U.S. patent number 3,865,942 [Application Number 05/138,314] was granted by the patent office on 1975-02-11 for method of increasing cerebral blood flow.
This patent grant is currently assigned to Societe Generale de Recherches et d'Applications Scientifiques"Sogeras". Invention is credited to Pierre Charles Wirth.
United States Patent |
3,865,942 |
Wirth |
February 11, 1975 |
Method of increasing cerebral blood flow
Abstract
A pharmaceutical composition adapted for treating patients for
cerebral vascular insufficiencies comprises a pharmaceutically
effective dose of viquidil or a physiologically acceptable salt
thereof in an inert physiological carrier.
Inventors: |
Wirth; Pierre Charles (Paris,
FR) |
Assignee: |
Societe Generale de Recherches et
d'Applications Scientifiques"Sogeras" (Paris,
FR)
|
Family
ID: |
22481480 |
Appl.
No.: |
05/138,314 |
Filed: |
April 28, 1971 |
Current U.S.
Class: |
514/314 |
Current CPC
Class: |
A61K
31/49 (20130101) |
Current International
Class: |
A61K
31/49 (20060101); A61k 027/00 () |
Field of
Search: |
;424/259 |
Other References
Physicians Desk Reference, (PDR), 25th Ed., p. 1371, (1971). .
Chemical Abstracts 48:10218f, (1954). .
Merck Index, 8th ed., 1968, pg. 903. .
J. Am. Chem. Soc. 66:873-874, (1945)..
|
Primary Examiner: Meyers; Albert T.
Assistant Examiner: Schenkman; Leonard
Attorney, Agent or Firm: Waters, Roditi, Schwartz &
Nissen
Claims
What we claim is:
1. A method of increasing cerebal blood flow of a patient suffering
from cerebal vascular insufficiencies which comprises orally
administering a cerebral vasodilating amount of viquidil to the
patient.
2. A method according to claim 1, in which the viquidil is
administered at a rate of approximately 300 mg per day.
Description
This invention is concerned with pharmaceutical compositions
containing viquidil (formerly known as quinicine).
Among the numerous alkaloids which are found together with quinine
in cinchona bark, there is the compound
1-(6-methoxy-4-quinolyl)-3-(vinyl-4-piperidyl)-propanone, which has
recently received the international common name "viquidil," it
previously having been called "quinicine."
This compound has long been considered to be responsible for the
symptoms of poisoning caused by quinine, since the latter can be
converted to viquidil in the presence of the acidity of gastric
juices. However, it is now known that intolerance to quinine is
only due to individual hypersensitivity reactions. It is
nevertheless the case that viquidil continues to be regarded as a
true toxin as is witnessed by the fact that it is commonly also
referred to as "quinotoxin."
We have now found, however, that viquidil and its salts are well
tolerated by human beings and animals and that it has a number of
useful pharmacological properties. In particular, we have found
that viquidil is useful in the treatment and prevention of
cerebro-vascular accidents; cerebro-vascular insufficiencies; brain
damage associated with cerebral circulatory insufficiency, and
disturbances of memory and balance.
Viquidil may be used therapeutically either alone or associated
with carriers such as excipients, diluents, coating agents,
preserving agents, wetting or lubricating agents, solution coloring
agents, or perfumes provided that such associated materials are
physiologically acceptable and appropriate to the method of
administration.
The invention thus contemplates a pharmaceutical composition which
comprises viquidil or a physiologically acceptable salt thereof,
together with a physiologically acceptable carrier therefor.
For oral administration, tablets, lozenges, powders, pellets or
capsules, emulsions, suspensions, solutions or syrups may, for
example, be used.
For parenteral administration, sterile aqueous or non-aqueous
solutions, suspensions or emulsions or sterile powders to be
dissolved at the time of use, may for example be used.
For rectal administration, suppositories may be used, and for
external use solutions, emulsions, suspensions or ointments may,
for example, be used.
We have carried out pharmacological and toxicological tests on
viquidil and its acid addition salts with the following
results.
A. TOXICOLOGICAL STUDY
I. acute toxicity
When administered in a single dose, viquidil has a toxicity
comparable with that of quinine hydrochloride or papaverine
hydrochloride. The 50 percent lethal doses (LD50) of the substances
are of the same general order of magnitude when they are orally
administered to rats and mice or subcutaneously administered to
guinea pigs.
When intravenously administered to mice, quinine hydrochloride is
tolerated better than viquidil. However, when similarly
administered, the latter is about half as toxic as papaverine.
Ii. test of tolerance to high doses.
Viquidil produces signs of intolerance (vomiting and diarrhea) in
dogs when orally administered in the very large dose of 60 mg/kg.
Similar doses of papaverine do not produce these rejection
phenomena, but the animals suffer shock and show tremors.
Viquidil, like papaverine, is poorly tolerated in dogs in doses of
3 mg/kg. Smaller doses (1 and 2 mg) have not produced any apparent
disturbance.
Iii. cardiac toxicity.
In order to find whether the toxicity of viq1uidil would increase
after it had accumulated in the organism, we determined the minimum
lethal dose when intravenously administered to animals who had
previously been subcutaneously treated for approximately 1 to 6
weeks. In the test, viquidil was compared with papaverine and
quinidine.
Perfusion under these conditions showed a slight increase in the
toxicity of quinidine, probably associated with the known
accumulation of this drug in the organism. Organisms appear to
become inured to papaverine, but none of these phenomena occured
with viquidil.
Iv. delayed toxicity
Daily doses of 25, 50, 100 and 200 mg/kg of viquidil were orally
administered to rats for nearly three months. It was found that
viquidil could cause a hepatosteatosis to form, if administered in
large doses (100 and 200 mg/kg). This action was confirmed in a
second test by giving the animals larger oral doses: 75, 150 and
300 mg/kg. At these doses, which are from 15 to 60 times as great
as the dose used in human medicine, the appearance of
hepatosteatosis was confirmed. Its intensity was proportional to
the doses, but was in no case accompanied by functional
disturbances of the liver. Furthermore, the excess is labile, since
it disappeared spontaneously after the treatment stopped.
Viquidil was orally administered to dogs in daily doses of 6 and 30
mg/kg for six months. The treatment was well tolerated by the
animals and no sign of hepatosteatosis was observed under the
microscope, unlike the findings with rats. With regard to
functional disturbances, only two dogs out of eight showed a slight
increase in the glutamicpyruvic transaminase, in small proportions
(6 mg/kg) and only towards the end of the treatment.
In short, the reversible hepatosteatoses observed in rats were not
found in dogs, although they had been given large doses for six
months. B. PHARMACOLOGICAL STUDY
Viquidil hydrochloride was pharmacologically studied in comparison
with quinine sulphate, papaverine hydrochloride and quinidine
sulphate. The aim of the tests was to see whether viquidil had a
spamsolytic and vasodilative action and to compare its action with
that of quinine and the known spasmolytics, papaverine and
atropine.
The experiments showed that viquidil has a more marked spasmolytic
action than quinine and papaverine, more particularly in the
musculotropic region.
In vitro
Viquidil is from 2 to 6 times more active than papaverine against
contractions produced by musculotropic, neurotropic or histaminic
agonists.
In vivo
In mice, viquidil inhibits the intestinal transit in the same
manner as papaverine, i.e. in large doses. In anaesthetized dogs, a
small dose of viquidil slightly increases the spontaneous
intestinal motility, whereas a larger dose reduces without stopping
it. Viquidil has a marked inhibiting action, slightly greater than
that of papaverine, on histaminic or acetylcholinic bronchiospasm.
Viquidil is well tolerated by the lungs when administered in
aerosol form.
Viquidil and papaverine have the same negative inotropic activity
on the isolated heart (Langendorff's method) and have the same
inhibiting effect on adrenalinic contractions of the isolated
aorta.
Papaverine has a more marked inotropic action, which takes longer
to reverse, on a flap of the isolated heart. Quinidine produces a
greater increase in the absolute refractory period, and viquidil
produces a slightly greater increase in latency. Papaverine seems
more toxic than quinidine and viquidil.
In mice, the antifibrillant activity of viquidil is less than that
of quinidine but greater than that of papaverine.
In rabbits and anaesthetized dogs, papverine causes greater
hypetension than viquidil in small doses. At medium and large
doses, the hypotension is the same, but lasts longer when viquidil
is administered.
The changes in blood pressure observed in rats, rabbits or dogs
after administration of viquidil are comparable in intensity with
changes observed under the same experimental conditions, using
papaverine. It was important to know whether the hypotensions were
due to vasodilatation alone or to an effect on the strength of
cardiac contractions. The decreases in the strength of cardiac
contractions were found to be small, independently of the doses
administered. The hypotension was therefore mainly due to the
vasodilative effect of the viquidil.
When intravenously administered to dogs, viquidil and papaverine
slightly increased the flow of the muscular and cerebral
territories and greatly increased the flow of the splanchnic
territory. After intra-arterial administration, the flows increase
in all the territories, and viquidil as before was slightly more
active than papaverine.
Papaverine and viquidil have little effect on the behavior of mice
at liberty.
Papaverine and viquidil do not have any central cholinolytic
action. Viquidil, unlike papaverine, shows a marked antinicotinic
activity but only at high doses, without any relation to the
results for ganglioplegics and neuroleptics.
Viquidil and papaverine are slightly ganglioplegic.
In summary, viquidil has important spasmolytic acitvity, which is
very similar in quality but always greater in quantity than that of
papaverine. Its vasodilative activity is two or three times greater
than that of papaverine. Viquidil is also an excellent bronchial
spasmolytic.
These pharmocological properties indicate that viquidil has an
important spasmolytic effect, particularly on the vascular and
bronchial coverings. It is superior in this respect to papaverine
and theophylline.
This spasmolytic effect is usefully associated with two properties
which complete the diaracterization of the product. First, studies
have shown that viquidil is an excellent inhibitor of platelet
clotting. Second, it has considerable affinity for tissue, but
surprisingly this affinity is not accompanied by disturbing
secondary effects, in particular with regard to the formation,
storage or use of cell energy.
As regards the first point, blood platelets are known to play a
very important part in the initiation of intravascular thromboses.
It is therefore very useful that viquidil, which helps to improve
vascular circulation, also has an anti-clotting action which is
capable of preventing the formation of the thromboses which are
often associated with vascular disorders. This anti-clotting action
is shown with very low concentrations, of the order of 10 mcg/ml,
which can readily be achieved in practice and which puts viquidil
amongst the best anti-clotting agents.
With regard to the second point, viquidil differs greatly from
papaverine, for studies have shown that, unlike papaverine,
viquidil has a very strong tendency to locate within the cell.
Viquidil therefore has a very high erythrocyte-plasma ratio, the
erythrocytes fixing two or three times more viquidil than does the
plasma. With regard to tissue concentration, oral administration of
200 mg/kg of viquidil and papaverine to rats leads to a myocardium
concentration of not more than 4 mcg per gram of tissue for
papaverine as compared with 50 mcg for viquidil. However, and this
is one of the advantages of viquidil, this intracellular location
is not associated with disturbances in the use of the energy
resulting from mitochondrial oxido-phosphorylations, since studies
have shown that viquidil has virtually no effect on
oxido-phosphorylation phenomena, whereas papaverine, in the same
conditions, has been found to act as a very powerful inhibitor of
mitochondrial respiration.
This tissue location tendency is definitely a factor favoring the
vasodilatory and spasmolytic action of viquidil even within the
vessel coverings and, in particular, increasing the duration of
effectiveness of the drug.
Extensive clinical studies have been made using a mixture of the
following composition: Viquidil 100 g Aerosil (silica aerogel)
Magnesium stearate q.s. to 104 g. Talc
The mixture was administered in the form of gelatin capsules
containing 0.10 g of the mixture, at the rate of 3 capsules a day,
to several hundred patients in a hospital for various kinds of
neurological vacular disorders and to patients with various
attention and wakefulness disturbances connected with insufficient
cerebral circulation. The results of the studies showed that
viquidil is definitely useful in the treatment of cases of
localized cerebral vascular insufficiencies (in the carotid or the
vertebro-basilary region) and of various disorders affecting
attention and wakefulness, particuularly in the case of old people
suffering from more or less severe brain damage.
The therapeutic activity of the drug was shown by means of a
cerebral circulation radiogram, and this is the first time that a
product of this kind has been clearly active, even when given
orally.
Remarkable results were obtained from double-blind administration
of the drug to patients suffering from brain damage associated with
cerebral circulation insufficiency.
As regards tolerance, more than 200 patients were given the drug
for periods of from 2 weeks to 3 months. There was intolerance in
about 2 percent of the cases, the intolerance taking the form of
mild digestive reactions.
Heptic function tests (measurement of blood bilirubin, serous
transaminases, blood protein level, glycemia, cholesterol) have
completely normal results in all cases, as did hematological checks
during treatment.
The following examples of preferred forms of the pharmaceutical
compositions according to the invention are given by way of
illustration only:
EXAMPLE 1
AMPOULES Viquidil hydrochloride 20 mg Codex citric acid 8.4 mg
Codex trisodium citrate 57.06 mg Sodium metabisulphite 10 mg
Distilled water q.s. for 2 ml
EXAMPLE 2
GELATIN CAPSULES Viquidil hydrochloride 0.100 g Colloidal silica
Magnesium stearate q.s. for a No. 3 gelatin capsule containing
0.104 g. Talc
EXAMPLE 3
TABLETS A. Formulation of tablets Viquidil hydrochloride 100 mg
Lactose Tricalcium phosphate Dried maize starch Pulverized gum
arabic q.s. for a 255 mg tablet. Vinyl acetate Talc Magnesium
stearate
B. varnishing and drageification vehicle
Cellulose acetophthalate, diethyl phthalate, talc, rice starch,
gelatin, gum arabic, saccharose, erythrosin, tartrazine and
purified water ............ q.s. for a dragee weighing 500 mg.
Viquidil is suitably given to patients in any of these three forms
at a rate of approximately 300 mg/day.
* * * * *