Life Flow One
The Solution For Heart Disease
by
Karl Loren
Vol 190
NATURE
April 15,
1961
No. 4772
pp263-234
GASTRO-INTESTINAL ABSORPTION OF HEPARIN AND SYNTHETIC HEPARINOIDS
HEPARIN
and synthetic heparinoids have to be administered parenterally to assure
clinical efficacy. Since oral administration of these drugs would be highly
desirable, numerous compounds were tested for their ability to effect absorption
from the gastrointestinal tract. The criterion of absorption was the appearance
of plasma lipemia-clearing activity, which was first described by Hahn.
Several compounds (‘adjuvants’) were discovered to have
this property, the best of these being certain salts of
ethylenediaminetetraacetic acid (EDTA). [Emphasis added.] Other active
compounds will be the subjects of future communications. The present
communication describes the use of salts of EDTA to obtain absorption of heparin
and synthetic heparinoids.
Rats weighing about 200gm were placed in individual cages and fed for 72hr. a liquid diet consisting of 30ml. of a 33 percent casein hydrolysate and water ad lib. The drug was given by intubation of aqueous solution at a volume of 10ml/kgm.
Table 1. Rat and Dog Lipemia-Clearing Activity 4 hr. after
Oral Sulphopolyglucin Plus EDTA
|
Animal |
Number of |
SPG |
Sodium salt |
Lipemia-clearing |
|
Rats |
5* |
500 |
--- |
0.04 ± 0.03 |
|
Dogs |
5 |
100 |
--- |
0.59 ± 0.41 |
*Means ± standard deviation
=====================================================================================
Table 2. Lipemia-Clearing Activity and Clotting Time After
oral Heparin Plus EDTA in Rats and Dogs
|
Rats |
Dogs |
||||
|
Heparin 50 mgm/kgm |
Heparin 100 mgm/kgm |
||||
|
Time (min) |
ClringActv(CU*) |
Clotting time (min) |
Time (hr) |
ClringActv(CU*) |
Cltgtime(min) |
|
0 |
0.04 ± 0.03 (5) |
7.0 ± 1.7 (16) |
0 |
0.19 ± 0.18 (4) |
11.3 ± 2.1 (8) |
Figures in parentheses are number of animals. >, some animals had incoagulable blood (> 60 min) *, mean ± standard deviation.
=====================================================================================================
At specified times, the rats were anesthetized with
pentobarbital sodium, and blood samples taken by cardiac puncture.
In dogs, after an overnight fast, the drugs were given orally
in gelatin capsules. Blood samples were taken by venipuncture at specified
intervals. Lipemia-clearing activity of citrated plasma was determined and
expressed in clearing units (C.U.) calculated according to Grossman, except that
incubation time was limited to 10 minutes and the substrate was ‘Ediol’ (SchenLabs),
diluted 1 to 50 with water. Whole-blood clotting time was determined by a
three-tube Lee-White method and indicated in minutes. When blood did not clot
within 60 min, a value of 60 min was used in calculating mean clotting time, but
the ‘>’ sign was added. All values for clearing activity and clotting
time are given as mean ± standard deviation for groups of 5-10 animals or as
specified.
The drugs used were heparin sodium U.S.P., potassium salt of
sulphopolyglucin (SPG) and various salts of EDTA. SPG is a sulphated
polysaccharide [Emphasis added.] of 5 to 15 glucose units connected by a,
1-4, and a, 1-6 linkages, with 2-3 sulphate groups per glucose unit.
Typical experiments demonstrating the adjuvant property of
sodium EDTA are presented in Table 1. Using lipemia-clearing activity as an
index of absorption, the result show, without a question, the adjuvant
properties of sodium EDTA. In dogs, where SPG alone produces measurable although
somewhat erratic clearing activity, absorption of the heparinoid is increased
about ten-fold by simultaneous administration of the sodium salt of
EDTA. [Emphasis added.] In rats, the effect of EDTA is even greater, since
SPG alone is practically not absorbed.
Similar results with SPG have been found in every animal
species studied (monkey, dog, cat, rabbit, and rat), as well as in man. The
adjuvant property of EDTA has also been demonstrated for other synthetic
heparinoids [Emphasis added.] (polyethylene sulphonate, dextran sulphate and
others).
The adjuvant property [Emphasis added.] of the sodium
salt of EDTA [Emphasis added.] can also be demonstrated for heparin,
using both clotting time and clearing activity [Emphasis added.] as
criteria of absorption (Table 2).
The effects of EDTA are again unequivocal. In rats, clearing
activity reached a peak about 30 min. after administration of the drug
combination, and then declined slowly to control-levels. A similar time course
was obtained for the anti-coagulant effect, with doubling of the clotting
[Emphasis added.] time at about 30 min. after the drug and subsequent return to
control-levels. Since it is known that heparin is not absorbed from the
gastro-intestinal tract, control experiments without EDTA were not made.
In dogs, the typical heparin effects appeared slower than in
the rates. The peak of clearing activity and anti-coagulant effects were reached
about 2 hr. after drug combination and returned to control-levels after more
than 4 hr.
Further experiments were carried out in dogs to establish
dose-response curves for SPG, both with and without EDTA. The results in Fig. 1
show good correlation between dose and clearing as well as anti-coagulant
activity. Statistical evaluation indicated that the efficacy of SPG was
increased approximately five-fold when EDTA, in the ratio 1:4, was used as
adjuvant. [Emphasis added.]
Significant amounts of heparin and synthetic heparinoids can
be absorbed from the gastro-intestinal tract when these drugs are given
orally together with an alkali salt of EDTA. The mechanism of this adjuvant
effect is not clear. [Emphasis added.] There is evidence that the Chelation
of calcium and/or magnesium ions of EDTA may be involved for the following
reasons: (1) Sodium, potassium and ammonium salts of EDTA are effective as
adjuvants; #2) calcium and magnesium EDTA are not effective; (3) adding a
calcium salt blocks the adjuvant action of alkali EDTA; (4) phosphate buffers
are not effective; (5) the adjuvant has to be given orally; intravenous
injection of the adjuvant does not influence the absorption of SPG from the
gastro-intestinal tract.
E. Windsor
G.E. Cronheim
Riker Laboratories, Inc.
Northridge California
__________________________________
1 Loomis, T.A., Pharmacology in Medicine, edit, By Drill, V.A., second ed. (Blakiston, New York, 1958).| The Links Below Jump To Pages On Whatever Web You Are In | |||
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