IE921824A1

IE921824A1 - New combination preparations for treatment of parkinson's¹disease

Info

Publication number: IE921824A1
Application number: IE182492A
Authority: IE
Inventors: Peter Andreas Loschmann; Dr Helmut Wachtel
Original assignee: Schering Ag
Priority date: 1991-06-05
Filing date: 1992-07-01
Publication date: 1992-12-16
Also published as: CA2070494A1; JPH05170668A; HU9201874D0; HUT64473A; ZA924128B; DE4118740A1; AU1807592A; IL102095A0; EP0517347A1

Abstract

The use of NMDA receptor antagonists for the symptomatic treatment of Parkinson's disease and combination products which have a synergistic action and contain NMDA receptor antagonists are described.

Description

NEW COMBINATION PREPARATIONS FOR TREATMENT OF PARKINSON’S DISEASE gwmnarv of the Application The invention relates to the use of antagonists of the 5 N-methyl-D-aspartate (NMDA) receptor complex or their physiologically compatible salts as pharmaceutical agents for symptomatic treatment of Parkinson's disease as well as pharmaceutical agents which contain these compounds and their combination with anti-parkinson agents with syner10 gistic action.

High concentrations of excitatory amino acids such as glutamate and aspartate are present in the central nervous system of mammals, including humans, (Fonnum, F., J. Neurochem. 42: 1-11, 1984). For the excitatory amino acids, various receptors exist which are designated corresponding to their specific agonists as N-methyl-Daspartate (NMDA), kainate (KA) and quisqualate (QUIS) receptors. The quisqualate receptors are also named AMPA receptors after the specific agonists (RS)-m-amino-320 hydroxy-5-methyl-4-isoxazole propionate. The synaptic function of the excitatory amino acid L-glutamate is also imparted by NMDA receptors.

From clinical and animal-experimental findings, there are indications that in Parkinson's disease (PD), increased glutamatergic neurotransmission occurs in various nuclei of TILLEN WHITE 'ZELhNO F-12S T-365 F-203/011 JUN 03 ”32 1?:3S -032-22-:2 - 2 ~ the basal ganglia as a result of the striatal deficiency of dopamine. The neostriatum (NEO) represents the entry structure of the basal ganglia; it obtains from the cortex a massive glutamatergic projection and from the substantia nigra pars compacts (SNC) the dopaminergic nigrostriatal pathway, which degenerates in the case of PD. From the NEO, there are direct pathways to the initial nuclei of the basal ganglia, the internal pallidum link (GPi) and the substantia nigra pars reticulata (SNR), as well as indirect ' pathways, which run by the external pallidum link (GPe) and nucleus subthalamicus (STH). The STH receives a direct glutamatergic innervation of its own from the cortex; its neurons projecting to the initial nuclei also use L-glutamate as a transmitter.

The synaptic functions of dopamine in NEO are complex.

Its effect on the striatal neurons projecting into the GPe is mainly inhibitory, so that as a result of the striatal dopamine deficiency, as it is present in PD, the excitatory glutamatergic influences on these neurons predominate. 0 Since both the striatal pathway to the GPe and the pathway projecting to the STH starting from there are inhibitory, in the case of PD the phenomenon of disinhibition with increase of tonic cellular activity in the STH results. By its glutamatergic projections, the STH finally produces a pathologically increased neuronal activity in the initial nuclei of the basal ganglia. Tests on animal models of PD show that after administration of dopaminergic substances, a normalization of the increased excitatory neurotransmission results, which runs parallel to the clinical'* 0 improvement.

Surprisingly, it turned out that NMDA receptor antagonists, which also have a neuroprotective effect on the MPP*-induced cell loss in the substantia nigra, alone or in combination with L-dopa and direct dopaminergic agonists, have an effect on the experimental Parkinson's syndrome.

J UU UU . - 3 ~ According to the invention, compounds are suitable which have a high affinity to NMDA receptors and cancel the synaptic effects of NMDA. Such NMDA antagonists are, for example: l. competitive NMDA antagonists such as 3-((2)-2carboxy-piperazin-4-yl)-propyl-l-phosphonic acid (CPP) and analogs, such as, for example, CPPenes; cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755) or CGP 40116 and analogs; and 2-amino-7-phosphonoheptanoic acid . (AP-7) and analogs. 2. Antagonists of the glycine binding site, such as, for example, kynurenic acid and analogs; l-hydroxy-3-aminopyrrolidin-2-one (HA-966) and analogs. 3. Polyamines, such as, for example, spermine and spermidine and polyamine antagonists, such as, for example, ifenprodil. 4. Inhibitors of the excitatory amino acid synthesis or of the release, such as, e.g., lambotrigen.

In particular, competitive NMDA receptor antagonists 20 are suitable according to the invention for symptomatic treatment of PD.

The physiologically compatible salts are derived from alkali or alkaline-earth metals or the usual inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, maleic acid or fumaric acid.

The effect according to the invention is demonstrated by the example of CPP administration following the triggering of contralateral rotations on unilaterally substantia nigra-injured rats.

Male Wistar rats were injured 8 months before the ( experiment by injection of 16 pg of 6-hydroxydopamine (6-OHDA) in the left substantia nigra. The measurement of the rotations took place in automated rotoaeters. The animals were placed in plexiglass half-shells (diameter 40 cm) and mechanically connected vith an incremental —υυ·>· μα - 4 angle-position encoder. The clockwise and counterclockwise movements were detected separately at 10 minute intervals for 2 hours.

The results of this test can be summarized as follows: 5 The animals treated with solvents show hardly any spontaneous rotations. The treatment with L+dopa (25 mg/kg i.p.) and benserazide (100 mg/kg/i.p.) triggers slight movements of rotation. If the animals are treated in addition with CPP (0.025, 0.8, 0.39, 1.56 and 6.25 mg/kg/i.p.), 10 the rotations induced by L-dopa are enhanced dose-dependent. The number of rotations in 2 hours in the highest dosage of CPP differs significantly from the L-dopa treatment. (Pig. 1).

In the same way, the compounds according to the 15 invention were tested on true marmosets, in which an experimental Parkinson’s syndrome was produced by the neurotoxin MPTP.

Here, too, it is shown that the effect of L-dopa (20 mg/kg/i.p.) and benserazide (20 mg/kg/i.p.) is enhanced dose-dependent by CPP (0.1, 0.39, 1.56 mg/kg/i.p.) (fig. 2).

In the same model, CPP (0.1, 0.39, 1.56 mg/kg i.p.) was tested with the direct dopaminergic agonist apomorphine (0.05 mg/kg i.p.) or lisuride (0.1 mg/kg i.p.) (fig. 3 and 4). Here, too, the combined treatment leads to a significant synergism (variance analysis and Tukey test, * p < 0.0.1).

These tests show that antagonists of the NMDA receptors in dosages, which alone are without effects, after systemic administration, enhance the effect of L-DOPA in the 6-DHDA rotation model and on MPTP-treated true marmosets.

The blocking of the central NMDA receptors in structures which with Parkinson's disease exhibit an increased neuronal activity, is suitable for symptomatic Ί 11_LίζΝ ωΗίΤ- .^-LHNLi ΙΕ 921824 0fa/011 *UN 0 ί,Η; η χ - 5 treatment of Parkinson’s disease by compounds with selective and nonselective effect on NMDA receptors. Especially advantageous is the combination with usual anti-parkinson agents such as L-DOPA, L-DOPA in combination with bensera5 zide and dopaminergic agonists, such as, for example, lisuride, bromocryptine, pergolide, terguride, ropinirol, N—0437 (2 (N,n-propyl-N-2—(2-thienyl) ethylamino) -5-hydroxytetraline, cabergoline as well as anticholinergic agents.

By combination of the pharmaceutical agents according 10 to the invention with usual anti-parkinson agents, the dose of the usual pharmaceutical agent to be administered is reduced and its effect is increased. The synergistic effect of the combination preparations therefore makes possible an earlier occurrence of the desired effect and a reduction of the side effects. The effect then observed is more pronounced and sustained longer than after single administration of the individual components.

The invention also comprises pharmaceutical agents which contain the above-mentioned compounds, their pro20 duction and combination preparations with synergistic effect. The pharmaceutical agents are produced according to processes known in the art, by the active ingredient being brought into the form of a pharmaceutical preparation with suitable vehicles, auxiliary agents and/or additives, a preparation which is suitable for enteral or parenteral administration. The administration can take place orally or sublingually as a solid in the form of capsules or tablets or as a liquid in the form of solutions, suspensions, elixirs or emulsions or rectally in the form of supposi30 tories or in the form of injection solutions optionally also usable subcutaneously. As auxiliary agents for the desired pharmaceutical agent formulation, the inert organic and inorganic vehicles known to one skilled in the art are suitable, such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. Moreover, preservatives. - 6 stabilizers, wetting agents, emulsifiers or salts to change the osmotic pressure or buffers optionally can also be comprised.

The pharmaceutical preparations can be present in 5 solid form, for example as tablets, coated tablets, suppositories, capsules or in liquid form, for example as solutions, suspensions or emulsions.

The dosage of the active ingredients can vary depending on the method of administration, age and weight of the patient, nature and severity of the disease to be treated and similar factors. The daily dose for the NMDA receptor antagonists is 0.01-5000 mg, and the dose can be given as a single dose to be administered one time or subdivided into 2 or more daily doses. For the above-mentioned types of substances, the following single dose ranges are to be considered as suitable: 1. For competitive NMDA antagonists, such as AP-7: -500 mg, preferably 150 mg, such as CPP and analogs: 1-250 mg, preferably 25 mg, such as CGS 19755: 0.1-100 mg, preferably 10 mg. 2. For antagonists of the glycine binding site, such as kynurenic acid and analogs: 100-5000 mg, preferably 500 mg, such as HA-966: 0.01-100 mg, preferably 5 mg. 3. For polyamin® antagonists, such as spermine and 25 spermidine: 100-5000 mg, preferably 500 mg.

In the combination preparations according to the invention, the active ingredients can be present in one formulation or else in respectively separate formulations, and the entire dose is administered once or is divided into several doses.

The daily dose of the total active ingredients in the combination preparations with typical anti-parkinson agents is about half the typical dosage of known anti-parkinson agents, depending on the nature and severity of the disease as well as the age and weight of the patient. The therapeutic dosages of NMDA antagonists in the combination of antagonist and anti-parkinson agent is also about half the dosage of the NMDA antagonist administered alone, noted above.

Without further elaboration, it is believed that one 5 skilled in the art can, using the preceding description, utilize the present invention to its fullest extent.

The entire disclosures of all applications, patents and publications, cited above and below, and of corresponding application German P 41 18 740.7, filed June 5, 1991, are hereby incorporated by reference.

Claims

WHAT IS CLAIMED IS:

1. A method for the treatment of the symptoms of Parkinson’s disease, comprising administering to a host an effective amount of an NMDA receptor complex antagonist or a physiologically compatible salt thereof.

2. A method of claim 1, wherein the antagonist is a competitive antagonist.

3. A method of claim 2, wherein the antagonist is 2-amino-7-phosphonoheptanoic acid, 3-((±)2-carboxypiperazin-4-yl)-propyl-l*-phosphonic acid or cis-4phosphonomethyl-2-piperidine carboxylic acid.

4. A method of claim 1, wherein the antagonist is a non-competitive antagonist.

5. A method of claim 4 ,wherein the antagonist is a polyamine.

6. A method of claim 5, wherein the antagonist is spermine or spermidine.

7. A method of claim 4, wherein the antagonist is a polyamine antagonist.

8. A method of claim 7, wherein the antagonist is ' ifenprodil.

9. A method of claim 4, where the antagonist is one which acts on glycine binding sites. - 9

10. A method of claim 6, where the antagonist is kynurenic acid or l-hydroxy-3-amino-pyrrolidin-2-one.

11. A method according to claim 1, wherein the antagonist is an inhibitor of the synthesis or release of excitatory amino acids.

12. A method according to claim 11, wherein the antagonist is lambotrigen.

13. A method according to claim 1, wherein the antagonist is administered in conjunction with a dopaminergic agonist or an anti-cholinergic agent.

14. A method according to claim 13, wherein the antagonist is administered in conjunction with L-dopa or benserazide.

15. A pharmaceutical composition comprising (1) an NMDA receptor complex antagonist or a physiologically acceptable salt thereof and (2) a dopaminergic agonist, an anti-cholinergic agent, or a mixture thereof.

16. A composition according to claim 15, comprising (1) an NMDA receptor complex antagonist or a physiologically acceptable salt thereof and (2) L-dope or benserazide. -1017. Use of an NMDA receptor complex antagonist or a physiologically compatible salt thereof for the preparation of a medicament for use in a method of prophylaxis or treatment of the symptoms of Parkinson's disease.

17. 18. Use as claimed in claim 17 wherein the antagonist is a competitive antagonist.

18. 19. Use as claimed in claim 17 or 18 wherein the antagonist is 2-amino-7-phosphonoheptanoic acid, 3-((+)2carboxypiperazin-4-yl)-propyl-l-phosphonic acid or cis4-phosphonomethyl-2-piperidine carboxylic acid.

19. 20. Use as claimed in claim 17 wherein the antagonist is a non-competitive antagonist.

20. 21. Use as claimed in claim 20 wherein the antagonist is a polyamine.

21. 22. Use as claimed in claim 21 wherein the antagonist is spermine or spermidine.

22. 23. Use as claimed in claim 22 wherein the antagonist is ifenprodil.

23. 24. Use as claimed in claim 20 where the antagonist is one which acts on glycine binding sites.

24. 25. Use as claimed in claim 21 where the antagonist is kynurenic acid or l-hydroxy-3-amino-pyrrolidin-2-one.

25.

26. Use as claimed in claim 17 wherein the antagonist is an inhibitor of the synthesis or release of excitatory amino acids .