CA2075107A1 - Pharmaceutical composition of dihydropyridine with neuroleptic - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Novel pharmaceutical compositions consisting of a dihydropyridine calcium channel blocker with a neuroleptic are disclosed. The compositions are effective in treating psychomotor stimulant abuse and psychoses.

Description

--` 2Q75iO7 The present invention relates to ph3rmaceutical 3 compositions for the treatment of stimulant abuse or psychoses.
4 More particularly the invention relates to synergistic combinations of neuroleptics with L-type calcium channel blockers 6 of the dihydropyridine type useful in the treatment of stimulant 1 abuse or psychoses.

8 BACKGROUND pF THE INVENTION
9 Former addicts of psychomotor stimulants continue to exhibit strong cravings and drug-like physiological responses 11 when presented with drug-related cues (O'Brien et al., 1988:
12 Pharmacological and behavioral treatments of cocaine dependence:
13 controlled studies. J Clin Psychiat 49:17-22; Muntaner et al., 14 1989: Placebo responses to cocaine administration in humans:
1~ effects of prior administration and verbal instructions.
16 Psychopharmacology 99:282-286.). Such responses are not 17 affected by usual drug-detoxification or drug Eehabilitation 18 programs. In humans, both the subjective euphoric and 19 cardiovascular effects of cocaine can be conditioned to situational stimuli (0'8rien et al., 1986: Classical canditioning 21 in human opioid dependence, in Goldberg SG, Stoleman IP (eds), Behavioral Analysis of Drug Dependence, Orlando, Florida:
23 Academic Press 1986, pp. 329-356; Muntaner et al., 1989). These 24 observations have led some researchers to propose tihat drug-conditioned responses may contribute to the maintenance of ...

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2~7~a7 1 addictive behaviours (O'Brien et al., 1986). O'Brien and his colleagues have attempted to extinguish the conditioned responses to drug-related stimuli in cocaine addicts. Repeated 4 exposure to individualized drug-associated cues diminishes conditioned-craving responses. Addicts, however, remain 6 vulnerable to relapse of drug cravings in response to stimulus l exposure (O'Brisn et al., 1988). The conditioned stimulant-8 cravings and physiological responses appear to be difficult to 9 extinguish.
Classical conditioning of the effects of psychomotor 11 stimulants i6 a process fundamental to mammalian species, 12 including rats and humans (Martin-Iverson et al., 1990:
13 Stimulant-conditioned locomotion is not affected by blockade of 14 D1 and/or D2 receptors during conditioning. Brain Research 521:175-184; O'Brien et al, 1988). Therefore, it can be 16 predicated that treatments that block the classical conditioning 17 of psychomotor stimulant effects in rats will have similar 18 effects in humans. In addition, it has been demonstrated that 19 the classically conditioned effects of psychomotor stimulants are ~Q mediated by actions of these drugs on neurons in the brain that 21 release the neurotransmitter dopamine, a short form of the name 3,4-dihydroxyphenylethylamine (DiLullo et al., 1992; Evidence for 23 presynaptic dopamine mechanisms underlying amphetamine-24 conditioned locomotion, Brain Research 578:161-167). However, drugs that block dopamine receptors are not effective at blocking 26 the conditioned effects of psychomotor stimulants IMartin-, . . : . ' "' - 2~7~7 1 Iverson and McMa~s, 19gO~; nor do such dopamine receptor 2 antagonists appear to block the euphoria effects of cocaine in 3 addicts (Gawin, 1986: Neuroleptic reduction of cocaine-induced 4 paranoia ~ut not euphoria. Psychopharmacology 90:142-143).
~herefore, although there is considerable evidence that dopamine 6 is involved in stimulant addiction and in conditioning, available 7 drugs that block dopamine receptors (neuroleptics) fail to block 8 either the conditioning or the euphoric effects of psychomotor 9 stimulants.
The calcium channel blockers or antagonists can 11 attenuate the psychomotor (Grebb, 1986: Nifedipine and 1~ flunarizine block amphetamine-induced behavioral stlmulation in 1~ mice, Life Science 38:2375-2381; Trouve and Nahas, 1986:
14 Nitredipine: an antidote to cardiac and lethal toxicity of cocaine, Proc Soc Exp Biol Med 183:392-397; Pani et al., 1990:
16 Nimodipine inhibits cocaine-induced dopamine release and motor 17 stimulation, Eur J Pharmacol 176:245-246), physiological (Trouve 18 and Nahas, 1986: Nitrendipine: an antidote to cardiac and lethal 19 toxicity of cocaine, Proc Soc Exp Biol Med 183:329-397~ Rowbotham et al., 1987: Cocaine-calcium channel antagonist interactions, 21 Psychopharmacology 93:152-154), central (Pani et al., 1990) and discriminative stimulus properties (Nencine and Woolverton, 1988:
Effects of nimodipine on the discriminative stimulus properties 24 of d-amphetamine, Psychopharmacology 96:40-44) of psychomotor stimulants. Calcium channel antagonism, though able to diminish 26 the effects of cooaine in naive animals, does not alter cooaine-' . ' , '~ ' -~!

207~107 1 induced responses by experienced human users (Rowbotham et al., 2 1987). Animal (Trouve and Nahas, 1986; Nencine and Woolverton, 3 1988) and clinical research suggests the efficacy of calcium 4 channel blockers in the treatment of stimulant addictlon (Nencine and Woolverton, 1988; Pani et al., l990), cocaine-induced cardiac 6 toxicity (Trouve and Nahas, 1986; Hale et al., 1991: Nifedipine l protects the heart from acute deleterious effects of cocaine if 8 administered before but not after cocaine. Circulation 84:1437-9 1443) and psychotic disorders (Bloom et al., 1987: Verpamil in refractory schizophrenia: a case report, Prog Neuro-11 Psychopharmacol & Biol Psychiat 11:185-188; Jacques et al., 1991:
12 Verpamil in major (psychotic) depression, Br J Psychiat 158:124-13 125; Bartko et al., 1991: Effects of adjunctive verapamil 14 administration in chronic schizophrenia patients, Prog Neuro-Psychopharmacol & Biol Psychiat 15:343-349; Jacques and Cox, 16 1991; Stedman et al., 1991: Effects of nifedipine on psychosis ll and tardive dyskensia in schizophrenic patients, J Clin 18 Psychopharmacol 11:43-47). U.S. Patent 5,124,340, issued June 19 23, 1992 to Jaffe et al. discloses the use of calcium channel blocking agents for the treatment of cocaine addiction.
21 Pharmacotherapy with a DA D2 and calcium channel antagonist has been suggested to be an attractive treatment 23 alternative for stimulant addiction. Diphenylbutylpiperidines, 24 neuroleptics which antagonize D~ D2 receptors and L-type calcium channels, appear to be more effective than selective DA D2 26 receptor antagonism in the treatment of unresponsive chronic ~ ,-, ' ' 20751~7 l schizophrenia a~d the alleviation of ne~ative schizophrenia syndrome (Laplerre, 1978: A controlled study of penfluoridol in 3 the treatment of chronic schizophrenia, Am J Psychiat 135:956-4 959; Gould et al., 1982: Antischizophrenic drugs of the diphenylbutylpiperidine type act as calcium channel antagonists, 6 Neurobiol 80:5122-5125; Feinberg et al., 1988: Pimozide treatment l of the negative schizophrenic syndrome: an open trial. J Clin 8 Psychiat 49:235-238).
9 Recent studies suggested to the inventors that DA-calcium synergism may be an attractive target for the treatment 11 of psychoses (Bloom et al., 1987; Bartko et al., 1991; Jacques 1~ and Cox, 1991; Stedman et al., 1991) and stimulant addiction 13 (Rowbotham et al., 1987; Nencini and Woolverton, 198a, Pani et 14 al., 1990). Clinical trials, although uncontrolled, have demonstrated the efficacy of certain combined L-type calcium 16 channel blockade and DA D2 receptor blockade in the treatment of 17 chronic schizophrenic and negative schizophrenic symptoms 18 (Lapierre, 1978; Feinberg et al, 1988). In addition 1~ schizophrenics with periodic psychosis show episodal increases of serum calcium levels (Carman and Wyatt, 1979: Calcium:
21 bivalent cation in the bivalent psychoses. Biol Psychiat 14:295-22 336).
23 As indicated above, neuroleptic or antipsychotic drugs known to be clinically effecti-~e in the treatment of psychoses, including those associated with schizophrenia, manic-depressive 26 psychoses, affective psychoses, organic psychoses, including `, ', .

2~7~1~7 1 drug-induced psychoses, and other psychoses, are acco~panied by 2 side e~fects. ~he most serious and/or common side effects of 3 neuroleptic medications include extrapyramidal symptoms such as 4 akathesia, dystonia, tremors and rigidity, tardive dyskinesia parkinsonisms and neuroleptic malignant syndrome (the latter 6 being frequently fatal). These side effects are related to dose, 1 i.e. more prevalent in the increasing dose. Thus, it would be 8 extremely useful to obtain a therapeutic effect with the lowest 9 possible dose of a neuroleptic drug.
It should be understood that the above studies are less 11 than conclusive and somewhat contrary in respect of the 12 desirability or effect of combining DA D2 and certain calcium 13 channel antagonists for either the treatment of stimulant abuse 14 or psychoses. For instance, a calcium channel blocker such as verapamil is not identical chemically or pharmacologically to 16 other calcium channel antagonists and thus does not predict the 17 utility of other calcium channel antagonists.

19 The inventors have discovered that dihydropyridines which block L-type calcium channels in the mammalian central 21 nervous system, in combination with neuroleptic drugs produce greater effects (i.e. superadditive or synergistlc effeots) in 23 animal models of dopamine function when used in cambination than 24 when given individually. This surprising synergistic effect is observed between nimodipine, a 1,4-dihydropyridine, and ... .

207~1~7 1 haloperidol, a butyrophenone, on amphetamine-induced and amphetamine-conditioned behaviours. Nimodipine i~ a standard representative of a dihydropyridine calcium channel blocker, 4 while haloperidol is a standard representative of a neuroleptic.
Broadly stated, the invention is a pharmaceutical 6 composition, comprising, as active substances, a neuroleptic l compound which functions as a dopamine D2 receptor blocker or 8 antagonist, or a non-toxic, pharmaceutically acceptable salt 9 thereof, and a dihydropyridine calcium channel blocker, or a non-toxic, pharmaceutically acceptable salt thereof. The active 11 substances may be present jointly in an admixture or in similar 1~ or different separate pharmaceutical forms for substantially 13 simultaneous administration.
14 Another aspect of the invention is a method of treating psychomotor stimulant addiction, dependency or abuse in an 16 individual, comprising administering to said individual, 17 concomitantly or consecutively, a therapeutically effective 18 amount of a neuroleptic compound which functions as a dopamine 19 D2 receptor bloaker or antagonist, or a non-toxic, ~0 pharmaceutically acceptable salt thereof, and a dihydropyridine 21 calcium channel blocker, or a non-toxic, pharmaceutically acceptable salt thereof.
Yet another broad aspect of the invention i8 a method of treating p8ycho6es in an individual, compri8ing admlnistering to said individual, concomitantly or consecutively, a 26 therapeutically effective amount of a neuroleptic compound which - . ., : ~
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`- ~Q751~7 l functions as a dopa~in~ D2 receptor blocker or antagonist, or a 2 non-toxic, pharmaceutically acceptable salt thereof, and a dihyd,ropyridine calcium channel blocker, or a non-toxic, 4 phar~aceutically acceptable salt thereof. The combined drugs allow for a lowering of the therapeutically effective amount of 6 the neuroleptic from that required when the neuroleptic is 1 administered without the calcium channel blocker.

9 Figure 1 is a sheet showing the chemical structures of typical dihydropyridine calcium channel blockers;
11 Figure 2 is a plot demonstrating attenuated AMP-12 induced locomotion (photobeam interruptions) with the combination 13 drug of the present invention;
14 Figure 3 is a plot demonstrating attenuated AMP-conditioned locomotion (photobeam interruptions) with the 16 combination drug of the present invention; and 17 Figure 4 is a plot demonstrating attenuated cocaine-18 conditioned locomotion with the combination drug of the present 19 invention.

DESCRIPTION OF THE PREFERRED EMBODIMENT
~1 The present invention provides novel pharmaceutical compositions contalning, as active substanoes~ a synergistic 23 combination of a neuroleptic compound and a dihydropyridine, L-24 type calcium channel blocker. The two drugs, when administered ~ .:

--` 207~107 1 concomitantly or consecutively, as described hereinbelow, are 2 effective in the treatment of psychoses and of psychomotor 3 stimulant abuse, dependency or addiction. With respect to the 4 treatment of s~imulant abuse, use of only one of the drugs in therapy is shown not to be totally effective, whereas treatment 6 with both drugs is shown to be effective in controlling both the 1 stimulant-induced and stimulant-conditioned behaviours. With 8 respect to the treatment of psychoses, the inclusion of the 9 calcium channel blocker drug is effective in lowering the therapeutically effective amount of the neuroleptic drug that 11 would be used if administered on its own. The lower dose is 1~ significant in decreasing the unwanted side effects of therapy 13 with neuroleptics.
14Neuroleptic compounds are well known for the treatment of individuals with psychoses such as schizophrenia. Such drugs 1~ act through antagonism of dopamine receptors. A good description 17of neuroleptic drugs is found in U.S. Patent 5,068,054, issued 18 to Parish, and in Goodman and Gilman's, The Pharmacological Basis 19 of Therapeutics, eds. A. Goodman Gilman et al., 8th ed., Pergamon Press, 1990. Typical and preferred neuroleptic drugs for the 21 purposes of the present invention, are of one or more of the 22 following general classes:
~ a) phenothiazines, for example chlorpromazine, 24 trlflupromazine, mesoridazine, perphenazine, prochlorperazine, and trifluoperazine;

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" 207~1~7 1 (b) thioxanthenes, for example chlorprothiaxine and thiathixine;
(c) dihydroindolones, for example molindone;
4 (d) dibenzoxazepines, for example loxapin;
S (e) diphenylbutylpiperidines, for example pimozide; a~d 6 (f) butyrophenones, for example haloperidol and droperidol.
7 All of these neuroleptic drugs are well described in the 8 patent and medical literature. Clinicians are familiar with 9 therapy involving one or more of these drugs in various lQ pharmaceutical forms and dosage amounts.
11 Particularly preferred in the combination preparation 12 of this invention are drugs of the butyrophenone class, 13 particularly haloperidol (4-[4-(p-chlorophenyl)-4-hydroxy-14 piperidino~-4'-fluorobutyrophenone). It has been demonstrated that the clinical antipsychotic efficacy of neuroleptics is 16 highly correlated with the ability of these drugs to displace 17 l3H]-haloperidol from its binding sites at dopamine D2 receptors 18 (Greese et al., 1976: Dopamine receptor binding predicts clinical 1~ and pharmacological potencies of antischizophrenic drugs.
Science 192:481-483). Haloperidol is one of the most widely used ~1 neuroleptics, and is considered to be a reference neuroleptic in 22 many scientific and clinical studies.
23 Dihydropyridine L-type calcium channel blockers or 24 antagonists are also well known drugs in the patent and medical literature. For lnstance, a good description of such drugs i9 included in U.S. Patents 5,089,502, issued February 18, 1992 to : ~ , . - .
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2~ 7 ,., l Sudilovsky et al, U.S. Patent 5,124,340, issued June 23, 1992 to 2 Jaffe et al., and in D. J. Triggle et al., Calcium Entry and 3 Action at the Presynaptic Nerve Terminal Annals of the New York 4 Academy of Sciences, Vol 635, 123, N.Y. 1991. Typical and preferred L-type calcium channel blocking drugs for the purposes 6 of the present inventlon, are 1,4-dihydropyridines, generally l having the formula I shown in Figure 1, wherein:

8 R is H or lower alkyl 9 Rl, R2 are same or different lower alkyl groups R3, R4 are same or different lower alkyl or ANR5~R6, wherein 11 A = lower alkylene and Rs~ R6 are same or different H, 1~ lower alkyl, lower alkoxy, phenyl, phenyl lower alkyl, 13 or phenyl lower alkyl substituted with a halogen atom;
14 and R7, Rg are same or different H, NO2, halide, trifluoromethyl 16 or = N-0-N = connected to the ring on adjacent C atoms.

17 Particularly preferred are nimodipine, amlodipine. felodipine, 18 isradipine, nicardipine, nitrendipine, nifedipine, nisolipine, 19 Bay K 8644 (Miles) and nilvadipine.
As with the neuroleptic component of the composition ~1 of this invention, cliniaians are familiar with varlous therapies 22 involving dihydropyridlne drugs in various pharmaceutioal forms 23 and dosage amounts.

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., . : : ' , 2~75~07 1 Particularly preferred in the combination preparation 2 of this invent1on is nimodipine. Nimodipine is a standard L-3 type 1,4-dihydropyridine.

4 Treatment of stimulant abuse S The synergistic combination of the present invention 6 is effective in treating individuals suffering from psychomotor l stimulant addiction, dependency or abu~e. Psychomotor stimulants 8 are substances or drugs that increase dopamine (3,4-9 dihydroxyphenylethylamine) neurotransmission in the brain by increasing the release of dopamine from neurons or by blocking 11 neuronal uptake of dopamine. Exemplary of psychomotor stimulants 12 are amphetamine (AMP), methamphetamine, cocaine and 13 methylphenidate.
14 The administration to a patient addicted to, dependent 1~ on, or suffering symptoms of withdrawal from , psychomotor 16 stimulants with a dihydropyridine compound that blocks brain L-17 type calcium channels, or a non-toxic salt of this class of 18 compound, concomitantly or consecutivelyj with a neuroleptic or 19 non-toxic salts of these compounds decreases many of the effects of the psychomotor stimulants, including the motor stimulant 21 effects (increase in feelings of energy), euphoric effects of the drugs, and stimulant craving (eg. cocaine craving, ~3 methamphetamine craving) and the elicitation of any conditioned 24 drug-like effects by external and internal stimuli previously associated with drug use in psychomotor stimulant addicts that . ... . . .

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1 contrlbute to the maintenance of addiction. The comblnation drug may he administered prior to, during or after stimulant abuse.
3 The active substances of the combination drugs of this 4 inve~tlon are administered in a therapeutically effective amount, S that is in an amount sufficient to suppress the above described 6 effects of psychomotor stimulants, especially craving. Persons 1 skilled in the art will appreciate that the effective dosage 8 ranges for the calcium channel blocksr and the neuroleptic will 9 vary widely with such factors as the particular drugs, route of administration, time and frequency of administration, and size, 11 sex, age, prior medical history and disease state of the patient.
12 The precise dose to be administered in each particular case will 13 be evident to skilled clinicians from the published literature 14 or can be determined by conventional dose titration techniques.
Without limitation, a dosage range for the neuroleptic is about 16 0.001-100 mg/kg body weight per day, more typically 0.001 - 10 17 mg/kg body weight per day. A dose range for the calcium channel 1~ blocker is 0.0001 - 100.0 mg/kg per day, more typically 0.0001 -19 10 mg/kg per day.
Each of the neuroleptics and the calcium channel 21 blocker~ are administered in the for~ of the drug or a ~2 pharmaceutically acceptable non-toxic salt thereof. The active substances may be formulated as pharmaceutiaal compositions by 24 oombination with approprlate pharmaceutlcally aaceptable, non-toxic carriers or diluents (i.e carriers and diluents which are chemically inert to the drugs and which have not detrimental side ... , ........................ . ~
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, ' ' ~ ; .'.' :' 207~107 l effects or to~lcity under conditions for use). The co~positions may be prepared in solid, semisolid, liquid or gaseous forms such as tablets, capsules, powders, granules, ointments, solutions, 4 suppositories, injections, inhalants, aerosols in usual ways for oral, parenteral or rectal administration. Such formulations may 6 include sustained release formulations. Further information l pertinent to the preparation of pharmaceutical composition may 8 be obtained by reference to standard literature, for instance 9 Remington's Pharmaceutical Sciences, Sixteenth Edition, Mack Publishing Co., Easton, PA (1980).
11 As indicated, the neuroleptic and the calcium channel 12 blocker are administered concomitantly or consecutively. When 13 administered concomitantly, the active substances are generally 1~ in admixture in the same pharmaceutical form. When administered consecutively, the active substances may be formulated in same 16 or different pharmaceutical forms. It should be understood that, 17 if the active substances are administered consecutively, they are 18 administered substantially simultaneously, that is, within a time 19 span so that the synergistic effect is achieved.
Treatment of psychoses 21 The synergistic combination of this invention is 22 effective in treating psychoses in an individual. Psychoses 23 include those associated with schizophrenia, manie depression 24 psychoses, affeetive psyehoses and organic psychoses, lncluding drug induced psychoses. The synergistie oombination allows the 26 use of lower doses of the neuroleptics than would otherwise be :

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' ' , ' , ~ 2075107 l possible, to achieve the same therapeutic effect, thereby decreasing the propensity of patients with psychotic 3 symptomatology to develop unwanted side effects of neuroleptics, 4 such as extrapyramidal motor symptoms and tardive dyskinesia.
The same broad formulation and dosage ranges as set forth for 6 stimulant addiction treatment can be used with an expected l reduction in the dosage of the neuroleptic of about 30 - 70~.
8 The synergistic effect of the neuroleptic - calcium 9 channel blocker of the invention is shown in the examples described below, in which nimodipine is used as exemplary of the 11 dihydropyridine calcium channel blocker and haloperidol is used 12 as exemplary of the neuroleptic. It will be understood that the 13 examples are given for purposes of illustration only, and that 14 the invention is not restricted thereto.

~ EXAMPLES
lh Example 1 17 The purpose of this example is to demonstrate the lB ability of nimodipine (NIM), a dihydropyridine calcium channel 19 blocker, to attenuate the establishment of environment-specific amphetamine-conditioned activity of amphetamine (AMP), when given 21 in conjunction with haloperidol (HAL), a neuroleptic with DA D2 receptor antagonist aotlvity.
Male Sprague-Dawley rat9 (n=12 or 24 for eaoh group), weighing 250 - 350 g with ad libitum access to food and water and maintained on a 12:12 h light cycle (lights on 0700 - 1900) were - , ':

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-~" 2~75107 1 used. Locomotor activity was measured by counting lnterruptions of infra-red photobeams in test box~s described previously 3 (Martin-Iverson and McManus, 1990; DiLullo and Martin-Iverson, 4 1991). (+)-AMP sulfate (SmithKline Beecham Pharma) was dissolved into a 1.5 mg/ml solution. NIM (Dr. Miles Scriabine of Miles Inc.) was dissolved into a 10 mg/kg solution. HAL (McNeil 7 (Haldol)) was diluted into 0.05 and 0.2 mg/kg solutions. The 8 vehicle (VEH) for AMP and HAL was double distilled water and for 9 NIM was polyethylene glycol 400.
The experiment consisted of 2 phases, a drug 11 conditioning phase and a test phase. During the conditioning 1~ phase (lasting 10 conseautive days) all rats received three 13 injections (VEH or NIM, VEH or HAL, and VEH or AMP~ followed by 14 placements into the conditioning box for 60 min. The test day occurred on the fourth day after the last conditioning day 16 injection (i.e. 3 intervening treatment-free days), to allow for 17 drug clearance. On this day, all animals received an injection 18 of VEH prior to placement for 60 min in the conditioning boxes.
19 There were 12 treatment groups with each animal receiving three treatments daily, consisting of NIM (10 mg/kg, 21 sc) or VEH (1 ml/kg, sc) 120 min before placements in the 22 conditioning boxes, HAL (0.05 or 0.2 mg/kg, ip) or VEH (1 ml~kg, 23 ip) 70 min before placements in the conditioning boxes, and AMP
24 (1.5 mg/kg, sc) or VEH (1 ml/kg, sc) 10 min prlor to placements in the conditioning boxes for 10 conseautive days~ The groups were as follows: VEH-VEH-VEH, VEH-VEH-AMP, NIM-VEH-VEH, NIM-VEH-: ' ~
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-` 2~7~1~7 l AMP,VEH-HAL(0.05)-VEH, VEH-HAL(0.05)-AMP, VEH-HAL(0.2)-VEH, VEH-HAL(0.2)-AMP,NIM-HAL(0.05)-VEH,NIM-HAL(0.05)-AMP,NIM-HAL(0.2)-VEH and NIM-HAL(0.2)-AMP. There were 12 animals in each group 4 which received HAL, and 24 in all other groups.
Locomotor activity for each rat during both phases of 6 the experiment was recorded in 5 min blocks and summed to produce l individual daily totals. The means of the individual rat's daily 8 totals were subjected to analysis of variance (ANOVA) with 9 planned comparisons between indivldual groups.
The results of the conditionlng phase of the experiment 11 were subjected to ANOVA with 3 independent factors: (1) NIM
12 pretreatment, consisting of 2 levels (VEH or NIM); (2) HAL
1~ pretreatment, consisting of 3 levels (VEH, 0.05 mgJkg or 0.2 14 mg/kg); and (3) AMP treatment, consisting of 2 levels (VEH or AMP).
1~ Figure 2 shows the effects of 3 daily injections of 17 VEH or NIM (10 mg/kg, s.c.), VEH or one of two doses of HAL
18 (i.p.) and VEH or AMP (s.c.) on mean photobeam interruptions 1~ (unconditioned locomotion) averaged over 10 consecutive days of 60 days of 60 min tests. The asterisk "*" indicates results 21 significantly different from the VEH-VEH-AMP group, p<0.05, 22 Tukey's Test. Figure 2 represents the unconditioned locomotion collapsed across days. AMP signifioantly inareased looomotion 24 depending on the pretreatment. Both low (0.05) and high (0.2 mg/kg) doses of HAL attenuated AMP-induced locomotion (HAL x AMP
26 interaction: F2l8o=18.8, p<0.001). ANOVA revealed a significant .

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2~al~7 1 interaction between NIM and AMP ~ 8o=6.0,p<0.02). Planned compsrisons show that NIM significantly (p<0.05) augmented the 3 decre,ase in locomotion produced by HAL but had no effect when NIM
4 was given without HAL.
The test phase of the experiment was subjected to ANOVA
6 with the same independent factors as in the conditioning phase.
1 A significant co~ditioning effect with AMP was observed (main effect: Fll8o=226.6, p<0.001, see Fig. 2). Figure 3 demonstrates 9 that the same groups of rats as in Figure 2, 4 days after the last drug treatments, were all given a placebo (s.c.) injection 11 and were tested 10 min later in the environment previously paired 12 with drug treatments for 60 min. Conditioned locomotion was 1~ evident in the AMP-treated groups as an increase in photobeam 14 interruptions relative to controls (p<0.001). Previous comhined treatments with NIM and HAL significantly attenuated AMP-16 conditioned locomotion. The asterisk "*" indicates results 17 significantly different from VEH (no NIM) control, p<0.05, 18 Tukey's Test. ANOVA revealed a significant interaction between 19 NIM and AMP (Fll8o2=4.8, p<0.03). Planned comparisons show that neither HAL nor NIM, when given independently influenced locomotion on the test day. AMP-conditioned locomotion was ~2 significantly attenuated with combined HAL and NIM pretreatment (p<0.05). This effect as seen in Figure 3 was not d~pendent on 24 the dose of HAL pretreatment.
The observation that NIM augmented the HAL-produced decrease in direct AMP-induced looomotion indicates that calcium ~... . . . . .
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- 2~7~107 l channel blockers are also useful as an adjunctive therapy with neuroleptics for the treatment of psychoses. This is indicated 3 from the high correlations between the EDsos of drugs for the 4 blockade of AMP~s behavioral effects in rats and the EDso5 for S displacing 3H-haloperidol binding to striatal tissue (Arnt, J.
6 (1982) ActaPharmacol et Toxicol. 51:321-329) which in turn highly l correlates with antipsychotic therapeutic doses (Seeman et al, 8 - 1976, Nature 261: ~17-719). As previously indicated, effective 9 doses of most neuroleptics can cause extrapyramidal side effects, as well as inducing tardive dyskinesia after long-term treatment.
11 The augmentation of HAL's effects by NIM, independent of the dose 1~ of HAL used, indicates that adjunctive treatment of schizophrenia 13 with calcium channel blockers allows clinicians to lower the 14 therapeutically effective dose-range of neuroleptics, thereby decreasing the incidence of extrapyramidal side effects. 3Ed 16 on the results of this example, it is evident that combined 17 therapy with a calcium channel antagonist and a neuroleptic is 18 efficacious for the treatment of stimulant addiction. The 19 observations from this study suggest that concomitant DA and ~Q calcium channel antagonism can attenuate or block both the 21 unconditioned and the conditioned "effects" produced by stimulants.

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-- 2~7~07 l ExamDle 2 This example was conducted to show the effects of 3 nimodipine and haloperidol on the expression of the classical 4 conditioning of cocaine.
Forty eight male Sprague-Dawley rats were given 6 consecutive daily single injections of cocaine hydrochloride (10 l mg/kg, IP) for 10 days prior to placement in the test boxes to 8 produce conditioning of cocaine's effects to the test boxes.
9 After a 3 day wash-out period, rats were placed into the test boxes without an injection of cocaine to test for conditioned 11 locomotion, measured by counting interruptions of infrared 12 photobeams transecting the test boxes. Group means for locomotor 13 activity are presented in Figure 4 as bars, with the linss on the 14 top of each bar representing the standard error of the mean for each group. Four groups were treated differently on the test l day. One group received two vehicle injections (VEH+VEH; one IP
17 and one SC), 70 minutes prior to placement in the test boxes.
18 A second group (VEH+NIM) received one vehicle injection (IP) and 12 one injection of NIM tl0 mg/kg, SC). The third group (HAL+VEH) ~Q received one injection of HAL (0.05 mg/kg, IP) and one injection 21 of VEH (SC). The last group (HALINIM) received two injections, one of each drug at the same doses as in the other groups. The 23 results are shown in Figure 4, wherein the asterisk "*" indicates group means signiflcantly different from the mean of the VEH+VEH
group, as analyzed with analysis of varianae, followed by planned ' ' ~' .

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~ 207~107 l comparisons using the Multiple F-test procedure, with an alpha set at P<0.05.
3 The test day data were analyzed by ANOVA followed by 4 the multiple F test planned comparison procedure. Results of the multi.ple F test are depicted in Figure 4, and indicate that only 6 the group receiving both HAL and NIM exhibited statistically l significant (p<0.05) differences from the group that received 8 only VEH injections on the test day and cocaine injections during 9 training. This finding indicates that the effects of cocaine that have already been conditioned to cues, as is the case with 11 cocaine addicts, are attenuated by a combination of HAL and NIM, 1~ but not by either drug give alone. ~hat is, the combination 1~ treatment blocks the expression of cocaine conditioning.
14 It will be understood that various changes may be made in the specific techniques and compositions described hereinabove 16 without departing from the scope of the invention. Accordingly, 17 the preceding description is intended as illustrative only, the 18 scope of the invention being determined solely by the following 19 claims.

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Claims (23)

1. A pharmaceutical composition, comprising, as active substances:
a) a neuroleptic compound which functions as a dopamine D2 receptor blocker or antagonist, or a non-toxic, pharmaceutically acceptable salt thereof; and b) a dihydropyridine calcium channel blocker, or a non-toxic, pharmaceutically acceptable salt thereof, said active substances being present jointly in an admixture or in similar or different separate pharmaceutical forms for substantially simultaneous administration.

2. The pharmaceutical compositions of claim 1, wherein the calcium channel blocker is a 1,4-dihydropyridine.

3. The pharmaceutical composition of claim 2, wherein the neuroleptic is selected from the group consisting of substituted or unsubstituted phenothiazines, thioxanthenes, dibenzoxazepines, diphenylbutylpiperidines and butyrophenones.

4. The pharmaceutical composition of claim 2, wherein the calcium channel blocker is a 1,4-dihydropyridine and wherein the neuroleptic is a butyrophenone.

5. The pharmaceutical composition of claim 2, wherein the calcium channel blocker is selected from nimodipine, amlodipine, felodipine, isradipine, nicardipine, nitrendipine, nifedipine, nisolipine, Bay K 8644 and nilvadipine.

6. The pharmaceutical composition of claim 5, wherein the neuroleptic is selected from haloperidol and dioperidol.

7. The pharmaceutical composition of claim 6, wherein the calcium channel blocker is nimodipine, and wherein the neuroleptic is haloperidol.

8. The use of a pharmaceutical composition according to claim 1 for treating psychomotor stimulant addiction, dependency or abuse in an individual, the active substances being administered to the individual concomitantly or consecutively in a therapeutically effective amount.

9. The use of claim 8, wherein the stimulant is selected from one or more of amphetamine, methamphetamine, cocaine and methylphenidate.

10. The use of claim 8 wherein the stimulant is one or both of amphetamine and cocaine.

11. The use of claim 8, wherein the calcium channel blocker is a 1,4-dihydropyridine.

12. The use of claim 11, wherein the neuroleptic is selected from the group consisting of substituted or unsubstituted phenothiazines, thioxanthenes, dibenzoxazepines, diphenylbutylpiperidines and butyrophenones.

13. The use of claim 11, wherein the calcium channel blocker is a 1,4-dihydropyridine and wherein the neuroleptic is a butyrophenone.

14. The use of claim 11, wherein the calcium channel blocker is selected from nimodipine, amlodipine, felodipine, isradipine, nicardipine, nitrendipine, nifedipine, nisolipine, Bay K 8644 an nilvadipine.

15. The use of claim 14, wherein the neuroleptic is selected from haloperidol and dioperidol.

16. The use of claim 15, wherein the calcium channel blocker is nimodipine, and wherein the neuroleptic is haloperidol.

17. The use of a pharmaceutical composition according to claim 1 for treating psychoses in an individual, the active substances being administered to the individual concomitantly to consecutively in a therapeutically effective amount, whereby the therapeutically effective amount of the neuroleptic is lowered from the therapeutically effective amount required when the neuroleptic is administered without the calcium channel blocker.

18. The use of claim 17, wherein the calcium channel blocker is a 1,4-dihydropyridine.

19. The use of claim 18, wherein the neuroleptic is selected from the group consisting of substituted or unsubstituted phenothiazines, thioxanthenes, dibenzoxazepines, diphenylbutylpiperidines and butyrophenones.

20. The use of claim 18, wherein the calcium channel blocker is a 1,4-dihydropyridine and wherein the neuroleptic is a butyrophenone.

21. The use of claim 18, wherein the calcium channel blocker is selected from nimodipine, amlodipine, felodipine, isradipine. nicardipine, nitrendipine, nifedipine, nisolipine, Bay K 8644 and nilvadipine.

22. The use of claim 21, wherein the neuroleptic is selected from haloperidol and dioperidol.

23. The use of claim 22, wherein the calcium channel blocker is nimodipine, and wherein the neuroleptic is haloperidol.