Method and Compositions for the Treatment of Neurological Disorders

The present invention relates to novel synergistic pharmaceutical compositions and to a method for the treatment of certain neurological disorders in mammals including man. More particularly, the invention relates to novel pharmaceutical compositions and a method for alleviating ailments caused by a lower than normal activity in the dopamine systems in the brain. Among such ailments may be mentioned parkinson's disease, which is considered to be a chronic neurological disorder and is characterized i.a. by tremor, rigidity of the limbs, hypokinesia, or abnormally decreased mobility, and akinesia, or abnormal absence or poverty of movements.

The pathophysiology of parkinsonism in man can, at least partly, be explained with a degeneration in the dopaminergic system in the brain, localized to the caudate nucleus, putamen and substantia nigra. These parts of the brain contain in normal human subjects about 80 percent of the total amount of dopamine in the brain. In patients suffering from parkinsonism a depletion of dopamine, ##SPC1##

In the brain is observed. For treatment of parkinsonism it has been suggested to administer to the patient a compound of the formula ##SPC2##

In which formula R.sup.1 is H or OH and R.sup.2 is H or an alkyl group containing from 1 to 3 carbon atoms. The formula I includes dopa, of the structural formula ##SPC3##

And esters thereof, and m-tyrosine, of the structural formula ##SPC4##

And esters thereof. Illustrative examples of groups R.sup.2 are CH.sub.3, C.sub.2 H.sub.5, CH.sub.2 CH.sub.2 CH.sub.3, CH(CH.sub.3).sub.2. Dopa is a precursor of dopamine, which substance does - in contast to dopamine itself - pass the blood-brain barrier and is decarboxylated in the brain with formation of dopamine. Another method for treatment of parkinsonism which has been tested comprises administration of apomorphine, ##SPC5##

Apomorphine is a dopaminergic agent which has been tested as an agent for treatment of parkinsonism, see Cotzias et al, The New England Journal of Medicine 282 31-33 (1970). Apomorphine has been found to have an alleviating effect on akinesia and rigidity occurring in connection with Parkinson's disease but its severe drawbacks, mainly the short duration of its desired therapeutic effect and its emetic effect, render the therapeutical use of apomorphine for treatment of parkinsonism practically impossible.

Still another method for treatment of parkinsonism which has been tested (Corrodi et al., European Journal of Phamacology Vol. 20 p. 195-204) comprises administration of the compound 1-(2'-pyrimidinyl)-4 (3", 4"-methylenedioxyphenyl)-piperazine, herebelow denoted ET 495, with the structural formula ##SPC6##

Or a therapeutically acceptable salt thereof. The compound of the formula (III) is known to have cadiovascular effects, see Laubie et al, European Journal of Pharmacology 6 (1969) 75-82, and it is being used in therapy against various vascular diseases, mainly in the legs. The toxicity of ET 495 is also reported by Laubie et al. loc. cit. The synthesis of the compound is described by Regnier et al., J. Med. Chem. 11, 1151 (1968).

It has been found according to the present invention that the effect of the aforementioned compounds I, II and III including dopa, apomorphine, ET 495, and m-tyrosine on the dopaminergic nerve system can be greatly enhanced and the duration of the effect vastly prolonged by administering a dopaminergic substance selected from the group consisting of the compounds I, II and III including dopa, apomorphine, ET 495, and m-tyrosine, in combination with a fosfodiesterase inhibitor selected from the group consisting of caffeine, teofyllamine and papaverine. Caffeine, teofyllamine and papaverine are all known compounds. Also mixtures of caffeine, teofyllamine and/or papaverine can be used together with a mixture of one or more of the dopaminergic substances. In this way the amounts of the dopaminergic substances which have to be administered in order to achieve the desired therapeutical effect can be minimized while at the same time the duration of the therapeutical effect is prolonged, which is a distinct medicinal advantage. By decreasing the amount of active substance which has to be given to the patients the risk for side effects decreases, resulting in a safer treatment because the gap between the therapeutic dose and the toxic dose is increased.

Thus, the present invention in one aspect provides novel pharmaceutical compositions containing a dopaminergic agent selected from the group consisting of the compounds I, II and III including dopa, apomorphine, ET 495, m-tyrosine, and 1-3 carbon atom alkyl esters of dopa and m-tyrosine, in combination with a fosfodiesterase inhibitor selected from the group consisting of caffeine, teofyllamine and papaverine, normally together with commonly used excipients and diluents. Where applicable, members of both the groups of compounds may be used in the form of a therapeutically acceptable salt. Dosage unit forms of the pharmaceutical preparations may be designed for administration by the oral or parenteral route or by injection.

In another aspect, the present invention provides a method for alleviating ailments caused by a lower than normal activity in the dopamine systems in the brain. In particular, the invention gives an improved method for treating parkinsonism, tha is a method for alleviating the symptoms of rigidity, akinesia and tremor in patients suffering from Parkinson's disease.

The novel compositions according to the present invention may also contain such substances which previously have been shown to improve the effect of dopa, m-tyrosin and other agents in the treatment of parkinsonism. Examples of such compounds are the compounds of the formula ##SPC7##

described in French Pat. specification No. 2,081,377, wherein R.sub.1 and R.sup.2 are H, OH, alkoxy containing 1-6 carbon atoms, R.sup.3 and R.sup.4 are H or alkyl containing from 1 to 6 carbon atoms, and R.sup.5 is H or a metal or an alkyl group containing 1-6 carbon atoms; the compounds of the formula ##SPC8##

described in the British Pat. specification No. 1,247,073, wherein R.sup.1, R.sup.2 and R.sup.3 are OH or groups convertible to OH, R.sup.4 is aminomethyl or a group convertible to aminomethyl; and the compound of the formula ##SPC9##

The formula IV includes the compound .alpha.-methyl-.alpha.-hydrazino-3,4-dihydroxyphenyl propionic acid: ##SPC10##

which compound herebelow is denoted with its code number MK 486.

Examples of fosfodiesterase inhibitors which besides caffeine, teofyllamine and papaverine can be used in combination with the compounds I, II and/or III above, are: ##SPC11##

Caffeine, theophyllamine and papaverine have the structural formulas ##SPC12##

Parkinsonism may be characterized not only by a lower than normal activity in the dopamine systems in the brain but also by a degeneration of the noradrenaline neurons in the brain. Thus, also the noradrenaline systems in the brain exhibit in such case a lower than normal activity. Such a state of lower than normal activity in the noradrenergic neurons also characterizes certain states of depression. It has been shown - reference is made to G. C. Palmer, Neuropharmacology Vol. 11 p. 145 (1972) and to Weiss, Strada, Advances in Cyclic Nucleotide Research Vol. 1 p. 357, Raven Press, New York (1972) that the noradrenaline receptors in the brain as well as the dopamine receptors in the brain exert their function via a cyclic AMP (adenosine monophosphate) mechanism. It is therefore concluded that the novel pharmaceutical compositions of the present invention, which affect the dopamine receptors very strongly, also will affect the noradrenaline receptors equally strongly. That the compositions of the invention do have an effect on intact noradrenaline receptors is shown below in the tests on acutely spinalized rats. Since it also is known that the noradrenaline receptors become supersensitive to noradrenergic substanses such as dopa and desipramine when the noradrenaline system is caused to degenerate - reference is made to the above mentioned papers by Palmer and Weiss, Strada - it is clear that the unexpectedly increased effect of the compositions of the invention in the tests in the dopamine model, that is on the turning behaviour of rats, will have a counterpart in an unexpectedly increased effect of the same compositions on a degenerated noradrenaline system, which means, in turn, that the novel compositions of the present invention also provide a new way of treating depressions.

Thus, it is an object of the present invention to provide a method for treating certain types of depressions by administering the novel pharmaceutical compositions according to the invention or the active ingredients thereof, in particular the caffeine-dopa and teofyllamine-dopa combinations with or without the addition of known antidepressants or the imipramine type, such as desipramine, imipramine and protriptyline. The combinations caffeine-desipramine, caffeine-imipramine, caffeine-protriptyline, and teofyllamine-imipramine, and teofyllamine-protriptyline may be mentioned as further useful combinations.

The mentioned antidepressant drugs which are known compounds, have the structural formulas ##SPC13##

Still another area where the compositions of the invention are of potential value is in the treatment of patients who have suffered cerebral strokes. It has been shown in experimental animals - reference is made to Wurtman, Zervas, J. Neurosurg. Vol. 40 p. 34-36 (1974) - that experimentally developed conditions which are similar to the conditions at hand in humans who have suffered strokes lead to a major reduction of the amount of dopamine in the brain, and degeneration of the dopamine system with development of dopamine receptor super-sensitivity. Therefore, it should be a therapeutic advantage in treating such patients with drugs which stimulate the central dopaminergic receptors. The novel compositions of the present invention should cause the same unexpected increase in dopamine receptor activity and therefore be highly useful in such treatment.

The invention also provides, as mentioned above, a novel method for the treatment of depressions by administering a therapeutically effective amount of at least one member of the group consisting of caffeine and teofyllamine in combination with or concurrently with an antidepressant drug of the imipramine type such as desipramine, imipramine and protriptyline, which preferably blocks noradrenaline-uptake. The invention also provides novel pharmaceutical compositions, and a method of their preparation, containing a member of the group consisting of caffeine and teofyllamine in combination with an antidepressant as mentioned above. The pharmaceutical preparations containing caffeine teofyllamine and an antidepressant are prepared in conventional manner analogously as described below.

In a still further aspect of the invention, a method is provided for potentiation of the dopaminergic effect of the compounds I, II and III including dopa, apomorphine, ET 495 and M-tyrosine, and 1-3 carbon atom alkyl esters of dopa and m-tyrosine, by incorporating into a composition containing one or more of said substances a suitable amount of a fosfodiesterase inhibitor selected from the group consisting of caffeine, teofyllamine and papaverine, or administering the active agents concurrently. Methoxylated metabolites, e.g. apocodeine, may be used in place of apomorphine itself, if desired.

In a still further aspect of the invention, a method is provided for treating patients who have suffered a stroke by administering a composition according to the invention.

In clinical practice the novel compositions of the present invention will normally be administered orally, parenterally or by injection in the form of pharmaceutical preparations comprising the active ingredient in the form of the free base or a pharmaceutically acceptable salt thereof, e.g. the hydrochloride, in association with a pharmaceutically acceptable carrier which may be a solid, semi-solid or liquid diluent or as ingestible capsule. Usually the dopaminergic substance and the fosfodiesterase inhibitor will together comprise between about 0.1 and about 95 percent by weight of the preparation, for example, between 0.5 and 20 percent for preparations intended for injection and between 0.1 and 50 percent for preparations intended for oral administration.

To produce pharmaceutical preparations in the form of dosage units for oral application containing a compound of the invention in the form of the free base, or a pharmaceutically acceptable salt thereof, the active ingredients may be mixed with a solid, pulverulent carrier, for example lactose, saccharose, sorbitol, mannitol, a starch such as potato starch, corn starch, amylopectin, laminaria powder or citrus pulp powder, a cellulose derivative or gelatine, and also may include lubricants such as magnesium or calcium stearate or a Carbowax or other polyethylen glycol wax and compressed to form tablets or centres for dragees. If dragees are required, the centres may be coated, for example with concentrated sugar solutions which may contain gum arabic, talc and/or titanium dioxide, or alternatively with a lacquer dissolved in easily volatile organic solvents or mixtures of organic solvents. Dyestuffs can be added to these coatings, for example, to distinguish between different contents of active substance. For the preparation of soft gelatine capsules (pearl-shaped closed capsules) consisting of gelatine and, for example, glycerin, or similar closed capsules, the active substances may be admixed with a Carbowax.sup.R. Hard gelatine capsules may contain granulates of the active substance with solid, pulverulent carriers such as lactose, saccharose, sorbitol, mannitol, starches (for example potato starch, corn starch or amylopectin), cellulose derivatives or gelatine, and may also include magnesium stearate or stearic acid. Dosage units for rectal application may be in the form of suppositorier comprising the active substances in admixture with a neutral fatty base, or gelatine rectal capsules comprising the active substance in admixture with a Carbowax.sup.R or other polyethylene glycol wax.

Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing from about 0.1 to 20 percent by weight of active substance, sugar and a mixture of ethanol, water, glycerine, propyleneglycol and optionally, aroma, saccharine and/or carboxymethylcellulose as a dispersing agent.

For parenteral application by injection preparations may comprise an aqueous solution of a water soluble pharmaceutically acceptable salt of the active substance desirably in a concentration of 0.5-10 percent by weight and optionally also a stabilising agent and/or buffer substance in aqueous solution. Dosage units of the solution may advantageously be enclosed in ampoules.

The relative amounts dopaminergic substance-fosfodiesterase blocker may vary but the ratios given in Table 1 below may be mentioned as illustrative. The percentages are given in weight percent calculated on the total weight of dopaminergic substance and fosfodiesterase inhibitor.

The figures given for dopa and m-tyrosine are valid also for the 1-3 carbon atom alkyl esters thereof.

Examples of further combinations dopaminergic substance-fosfodiesterase inhibitor are m-tyrosine-caffeine, m-tyrosine-teofyllamine and m-tyrosine-papaverine.

Another way of expressing the information contained in Table I is to say that suitably 2 parts of dopa and 5 parts of any of caffeine, teofyllamine and papaverine suitably are combined; that 1 part of ET 495 and 25 parts of any of caffeine, teofyllamine and papaverine suitably are combined; and that 1 part of apomorphine and 100 parts of any of caffeine, teofyllamine and papaverine suitably are combined. All "parts" are parts by weight.

Dosage units for oral administration preferably contain the following relative amounts of dopaminergic substance and fosfodiesterase inhibitor: Dopa: up to about 400 mg. Any of caffeine, teofyllamine and papaverine: from about 100 to about 1000 mg. ET 495: up to about 40 mg. Any of caffeine, teofyllamine and papaverine: from about 100 to about 1000 mg. Apomorphine: up to about 10 mg. Any of caffeine, teofyllamine and papaverine: from about 100 to about 1000 mg. m-Tyrosine: up to about 1000 mg. Any of caffeine, teofyllamine and papaverine: from about 100 to about 2500 mg.

The amounts given for dopa and m-tyrosine are also valid for the 1-3 carbon atom alkyl esters thereof.

The maximum daily doses of ET 495 when administered without fosfodiesterase inhibitor is about 300 mg at oral administration and about 100 mg at parenteral administration. The maximum daily doses of dopa when administered without fosfodiesterase inhibitor is about 10 g at oral administration. These dosages are upper limits also for the said substances when administered with a fosfodiesterase inhibitor according to the present invention. Use of the novel compositions according to the present application naturally means that these limits need not be fully utilized.

The biological effectiveness of the novel compositions according to the present invention is illustrated in the following.

One animal model available for the evaluation of central dopaminergic substances is a test on rotation of rats with unilateral lesions in the brain. As described by Ungerstedt (European J. Pharmacology 5, 107 (1968) interruption of the nigroneostriatal dopamine neurons by injection of 6-hydroxydopamine into the substantia nigra causing a degeneration of the cell bodies of these neurons leads to parkinson-like symptoms in rats. Injection of dopaminergic substances leads to a dose dependant rotation of the animals towards the unoperated side away from the lesion. This rotation can easily be measured and the duration of the effect determined. In this test known substances having a clincally verified antiparkinson action are active. Rats with a unilateral lesion in the left nigro-neostriatal dopamine pathway, produced according to Ungerstedt, loc.cit, were injected intraperitoneally with the test substance and the animal placed in a rotometer where the total number of rotations could be recorded. The test results are summarized in Tables 2-7 below. The letters DA mean "dopaminergic." The letters "s.e.m." mean "standard error of the mean."

As is seen in Table 2, the fosfodiesterase inhibitors caffeine and teofyllamine have no significant effect on the number of rotations of the rats except for a slight effect in a dose of 25 mg/kg. In Tables 3 and 4 it is also seen that dopa in the dose 10 mg/kg body weight had no significant effect on the number of rotations. Presence of caffeine or teofyllamine gave a more than 20-fold increase (Table 3) in the number of rotations at the same dose of dopa, 10 mg/kg. Similar effects, although not so pronounced, are seen in Table 5 for the combination dopa-papaverine. The very pronounced potentiation of ET 495 with teofyllamine and caffeine is seen in Table 6. Papaverine did not give the same degree of potentiation. Also apomorphine is strongly potentiated by caffeine and teofyllamine, as is seen in Table 7. The potentiating effect was very clear both when the fosfodiesterase inhibitors were administered 1 hour before the dopaminergic substance was administered and when the inhibitor was administered immediately before the dopaminergic substance was administered.

As is seen in Table 6, the substance pimozide, that is 1-[1-[4,4-bis(p-fluorophenyl)butyl]-4-piperidyl]-2-benzimidazolinone, which substance is a known antipsychoticum, effectively blocks the dopaminergic effect of ET 495. The combination caffeine-ET 495 does, however, as is seen in Table 6, overcome the blocking effect of pimozide on the effect of ET 495 and give a pronounced dopaminergic effect. This means that such parkinsonism that is induced by neuroleptica can be effectively treated with the combination caffeine-ET 495 according to the present invention. Such parkinsonism, which cannot be treated with ET 495 per se because of the blockade of the effect of ET 495 caused by the neurolepticum, may occur for example in psychotic patients who are treated with antipsychotic drugs. This effect achieved by caffeine-ET 495 may also be obtained using cafeine in combination with small doses of any dopa and apomorphine and other compounds included in formula I above.

From the test results given in Tables 9 and 10 it is seen that caffeine and teofyllamine greatly enhance and prolong the activity exerted by the MK 486-dopa and MK 486-m-tyrosine ethyl ester combinations in spite of very low amounts of dopa and m-tyrosine. In Table 9 it is also seen that the m-tyrosine ethyl ester in combination with MK 486 caffeine can be used in dosages which are about the same as the dopa dosages in such combinations. This is important since m-tyrosine or esters thereof normally is less active than dopa.

Those combinations are preferred which contain

dopa-MK 486-caffeine

dopa-MK 486-teofyllamine

m-tyrosine ethyl ester MK 486-caffeine

m-tyrosine ethyl ester -MK 486-teofyllamine

and corresponding combinations containing substances included in the formulas I, II and III together with MK 486 and caffeine, teofyllamine and papaverine. Of these combinations, the dopa-MK 486-caffeine and m-tyrosine ethyl ester -MK 486-caffeine are preferred. The proportions dopa-MK 486 may in these compositions vary between about 0.2:1 and about 8:1. The proportion dopa-caffeine is from about 1:4 to about 1.5:1. The same proportions are valid for dopa-MK 486-teofyllamine combination and for the corresponding m-tyrosine ethyl ester combinations. The relative dosages of the three components when used in clinical practice will depend on the individual requirements in each case. As examples of specific combinations may be mentioned tablets which contain in addition to the usual carrial ingredients

The effect of compositions of the invention on intact noradrenaline receptors was tested on acutely spinalized rats by the method described by Anden, Corrodi, Fuxe, Hogfeldt, European Journal of Pharmacology v. 2, p 59 (1967) and by Carlsson, Magnusson, Rosengren, Experientia Vol. 19 p. 359 (1963). In this test an increased effect on the noradrenaline receptors is indicated as an increase in the flexor reflex activity.

It is seen in Table 13 that teofyllamine increases the effect of dopa on the intact noradrenaline receptors in the test animals. These results show that teofyllamine and caffeine have increased the sensitivity of the noradrenaline receptors for activation by noradrenaline formed at the metabolism of dopa. Similarly it is seen in Table 14 that caffeine and teofyllamine increase the effect of protriptyline on the noradrealine receptors.

These results give experimental support for the conclusion that the compositions of the present invention also exhibit an increased stimulating effect on noradrenaline receptors which means that also ailments caused by lower than normal activity in the noradrenaline neurons such as certain types of depression, especially those where dopamine supersensitivity has developed may be treated with the compositions of the present invention.

The following Examples illustrate how the novel compositions of the present invention can be incorporated in pharmaceutical compositions.

140 g of dopa and 360 g of caffeine were mixed with 500 g of corn oil whereafter the mixture was filled in soft gelatine capsules, each capsule containing 100 mg of mixture.

The operation described in Example 1 was repeated using 140 g of dopa and 360 g of teofyllamine instead of dopa and caffeine.

The operation described in Example 1 was repeated using 140 g of dopa and 360 g of papaverine instead of dopa and caffeine.

16 kg of dopa and 32 kg of caffeine were mixed with 20 kg of silicon dioxide of the trade mark Aerosil, whereafter 45 kg of potato starch and 50 kg of lactose were mixed in and the mixture moistened with a starch paste prepared from 5 kg of potato starch and distilled water, whereafter the mixture was granulated through a sieve. The granulate was dried and sieved whereafter 2 kg of magnesium stearate were mixed in. Finally the mixture was pressed into tablets, each weighing 172 mg.

The operation described in Example 4 was repeated using 2 kg of ET 495 and 48 kg caffeine instead of dopa and caffeine.

The operation described in Example 4 was repeated using 0.5 kg of apomorphine and 49.5 kg of teofyllamine instead of dopa and caffeine.

30 g of dopa and 70 g of caffeine were dissolved in 2500 g of peanut oil. From the solution thus obtained, 90 g of Gum Arabic, aroma and colour (q.s.) and 2500 g of water an emulsion was prepared.

4 g of ET 495 and 96 g of teofyllamine were dissolved in 300 g of 95 percent ethanol where 300 g of glycerol, aroma and colour (q.s.) and water 1000 ml were mixed in. A syrup was thus obtained.

30 g of dopa and 70 g of caffeine were dissolved in 2000 g of polyoxyethylene sorbitan monooleate, whereafter aroma and colour (q.s.) and water to 5000 ml were mixed in. A drop solution was thus obtained.

The operation described in Example 4 was repeated using 16 kg .alpha.-methyl-.alpha.-hydrazino-3,4-dihydroxyphenyl propionic acid as a further ingredient.

The operation described in Example 4 was repeated using 16 kg m-tyrosine ethyl ester and 16 kg .alpha.-methyl-.alpha.hydrazino-3,4-dihydroxyphenyl propionic acid instead of the 16 kg dopa.

Where combinations of active agents are referred to herein, the active agents can obviously be administered concurrently, i.e. at or about the same time, as well as together in the same dosage form or unit. Also, where such combinations of active agents are administered in the dosage form or unit usual pharmaceutical carriers are normally included, but may in some cases be omitted, if desired.