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.

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.

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.