitumoral activity and the mechanism by which this activity is manifested.
Experiment 1
Action of Proglumide on the rate of pentagastrin-induced growth of normal
and tumoral colic cells
Male mice having a weight of 20-25 g were innoculated subcutaneously in the interscapular region with a suspension of 8.times.10.sup.4 colic-adenocarcinoma tumour cells taken from a mouse.
Four groups of 12 animals were used, that is: a group of control animals, a group of animals treated with 200 mg/kg i.p. doses of proglumide 3 times a day, a group of animals treated with 200 .mu.g/kg of pentagastrin every eight hours and a group of animals treated with proglumide and pentagastrin in the manner indicated above.
After 20 days the animals were killed and the fundic mucous membranes and tumours were removed, weighed and extracted to determine the DNA. The results obtained are given in Table 1.
TABLE 1 __________________________________________________________________________
Antagonistic activity of Proglumide towards the growth of colic
tumours induced by pentagastrin
Weight of weight of
No the mucous the colic
Ani- membrane
student's
fundic
student's
tumour
student's
tumour
student's
GROUPS mals
Dose (mg) t DNA (mg)
t (mg) t DNA (mg)
t
__________________________________________________________________________
A: Control
12 -- 15.9 .+-. 1.44
-- 0.21 .+-. 0.02
-- 500 + 12.6
-- 2.90
--0.23
B: Pentagastrin
10.sup.(.degree.)
200 mcg/kg-3
40.9 .+-. 1.26
12.78.sup.(***)
0.49 .+-. 0.03
9.46.sup.(***)
800 .+-. 12.8
16.6.sup.(***)
4.56
3.37.sup.(**)
(PEG) per day
C: Proglumide
12 200 mcg/kg-3
13.3 .+-. 1.58
1.21
0.12 .+-. 0.02
3.17.sup.(**)
470 .+-. 11.5
1.75
2.54
1.10 0.23
(PR) per day
D: PEG + PR
12 200 mcg/KG
16.0 .+-. 1.27
vsA: 0.21 .+-. 0.05
vsA:0
519 .+-. 11.8
vsA: 2.80
vsA: 0.24
PEG + 0.05 vsB: 1.11 0.32
200 mg/kg vsB: 4.43.sup.(***)
vs
REFERENCES:
The Merck Index, Tenth Edition, Merck & Co., 1983, Rahway, New York, (U.S.), See p. 1120, Monograph 7680 "Proglumide".
Surgical Forum, vol. 33, 1982, Owen E. Winsett et al. "Gastrin Stimulates Growth of Colon Cancer", pp. 384-386.
Gastroenterology, vol. 80, No. 5, 1981, B. Rae-Venter et al.: "Gastrin Receptors in Human Colon Carcinoma", p. 1256.
Surgical Forum, vol. 35, 1984, Proceedings for the 40th Annual Sessions of the Forum on Fundamental Surgical Problems 70th Clinical Congress, American College of Surgeons, San Francisco, Oct. 1984, P. Singh et al.: "Gastrin Receptors in a Mouse Colon Cancer Cell Line Responsive to Trophic Effects of Gastrin", pp. 205-206.
Digestive Dieases and Sciences, vol. 29, No. 8, Aug. Supplement 1984, P. Singh et al.: "Mouse Colon Cancer and Trophic Effects of Pentagastrin in Relation to Gastrin Receptor Levels in Vivo", p. 80S.
Surgical Forum, vol. 32, 1981, Courtney M. Townsend et al.: "Stimulation of Pancreatic Cancer Growth by Caerulein and Secretin", pp. 228-229.
Proc. Natl. Acad. Sci. U.S.A, vol. 78, No. 10, Oct. 1981, W. F. Hahne et al.: "Proglumide and Benzotript: Members of a Different Class of Cholecystokinin Receptor Antagonists", pp. 6304-6308.
Ann. Surg., vol. 202, No. 3, Sep. 1985, R. Daniel Beauchamp et al.: "Proglumide, a Gastrin Receptor Anatagonist, Inhibits Growth of Colon Cancer and Enhances Survival in Mice", pp. 303-309.
J. Clin Gastroenterol, vol. 5, No. 1, Feb. 1983, C. B. H. W. Lamers et al.: "The Effect of a Gastrin-Receptor Antagonist on Gastric Acid Secretion and Serum Gastrin in the Zollinger-Ellison Syndrome", pp. 21-25.
Rev. Med. Limoges, vol. 5, No. 3, 1974, R. Claude et al.: "Interet du Milide (*) dans le Traitement des Affections Gastroduodenales (a Propos de 30 cas)", pp. 183-187.
Makovec Francesco
Rovati Angelo L.
Rovati Claudio L.
Goldberg Jerome D.
Rotta Research Laboratorium S.p.A.
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