An anti-inflammatory and analgesic composition containing indomethacin and an H sub 1 or an H sub 2 histamine receptor antagonist in an amount sufficient to reduce gastric distress caused by the indomethacin is described. Usable antagonists include pyrilamine, promethazine, metiamide and cimetidine

Brown, P. A.

Danellis, J. V.

English

NASA Technical Reports Server

United States Patent 1191 
Brown et al. 
[111 4,279,906 
1451 Jui. 21, 1981 
INDOMETH ACIN-ANTIHISTAMINE 
COMBINATION FOR GASTRIC 
ULCERATION CONTROL 
Inventors: 
Appl. No.: 
Filed: 
Robert A. Frosch, Administrator of 
the National Aeronautics and Space 
Administration, with respect to an 
invention of Patricia A. Brown, 
Menlo Park; Joan V. Danellis, 
Cupertino, both of Calif. 
850,504 
Nov. 10, 1977 
Int. c1.3 ..................... A61K 31/40; A61K 31/54; 
A61K 31/46 
U.S. (3. .................................... 424/247; 424/267; 
424/274 
Field of Search ........................ 424/247, 267, 274 
~561 References Cited 
Chem. Abst., 71-59356q (1969). 
Chem. Abst., 73-337962 (1970). 
Chem. Abst., 66-274678 (1961). 
Primary Examiner-Stanley J. Friedman 
Attorney, Agent, or Firm-Darrell G. Brekke; John R. 
Manning 
ABSTRACT 1571 
An anti-inflammatory and analgesic composition con- 
taining indomethacin and an Hi or an H2 histamine 
receptor antagonist in an amount sufficient to reduce 
gastric distress caused by the indomethacin. Usable 
antagonists include pyrilamine, promethazine, metia- 
mide and cimetidine. 
PUBLICATIONS 
8 Claims, 5 Drawing Figures 
https://ntrs.nasa.gov/search.jsp?R=19810021226 2020-03-21T09:43:25+00:00Z
U.S. Patent Jui. 21,1981 Sheet 1 of 3 4,279,906 
n I  
DOSE OF INDOMETHACIN (rng/kg) 
FIG. I 
z A" F  20 
1 2.5 5 10 20 40 80 160 
DOSE OF ASPIRIN (mg/kg) 
FIG. 2 
U.S. Patent Jui. 21, 1981 Sheet 2 of 3 4,279,906 
FIG. 3 
U.S. Patent Jui. 21,1981 
w 
CE 
0 
0 m 
c 
W 
3 
Z 
W 
2 
Y 
a 
60c 
Sheet 3 of 3 
Z 
l o  3 
0 20 40 60 80 100 Z 
DOSE OF PYRILAMINE (,umol/kg) 
FIG. 4 
60 I- 
4,279,906 
DOSE OF METIAMIDE (PrnoVkg) 
FIG. 5 
4,279,906 
3 4 
cially available Plexiglas devices placed in an environ- whereas that for indomethacin rises abruptly over less 
mental chamber maintained at 5" C. [See R. J. Levine, than 1 log unit. 
Peptic Ulcer, (Ed. C. J. Pfeiffer), pages 92-97, Lippin- Since both stress and high doses of aspirin are known 
cott (1971); E. C. Senay and R. J. Levine, Proc. SOC. to individually elevate the level of corticosteroids and 
Exp. Biol. Med. 124, 1221-1223 (1967)l. Within each 5 since corticosteroids are known to be ulcerogenic, an 
condition, the animals received orally one of several attempt was made to determine whether the ulceration 
doses of aspirin or indomethacin. Thirty minutes after attributed to either indomethacin or  aspirin could have 
drug administration, the animals were subjected either been caused in part by an augmented adrenocortical 
to two hours of cold restraint (stress condition) or re- response. 
turned to their home cages (non-stress condition) for the 10 Mean plasma corticosterone levels were therefore 
same duration of time. determined on the two-hour blood samples earlier men- 
At  the end of the two-hour Period, the animals were tioned and the results of the tests are shown in the fol- 
sacrificed by decapitation and blood was collected from lowing table. 
the trunk in chilled heparinized tubes and centrifuged. 
The plasma was separated and frozen for subsequent 15 
fluorometric assay of corticosterone [Vernikos-Danellis 
J. et al. Changes in adrenal corticosterone concentra- 
tion in rats. Method of bioassay for ACTH. Endocrinol- 
ogy, 1966, 79, 624-6301. The stomach then was re- 
moved from the animal, cut along the greater curva- 20 
ture, opened, rinsed with tap water and pinned in a 
0 32.0 f 3.7 134.1 f 5.3 
standard position for microscopic examination and scor- 20 27.3 f 7.2 138.9 f 4.4 
ing of ulcers. Ulcers measuring less than 1 mm were not 137.2 f 3.9 
scored. For each animal, the overall ulcer score was 137.3 f 7 1 
defined as the sum of the maximum continuous lengths 25 126.0 f 9 2 
Indomethacin + (in mm) of each ulcer. This scoring method was found previously to be highly reliable (Brown et al. 1976). 
Representative stomachs were fixed in 10% formol (n = IO) (n = IO) 
saline and 8p paraffin sections from tissue blocks taken 0 21.1 f 3.7 134.3 f 5.0 
from ulcerated areas were stained with hematoxylin and 30 1.5 23.6 f 4.9 132.4 f 5.7 
eosin and examined microscopically. 3.0 21.1 f 5.2 138.5 f 3.9 
6.0 29.0 f 5.9 136.5 f 3.5 
139.4 f 8.7 
TABLE 1 
EFFECT OF ANTI-INFLAMMATORY AGENTS ON MEAN 
PLASMA CORTICOSTERONE LEVELSa IN STRESSED 
A N D  NONSTRESSED RATS 
Experimental Condition 
Aspirin Aspirin + Stress 
(n = 9) (mg/kg) Dose (n = 9) 
40 
80 
160 
26.9 f 5.0 
34.7 f 5.9 
63.9 f 7.1 
Indomethacin Stress 
32.9 f 6.5 
The dosages of aspirin and indomethacin and the 
consequences of such dosages are shown in FIGS. 1 and 
2 of the drawings. 
between aspirin and environmental stress in'the produc- From the table, it can be readily seen that corticoster- 
tion of gastric ulceration. Control stressed animals that One levels at the end Of the two-hour period were mark- 
received only the methylcellulose vehicle (zero dose of edly in rats under stress. However, neither 
aspirin) essentially did not ulcerate (ulcers generally indomethacin nor aspirin produced any significant addi- 
were less than 1 mm) and very high doses of aspi- 40 tional increase in corticosterone in these animals. Thus, 
rin failed to produce appreciable gastric damage in the increasing gastric damage Produced by the drugs in the 
absence of stress. H ~ ~ ~ ~ ~ ~ ,  in conjunction with stress, stressed rats was not associated with an increase in 
the administration of low doses (2.5 mg/kg) did result in circulating corticosterone. The mean corticosterone 
minor ,,iceration (FIG. 1). ~~~~~~~i~~ the dose to 20 levels of nonstressed animals were also unaffected by 
mg/kg resulted in substantial ulceration in these animals 45 the drugs, except at the highest dosage tested. This 
with a mean Score of 27.4. Maximum ulceration was latter rise in corticosterone was not accompanied by 
obtained with 160 mg/kg of aspirin, yielding a mean any corresponding increase in gastric U~CeratiOn. 
EXAMPLE 2 ulcer score of 56.9. Still higher doses produced no fur- ther increase in gastric ulceration. The dose-response 
relationship was highly significant as tested with a one- 50 In this example the size and regional distribution of 
way analysis of variance (F=4.88; df=6,63; p <().()I). ulceration produced by indomethacin and aspirin are 
Similarly, in the absence of stress, high doses (12 compared. 
mg/kg) of indomethacin failed to produce gastric ulcers For the experiment, animals were assigned randomly 
as shown in FIG. 1. However, the lowest dose of indo- to groups receiving either 12 m g k g  of indomethacin or  
methacin administered (1.5 mg/kg) produced apprecia- 55 20 mg/kg of aspirin. The doses administered were se- 
ble gastric damage in stressed rats. Increasing the dose lected on the basis of results of the first experiment 
to 12 mg/kg resulted in a mean ulcer score of 28.2. Still (FIGS. 1 and 2) to give approximately the same mean 
higher doses produced no further increase in ulceration. ulcer score. Thirty minutes after drug administration, 
The dose-response relationship was highly significant as the animals were put in cold restraint for two hours. At 
tested with a one-way analysis of variance (F=7.35; 60 the end of the stress period, the animals were sacrificed 
df=4.45; p<O.OOl). The difference between the maxi- and ulcers were scored as described in Example 1. 
mum ulcer scores produced by indomethacin and aspi- The gastric ulcers produced by aspirin and indometh- 
rin was also significant (p<O.O5). acin in stressed rats appeared as black or brown punc- 
The dose-response relations for aspirin and indometh- tate or elongate regions with sharply defined edges. 
acin appear to differ in several respects. First, the maxi- 65 Microscopic examination of hematoxylin and eosin 
mum response to aspirin is more than twice that for stained paraffin sections taken from regions of ulcer- 
indomethacin. Second, the dose-response relation for ation revealed necrosis of the gastric mucosa sometimes 
aspirin rises gradually over about a 2 log unit range, extending to, but never through, the muscularis mucosa 
12.0 
'Mean ?z S E. (pg/lOo ml of plasma) 
As FIG. 2 indicates, there was a dramatic synergism 35 
6 
4,279,906 
5 
In stressed animals, high doses of aspirin (L 80 gastric ulceration [Wilson, T. R., Monthly Variations in 
mg/kg) produce very large ulcers (see FIG. Ib, Brown the Severity of Experimental Stress Ulcers in Rats. In 
et a]., 1976) generally not Seen with very high doses C. J. Pfeiffer (Ed.) Peptic Ulcer, Philadelphia: J. C .  
( z 2 4  mg/kg) of indomethacin. However, at lower Lippincott, 19713. At the lowest dose of pyrilamine 
doses, for a given mean ulcer score, the Size as well as 5 administered, the mean ulcer score was reduced 38%. 
the regional distribution of the ulcers were similar for similarly the lowest dose of metiamide reduced the 
aspirin and indomethacin. At the doses selected, both mean ulcer 24%. ~~~~~~~i~~ the dose of both 
"' to 2.9 mm and Only 3*0 mm Or severity resulting in a mean score of 10.1 and 11.2 for 
larger. Following the scoring method of Tagaki et a]. io pyrilamine and metiamide, respectively. The dose- 
[Chemical and Pharmaceutical Bulletin, 1964, 12, pages 
465 to 4723, the number of of response relationship for these antihistamines was 
has been opened along the greater curvature and pinned 15 Metiamide: F=4.65; df=3,52; p<O.Ol). The IDXI was 
out. As can be seen from the drawing, the stomach is 35 Pmol& for Pyrilamine and 55 Pmol/kg for 
divided into three main areas, Le., the rumen (11), the 
body (12), and the antrum (19, with each area compris- 
ing the anatomical divisions indicated (I, 11,111, IV, and 
V). The distribution of gastric ulcers observed is shown 20 
agents produced 'Icers the range Of antihistamines produced further reductions in ulcer 
in each of five 
the stomach was determined. FIG. 3 shows the anatom- Of 
ita] divisions o fa  stomach which for better visualization variance (Pyrilamine: F=6.47; df=3,53; P <'.m1; 
significant as tested by a Onemway 
metiamide. 
TABLE 3 
THE ANTIULCER EFFECTS OF METIAMIDE AND 
ULCERS IN STRESSED RATS 
PROMETHAZINE ON PRODUCED 
in the following table. 
% Reduction TABLE 2 Condition Mean -C SEM 
REGIONAL DISTRIBUTION OF GASTRIC ULCERS IND 46.2 & 6.8 
PRODUCED BY ASPIRXN AND INWMETHACIN IN IND + MET 14.3 +- 2.5 69.0 
STRESSED ANIMALS 25 IND-tPROM 19.6 t 4.9 57.0 
*1(15,1% = 4.25. O C . 0 0 5  Mean Number of Ulcers 
Aspirin Indomethacin **l(iS.lS) = 306:p<.005 
(20 mgfig) (12 m a g )  
As can be seen further from Table 3, the H1 receptor 
I 0.0 0.0 30 antagonist, promethazine, achieved reductions in gas- 
tric ulceration that are comparable to those produced I1 23.5 12.3 111 1.6 2.5 
iV 15.0 18.9 by metiamide. The latter tests were carried out with 
V 0.9 1.3 high doses of antihistamine (80 pmol/kg) in stressed rats 
receiving 6 mg/kg of indomethacin. 
AS the present results clearly demonstrate, a dramatic 
aspirin caused ulcers in Zone I, the rumen of the stom- SWergiSm Occurs between acute Stress and moderate 
ach, but both drugs induced numerow ulcers in Zones dosages of anti-inflammatory agents in the production 
I1 and IV of the body. On the other hand, few ulcers of gastric ulceration (FIGS. 1 and 2). The difference 
were produced by either agent in Zone I11 of the body between the effects of aspirin and indomethacin cannot 
or Zone V, the antrum. 40 be attributed, however, to any additional effects in 
plasma corticosterone levels. The results do indicate 
that the level of plasma corticosterone was greatly in- EXAMPLE 3 
In these tests to determine the effect of antihistamines creased by the stress procedure, but neither anti-inflam- 
on ulceration caused by the combined action of indo- matory agent was found to produce any additional in- 
methacin and stress, animals again were assigned ran- 45 crease in corticosterone level. 
domIY to groups receiving either Pyrilamine maleate Or  As to the effect of antihistamines on gastric ulceration 
metiamide at the dosages indicated in FIGS. 4 and 5. caused by a of anti-inflammatory agents 
each animal received ti mg/kg Of hd0- and stress, it was rather surprising to discover that not 
methacin. Both the antihistamine and the anti-Mamma- only metiamide could reduce ulceration, but that the 
lory agent were de'ivered m1 Of 50 H1 receptor antagonist, pyrilamine and promethazine, 
methycellulose solution. Thirty minutes after drug ad- also did. Earlier published data (Brown et al. 1976) ministration each animal was subjected to two hours of showed that the latter drugs do not function in that 
capacity with aspirin. These data suggest generally that cold restraint. At the end of that stress period, all ani- mals were sacrificed by decapitation and the stomachs 
were removed, pinned, and scored as in Example 1. 55 the mechanism of action of indomethacin differs, in an 
To determine whether the antiulcerogenic properties unknown from that Of aspirin. 
of pyrilamine is specific to that drug, other animals Although the invention has been described in terms 
were treated in the same manner with a structurally of certain preferred embodiments, it is contemplated 
different HI receptor blocker, promethazine. that the man skilled in the art may carry out modifica- me effectiveness of the antihistamines in inhibiting 60 tions that will remain within the spirit and the scope of 
gastric ulceration produced by indomethacin in rats the following claims. 
under stress in shown in FIGS. 4 and 5, and in Table 3. What is claimed is: 
As can be seen from the curves plotted, the do%- 1. A process for reducing gastric distress in a mammal 
response curves for pyrilamine and metiamide are very caused by the administration of indomethacin, which 
similar. In the absence of antihistamine, the mean ulcer 65 comprises administering to said mammal an antihista- 
score in both control groups was somewhat higher than mine substance selected from the group consisting of 
expected from the results of the first experiment, proba- promethazine and pyrilamine in a quantity sufficient to 
bly reflecting monthly variations to susceptibility to reduce gastric distress caused by the indomethacin. 
Zone of Stomach N = 8  N = 8  
As can seen in Table 2, neither indomethacin nor 35 
in the same 
4,279,906 
7 8 
2. The process of claim 1 wherein the antihistamine 
substance is promethazine. the indomethacin. 
3. The process of claim 1 wherein the antihistamine 
substance is pyrilamine. 
4. The process of claim 1 wherein there is adminis- 5 
tered about 0.025 to 0.400 gram of indomethacin and 
from about 0.2 to 2.0 grams of the antihistamine. 
5. A pharmaceutical composition comprising indo- 
methacin and an antihistamine substance selected from 
the group consisting of promethazine and pyrilamine in 10 
a quantity sufficient to reduce gastric distress caused by 
6. The composition of claim 5 wherein the antihista- 
mine substance is promethazine. 
7. The composition of claim 5 wherein the antihista- 
mine substance is pyrilamine. 
8. The composition of claim 5 comprisilig about 0.025 
to 0.400 gram of indomethacin and about 0.2 to 2.0 
grams of the antihistamine. * * * * *  
15 
20 
30 
35 
45 
50 
55 
60 
65 


Indomethacin-antihistamine combination for gastric ulceration control

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