Note: Descriptions are shown in the official language in which they were submitted.
PREPAR~TION AND METHOD FOR TREATMENT OF HYPOCALCE-
MIA, HYPOPHOSPHATEMIA AND DO~ER COW ~NDROME IN ANIMA~
The present invention relates to therapeutic calci-
um electrolytic solutions ~or intravenous administration
in ruminant animals suffering with the clinical signs or
pathology of hypocalcemia, hypophosphatemia and downer
cow syndrome. These conditions describe what is commonly
known as ~milk fever~
In ruminant animals, the occurance of hypocalcemia
has several profound effects. Physically, paresis is ex-
hibited in varying degrees ranging from ataxia to para-
plegia. Clinical pathology of the serum of these animals
reveals significant decreases in serum calcium, serum
phosphorus and declining insulin levels. Simultaneous-
ly, the serum magnesium and serum glucose levels climb
to abnormal highs.
Traditional treatment has consisted of the adminis-
stration of calcium salts intravenously, subcutaneouslyor intramuscularly. Examples of these treatments are cal-
cium salts such as calcium chloride, calcium gluconate,
calcium borogluconate, calcium hypophosPhite, calcium lac-
tate, calcium glycerophosphate, calcium levulinate used
either alone or in combination or with salts of magnesium,
potassium, phosphites and glucose~ Examples of prepa~a-
tions previously tried are glven in U. S. Patents Nos.
1 2,140,291 and 3,553,148.
Calcium chloride, while providing a rapid response
in the patient animals, has potential for toxicity and
acute neart block if administered too raPidly or in too con-
centrated a solution. Perivascular administration resultsin tissue necrosis.
Calcium borogluconate has the disadvantage of con-
taining boron which is noted for its toxic effect on
hepatic tissue making this salt, although widely used,
10 less than good therapy.
Calcium hypophosphite is proclaimed as a s~urce of
~both calcium and phosphorus. ~owever, studies have shown
that the hypophosphite, in addition to being a strong re-
ducing agent, i5 excreted in the urine, biologically un-
15 changed and unutilized.
Certain combinations of calcium salts in suspensionhave been tried, i.e. calcium lactate and calcium gly-
cerophosphate. This combination contains insufficient
calcium ~o ~e efective by recommended intermuscula~ ad- :
20 ministration.
The addition of magnesium salts to these solutions is
contraindicated since hypocalcemic ruminants already have
an elevated serum magnesium level.
The addition of glucose to calcium solutions is
25 unacceptable. In order for the body to use glucose r it
must utilize phosphorus from the serum thus aggravating
the pre-existing hypophosphatemia. When serum phospho-
rus levels drop low enough, a serious shift in the oxy-
hemoglobin occurs which can result in tissue anoxia with
30 brain, hepatic and eryth~ocyte damage.
It is an object of this invention to provide a new
ccmbination of calcium salts containinq calcium chloride, calcium
lactate and calcium levulinate. This is a clear, stable,
aqueous solution.
An important advantage of the present invention
is to provide therapeutic solutions which produce a ra-
pid rate of therapeutic response in the patient. A fur-
3L~
1 ther impor-tant advantage is to provide such solutions
which provide a high level of ccntinuing effectiveness
after administratlon. Further important advantages of the
invention are the provision of therapeutic electrolytic
solutions having very low toxicity and lowered irrita-
bility. The solutions also have the advantage of stabi-
lity and ease of induction. ~nother advantage is the pre-
sence in the solution of calcium lacta~.e which provides
a vehicle for potential buffer formation thus avoiding un-
desirable pH variations.
Calcium chloride, when used as 10~ to 30% of the cal-
cium ion source in such combination of ingredients,provides
a more rapid recovery without the previously noted toxicity
effects.
~he calcium lactate supplying 20~ to 60% of the cal-
cium ion source also provides the lactate fraction which
may be converted to bicarbonate. This may provide a
buffering capability ~o the solutions which restores the
ruminant's base deficit ~hat exists in hypocalcemia and
hypophosphatemia.
l'he calcium levulinate is an excellent source for 20
to 60~ of the calcium ions. Because it is non irritating
it dilutes the irritating effect of the lactate and chloride
salts.
The foregoing and related objects of the invention
can be achieved by preparing an aqueous solution containing
from 7 to 28 grams of dissolved calcium ion per 500 cc's of
solution in the form of a water soluble mixture of calcium
chloride, calcium lactate and -calcium levulinate. Such solu-
tions have been found effective in formulations wherein 10%
to 30~ of the dissolved cal~ium ion is provided by calcium
-chloride, 20% to 60-~ thereof by calcium lactate and 20~ to
60~ thereof by calcium levulinate.
Solutions of the present invention are preferably pre-
pared by adding the salts in the foregoing proportions towater and heating the resultant mixture until all of the
salts have been dissolved. The solution is then cooled and
3~
l filtered to remove impurities. The resulting solution is
colorless and stable even at low temperatures and after
long periods of storage.
The preferred formulation of this invention is a mix-
ture in which calcium chloride furnishes 20~ o~ the calci-
um ions by weight, calcium levulinate furnishes 40~ by weight
and calcium lactate furnishes 40~ by weight. This specific
combination after exte~sive testing has been determined to
provideroptimum results in the treatment of dairy cows
suffering ~rom the above no~ed milk fever symptoms.
In accordance with the present invention it has been
determined that superior results are achieved in the treat-
ment of ruminant animals suffering from milk fever symp-
~oms by intravenous administration of the preparations of
the present invention if they are free of sugars such as
glucose or dextrose, free of boron compounds and free of
magnesium compounds. These ingredients, which are usually
present in commercially available preparations, have been
found to be unnecessary or to cause undesirable complica-
tions, or both.
It will be appreciated by those s~illed in the artthat the preparation of this invention can be modiied by
the addition thereto in minor amounts of calcium acetate,
calcium chlorate, calcium gluconate or calcium propionate
without departing from the spirit of the invention~
While the foregoing discussion has contemplated the
use of water as a preferred vehicle, or pharmaceu~ically
acceptable base, for carrying the mixture o calcium salts
of the present invention it will be apparent to those s~illed
in t~e ar~ that other bases might be employed. Other modifi-
cations falling within the purview of the invention will also
be apparent to those skilled in the art.
- s -
1 The following examples illustrate the principles and
practice of the present invention.
EXAMPLE 1
A mixture consisting of 42.2 grams calcium lactate,
42.2 grams calcium levulinate and 8.32 grams calcium chloride
was dissolved in 1000 ccls of QS water by heating and
stirring. When all of the salts were completely dissolved,
the solu~ion was cooled and filtered. The solution was ad-
ministered to 83 dairy cows having mil]c fever symptoms.
The solution was administered in~ravenously in doses of
1000 cc's. Sixty-four of the cows got up without relapse
after a single treatmen~ and recovered Eully. ~en of the
cows recovered after two or more treatments~ Nine of the
cows failed to recover after treatment.
A group of 147 dair~ cows suffering from milk fever
symptoms was treated under similar controlled conditions
with the largest selling commercially available formula-
tion for treatment of milk fever, which was a solution de-
termined to contain calcium borogluconate, dextrose, magne-
sium and phosphorus compounds. Of these cows 111 recovered
after one or more treatments of the solution by intravenous
in~ection (76~. Thirty-six cows either died or had to be
disposed of (24%). Thus the death rate of patients treated
with the preparation of the present invention was considera-
bly less than hal`f that experienced ~ith the leading commer-
cially available preparation.
EXAMPLE 2
Tb 500 cc's dis~lled water were added enoug~ calcium ~ s
to provide 7 grams of dissolved calcium ions. This consisted of suffi-
30 cient calcium chloride to provide 2.1 grams of calcium ions, calciumlactate to provide 1.4 grams of calcium ions and calcium levulinate to
pr~vide 3.5 grams of calcium ions. The weight percentages of the cal
cium ions were thus provided in the ratio of 30~ frcm ca~ciu~ chloride,
20~ frcm calcium lac~ate and 50~ from calcium l~linate. The m~re
35 was formed into a solution by heatin~ the m~Yture~and was ~ subsequently
filtered to remove impurities. The re~ting solution was colorless and
could be autoclaved. The solution was intravenously admmistered to a
z
1 dairy cow which had been diagnosed as suffering from hypo~
calcemla. The patient rapidly recovered af~er administration
of the solution.
S EX~IPL13 3
To 500 cc's distilled water were added enough cal-
cium compounds to provide 7 grams of dissolved calcium ions.
This consisted of sufficient calcium chloride to provide
2,1 grams of calcium ions, calcium lactate to pravide 3.5
grams o~ calcium ions and calcium levulinate to provide 1.4
grams of calcium ions. The weight percentages of the cal-
cium ions were thus provided in the ratio o~ 30~ from cal-
cium chloride, 50~ from calcium lactate and 20~ from cal-
cium levulinate. The mixture was formed into a solut.ion by
heating the mixture and was subsequently filtered to remove
impurities. The resulting solution was colorle.ss and stable
and could be au~oclaved. The solution was suitable for intra-
venous administration to cattle suffering from hypocalcemia.
EX~tLE 4
To S00 cc's distilled water were added enough calcium
compounds to provide 7 grams of dissolved calcium ions. This
consisted of sufficient calcium chloride to provide 0.7
grams of calcium ions, calcium lactate to provide 3~15 grams
of calcium ions and calcium levulinate to provide 3.15 grams
of calcium ions. The weight percentages of the calcium ions
were thus provided in the ratio of 10% from calcium chloride,
45% from calcium lactate and 45~ from calcium levulinate.
The mixture was formed into a solution by heating the mixture
and was subsequently filtered to remove impurities. The re-
sulting solution was colorless and stable and could be auto-
claved. The solution was administered to a dairy cow which
had bsen diagnosed as suffering from hypocalcemia. The pa-
tient rapidly recovered a~ter administration of the solution,
EXAMPLE 5
To 500 cc's distilled water were added enoush calcium
compounds to provide 7 grams of dissolved calcium ions. This
consisted of sufficient calcium chloride to provide 0.7 grams
` -
--7--
l of calcium ions, calcium lactate to provide 2.1 grams of cal-
cium ions and calcium levulinate to provide 4.2 grams of cal-
cium ions. The weigh~ percentages of the calcium ions were
thus provided in ~he ra~io of lO~ from calcium chloride, 30%
from calcium lacta-te and 60% from calcium levullnate. The
mixture was formed into a solution by heating the mixture and
was subsequently iltered to remove impuri.ties. The re-
sulting soLution was colorless and stable and could be auto-
claved. The solution was administered to a dairy cow which
had been diagnosed as su~fering from hypocalcemia. The pa-
tient rapidly recovered after administration of the solution.
EX~MPLE 6
To S00 cc's distilled water were added enough calcium
compounds to provide 7 grams of dissolved calcium ions. This
consisted of sufficient calcium chloride to provide 0.7 grams
of calcium ions, calcium lac~ate to provide 4.2 grarns of
calcium ions and calcium levulinate to provide 2.1 grams
of calcium ions. The weight percentages of the calcium
ions were thus provided in the ratio of 10% from calcium
chloride, 60% from calcium lactate and 30% from calcium levu-
linate. The mixture was formed into a solution by heating
the mixture and was subsequen~ly filtered to remove impuri~
ties. The resulting solution was colorless and stable and
could be autoclaved. The solu~ion was administered to a dairy
cow which had been diagnosed as suffering from hypocalcemia.
The patienk rapidly recovered after administration of the so-
lution.
EXAMPLE 7
~o 500 cc's distilled water were added enough calcium
compounds to provide 7 grams of dissolved calcium ions. This
consisted of sufficient calcium chloride to provide 1.5 grams
of calcium ions, calcium lactate to provide 2.75 grams of cal-
cium ions and calcium levulinate to provide 2.75 grams of cal-
cium ions. The weight percentages of the calcium ions were
thus provided in the ratio of 21.4% from calcium chloride,
39.3% from calcium lactate and 39.3% from calcium levulinate.
The mixture was formed into a solution by heating the mixture
--8-- .
1 and was subsequently filtered to remove impurities. The re-
sulting solution was administered to a dairy cow which had
been diagnosed as suffering from hyp~calcemia. The patient
rapidly recovered after administration of the solution.
