WO1991018592A1

WO1991018592A1 - Pharmaceutical composition containing a lithium salt and an l-phenyl isopropylamine derivative for increasing the life expectancy

Info

Publication number: WO1991018592A1
Application number: PCT/GB1991/000832
Authority: WO
Inventors: Merton Sandler; Alec Coppen
Original assignee: Britannia Pharmaceuticals Ltd
Current assignee: Britannia Pharmaceuticals Ltd
Priority date: 1990-05-25
Filing date: 1991-05-24
Publication date: 1991-12-12
Anticipated expiration: 1992-11-25
Also published as: GB9011767D0; GB2249724A; GB9111314D0

Abstract

A method for increasing the life expectancy of a human, or animal subject, comprising administering lithium in a pharmaceutically acceptable form to the subject, preferably in combination with a pharmaceutically acceptable form of an L-phenyl isopropylamine derivative of formula (I), in which R1? is an alkyl group having 1 to 5 carbon atoms, R2? is a propyl, propenyl or propynyl group which may be substituted by a hydrogen group or a halogen atom or, if R3? or R4? is not hydrogen, R2? can be hydrogen, and R3? and R4? are each hydrogen, halogen or a nitro, amino or diazonium group, or a pharmaceutically acceptable acid addition salt thereof.

Description

PHARMACEUTICAL COMPOSITION CONTAINING A LITHIUM SALT AND A L-PHENYL ISOPROPYLAMINE DERIVATIVE FOR INCREASING THE LIFE EXPECTANCY

DESCRIPTION

The present invention relates to pharmaceutical compositions. In particular, the present invention relates to chemical compounds and compositions for use in increasing the life-span (expectancy), or reducing the mortality rate of human beings or other animals. The present invention also relates to methods of increasing human or animal life-spans (expectancy) or reducing their mortality, involving the use of such compounds or compositions.

Certain phenyl isopropylamine derivatives are known to inhibit the activity of the enzyme monoamine oxidase B (MAO-B), which is a major catabolic enzyme for dopamine in the brain. These compounds include the L or (-) enantiomers of the general formula I:

in which R₁ is an alkyl group having 1 to 5 carbon atoms, R₂ is a propyl, propenyl, propynyl group which may be substituted by a hydroxy group or a halogen atom or, if R₃ or R₄ is not hydrogen, R₂ can be hydrogen, and R₃ and R₄ are each hydrogen, halogen or a nitro, amino or diazonium group and their pharmaceutically

acceptable acid addition salts, such as their

hydrochlorides. Of these compounds, the most widely studied are (-) N-(1-phenyl isopropyl)-N-methyl-N-propinyl amine and its hydrochloride, more commonly known as selegiline or L-deprenyl. L-deprenyl is available from Britannia Pharmaceuticals Limited under the Trade Mark ELDEPRYL.

The compounds of formula I, including L-deprenyl, are disclosed in British Patent No. 1153578 and

European Patent No. 0099302, together with various methods of preparing the compounds. The MAO inhibitory effect of these compounds is also described in British Patent No. 1153578 and the selective inhibitory activity against MAO-B of L-deprenyl is discussed in Knoll, J., Magyar, K (1972).

L-deprenyl was first shown to be effective in

Parkinson's disease by Birkmayer et al. in J. Neural

Transm., 36, 303-326 (1975) as an adjuvant treatment for L-dopa-peripheral decarboxylase inhibitor therapy (for reviews, see Sandier M. and Stern G.M., 1982; Yahr and Kaufmann, 1989). In a subsequent evaluation of the aforementioned early results of their treatment of Parkinson's disease, Birkmayer et al (1985) found evidence that those sufferers who received L-deprenyl in addition to L-dopa, during dopamine replacement therapy, exhibited an increased life expectancy. In a subsequent study carried out in aged male rats. Knoll and his co-workers (Knoll, 1988; Knoll et al 1989) found that chronic L-deprenyl treatment significantly prolonged the rats' life-spans. It has been surmised that this effect results from an action which causes increased amounts of dopamine to be present at receptor level, and which slows age-related deterioration in the rat nigrostriatal system. Two studies involving the use of L-deprenyl alone in Parkinson's disease have recently been published

(Tetrud and Langston, 1989; The Parkinson's Study group, 1989). In both the time required before

it was necessary to institute L-dopa therapy was shown to be significantly increased in those groups of Parkinsonians treated from an early stage with

L-deprenyl, compared to those suffers who received no early treatment. These data have been interpreted to suggest that L-deprenyl protects nigral neurones and, thus, slows the progression of the disease. Whether it does so merely by increasing nigral dopamine

concentrations, through inhibiting the action of MAO-B (dopamine is mainly metabolized in the human brain by MAO-B; See Glover et al, 1977), or whether some more subtle mechanism, such as preventing the conversion of an exogenous MPTP-like protoxin to its neurotoxic

MPP⁺-like derivative is involved (see Sandier and Glover), has yet to be decided. MPTP(1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine) has been shown to cause Parkinsonism in young drug abusers and its action is known to be blocked by MAO inhibitors, including L-deprenyl. MAO-B mediates in the conversion of MPTP to MPP⁺(1-methyl-4-phenylpyridinium ion), its putative toxic metabolite. It is well established that lithium, usually

administered in the form of lithium carbonate, is very effective in the acute treatment of mania. It is also well established that lithium is effective in

preventing relapses of bipolar illness (manic

depressive illness), and recurrent depression (see

Coppen and Abou-Saleh, (1988)). It is not certain how lithium functions in relieving these conditions.

However, it is known that lithium affects the levels of the neurotransmitter 5-hydroxytryptamine, which is thought to be present in abnormal amounts in subjects with mood disorders, such as mania and depression.

It is well documented that the mortality rate amongst subjects with mood disorders is increased compared to that of the general population, mostly as a result of an increased rate of suicide. For example, Guze & Robins (1970) have shown from an extensive review of 17 investigations into mortality in depression, that some 15% of depressed patients could expect to die from suicide. In a more recent work Lee & Murray (1988) discovered, from a study covering 18 years, that in addition to a very high on-going morbidity, depressed patients suffer from an increased mortality rate. They found a Standardized Mortality Ratio of 1.9 (p <0.01) in the studied group and that 45% of deaths were due to suicide. In three further recent studies it has been reported that amongst populations of depressed patients 55%, 21% and 17% of the recorded deaths amongst depressed patients over periods of between 15 and 25 years, were due to suicide. See Lehmann et al, (1988); Kiloh et al (1988) and; Angst J. et al (1989).

Although this excess mortality has previously been related, at least in part, to other causes, there is recent evidence that most excess mortality in

depression is due to suicide; See Black et al., (1987) and Eastwood et al., (1982). None of the patients in the aforementioned studies were treated with lithium on a long term basis or with any other prophylactic medication. It is an object of the present invention to provide methods and compositions for increasing human or animal life-spans or expectancies; so that by using, or by being subjected to the present invention, members of a normal human or animal population can enjoy a life expectancy in excess of the present average human or species life expectancy.

According to a first aspect of the present invention there is provided a method of increasing the life expectancy of a human, or animal subject comprising administering lithium in a pharmaceutically acceptable form to the subject. Preferably, this method further includes the simultaneous, separate or sequential adminstration to the subject of a pharmaceutically acceptable form of a compound in accordance with formula I. Most preferably, the administration of lithium or the compound according to formula I is carried out on a regular basis.

In a second aspect, the present invention provides lithium in a pharmaceutically acceptable form, for use in a method of increasing the life expectancy of a human or animal subject. Preferably, the lithium is included in a combined preparation with a

pharmaceutically acceptable form of a compound in accordance with formula I for simultaneous, separate or sequential use in a method of increasing the life expectancy of a human or animal subject.

In a third aspect, the present invention provides a combined preparation of a pharmaceutically acceptable form of lithium and a pharmaceutically acceptable form of a compound in accordance with formula I for

simultaneous, separate or sequential use. Preferably the combined preparation is for use in a method of increasing the life expectancy of a human or animal subject.

In a fourth aspect, the present invention provides a pharmaceutical pack comprising a pharmaceutically acceptable form of lithium together with a

pharmaceutically acceptable form of a compound in accordance with formula I . In a fifth aspect, the present invention provides the use of lithium, or a pharmaceutically acceptable form of lithium for the manufacture of a medicament for use in a method of increasing the life expectancy of a human or an animal subject. Preferably, the lithium, or pharmaceutically acceptable form of lithium, is used together with a compound in accordance with formula I, or a pharmaceutically acceptable form thereof. In all the aforementioned aspects of the present invention, the preferred compound of formula I is L-deprenyl or its hydrochloride and the preferred form of lithium is a lithium salt, most preferably lithium carbonate. In preferred forms of the present

invention, the active ingredient or ingredients

(including the lithium or compound according to formula I) are admixed with suitable pharmaceutical carriers or excipients, such as lubricating and filling agents, and provided in the form of tablets, coated pills, pills, suppositories, capsules, solutions, powder mixtures, emulsions or injectable solutions. These compositions can be suitable for oral or parenteral administration. Preferably, in carrying out the method of the invention compounds, compositions or preparations in accordance with the invention are taken, regularly and over a prolonged period (of at least 1 year's duration and preferably over a substantial period of the subject's life span) of time by the human or animal subjects.

In a most preferred form of the present invention a daily dose of between five and fifteen milligrams of L-deprenyl is provided to a human subject and the lithium is used at a rate to provide a twelve hour blood plasma level of about 0.6 mmol/1; which may be achieved by the administration to a human subject of lithium carbonate at a rate of 800-400 mg per day.

The following examples are provided in order to illustrate the invention.

Example 1

Between 1 and 3 ELDEPRYL^R tablets (5mg selegiline per tablet) and between 2 and 4 PRIADEL^R (available from Delandale Laboratories Ltd. Canterbury, Kent, United Kingdom) tablets (200mg lithium carbonate per tablet) are administered per day, to a human subject. The exact dose of PIRADEL is selected to give a lithium blood plasma level of about 0.6mmol/l. The regime should be continued indefinitely or until any adverse effects are noted by the responsible physician.

Optionally, the PIRADEL can be administered alone, at a dose rate determined in order to provide the

aformentioned blood plasma level. The ELDEPRYL and PIRADEL may be self-administered by the subject and the subject's health should be monitored by a competent physician, in order to ensure that appropriate blood plasma levels are maintained and that no adverse side effects are caused.

Example 2

The tablet core ingredients set out in the following table are weighed separately in amounts required to prepare 5000 tablets. The L-deprenyl hydrochloride and the lithium carbonate are admixed with the lactose and the polyvidone is dissolved in warm ethanol. The resulting mixture of active agents and lactose is homogenized with the polyvidone solution and the magnesium stearate, and the resulting composition is dried and then granulated. The starch is added to the granulate, which is then pressed, using conventional tablet pressing equipment, into tablet cores weighing 400 milligrams each.

The coating suspension is prepared by homogenizing the coating components set out below, in amounts required to coat 5000 tablets, and dissolving the resulting mixture in isopropanol. The coating is applied to the tablet cores by spraying and then the tablets are dried in an air stream at an elevated temperature. The coated tablets are then polished with a 1:1 mixture of isopropanol and water, containing 10% of carbowax to provide finished tablets having an average weight of 450 mg which, thereafter, may be packed in a

conventional manner or as set out below in Example 3.

Tablet Core

L-deprenyl hydrochloride 5.0 mg

Lithium carbonate 200 mg

Lactose 138 mg Starch 25 mg

Polyvidone 25 mg

Magnesium Stearate 7 mg

Total 400 mg

Coating

Luviscol VA64 13 mg

Talc 10 mg

Titanium dioxide 20 mg

Carbowax 6000 7 mg

Total 50 mg

The tablets prepared in the manner set out above should be administered at a dose level determined in a similar manner to that set out in Example 1 and under

supervision, also in the manner set out in Example 1.

The ratio of active ingredients used may be varied from those set out above, as may be their absolute amounts, to provide a range of tablets having different

strengths, so that a supervising physician may select an appropriately formulated tablet for a particular subject.

Example 3

A packaged pharmaceutical of the type to which the present invention relates, can take the form of a conventional blister pack, formed from plastic resin material and shaped to provided an array of

compartments, each of an appropriate size and shape to accommodate a single tablet. In one version, the compartments are shaped so as to accommodate,

individually, ELDEPRYL and PRIADEL tablets. The ratio of ELDEPRYL compartments to PRIADEL compartments can be varied between the limits set out for these drugs in Example 1. Once loaded with tablets, the tablets should be sealed in place with aluminium foil, in the conventional manner.

Preferably, the aluminium foil is printed with

instructions intended for the subject, directing him or her to take the tablets in an order, combination and frequency, suitable to that subject. Clearly, the aluminium foil can be printed in any one of a plurality of different standard forms, directing different orders, combinations and frequencies of doses.

Similarly, tablets manufactured in accordance with the instructions in Example 2 can be accommodated in a foil covered blister pack carrying instructions concerning the frequency at which the tablets should be

administered. In other embodiments, the lithium carbonate and/or L-deprenyl hydrochloride can be accommodated in a sustained release formulation, possibly suitable for subcutaneous insertion and including sufficient active ingredients to maintain the required blood plasma level over a long period of time.

Trial

A trial involving the regular administration of lithium carbonate to 104 patients suffering from depressive illness was carried out over a 10 year period. The patients treated were all bipolar or suffered from recurrent depressive disorders (having had at least three attacks of depression). The patients were seen regularly at intervals of between 6 and 8 weeks. All the patients received lithium in the form of lithium carbonate sustained release tablets (available as

Priadel from Delandale of Canterbury, Kent in the United Kingdom). The lithium was administered once daily at night at the optimum dosage required to produce a twelve hour plasma level of about 0.5-0.6 mmol/l. The lithium concentration in plasma was regularly measured and the compliance rate was found to be very high. The patients' clinical state was systematically assessed at each visit.

The cumulative mortality of the patients studied, at the end of the study period, is shown in Table I under the heading of "observed deaths". The figures for the "expected deaths" are derived from the age-sex-year specific rates for the general population of England and Wales, obtained from the National Health Service Central Register of the Office of Population Censuses and Surveys. From these data, the number of "expected deaths" (for a 'normal' population) was estimated, by means of the programme "Person/Years" and "Exact", and 95% confidence levels for the standardized mortality ratio were obtained, using the relation between the Poisson and chi-square distributions (See Coleman et al 1986 and Liddell 1984). As can be seen from Table I, the total number of expected deaths for a normal population of 104 (having the same age

distribution as the studied population) over the study period was 22.24; whereas the number of deaths in the studied population was only 10. The standardized mortality ratio for the combined group of males and females was 0.45 (95% confidence limits 0.22-0.83;

p-0.0006 two tailed). A decreased Standardized

Mortality Ratio was observed in both men and women.

The striking and surprising result of this trial is that the mortality rate amongst the depressed patients being treated with lithium was reduced to a figure significantly below that which would have been expected for a similar normal population, not suffering from any form of depression. The reduction was due, in part, to the absence of suicide in the studied population, which is probably the result of the marked reduction in morbidity that occurs when lithium is administered to depressed patients (See Coppen et al 1988). However, this effect cannot explain the totally unexpected reduction in mortality below that which would have been expected in a normal population. The various features and aspects of this invention, which are set out in the foregoing and in the following claims, may be combined at will, to provide additional embodiments or aspects of the invention, which may not be set out in the foregoing description or the

following claims but which, nevertheless, are

considered to be within the scope of the invention and to be disclosed hereby.

REFERENCES

Birkmayer, W., Riederer, P., Youdim, M.B.H. Linauer, W. (1975). The

potentiation of the anti-kinetic effect after L-dopa treatment by an inhibitor of HAO-B, deprenyl. J. Neural Transm., 36, 303-326.

Birkmayer, W., Knoll, J., Riederer, P., Youdim, M.B., Hars, V., Marton, J.

(1985). Increased life expectancy resulting from addition of L-deprenyl to Madopar treatment in Parkinson's disease: a long-term study. J. Neural Transm., 64, 113-127.

Glover, V., Sandier, M., Owen, F., Riley, G.J. (1977). Dopamine is a monoamine oxidase B substrate in man. Nature, Lond., 265, 80-81.

Knoll, J. (1988). The striatal dopamine dependency of life span in male rats. Longevity study with (-)deprenyl. Mech. Ageing Devel., 46,

237-262.

Knoll, J., Dallo, J. and Yen, T.T. (1989). Striatal dopamine, sexual activity and lifespan. Longevity of rats treated with (-)deprenyl.

Life Sci., 45, 525-531.

Knoll, J., Magyar, K. (1972). Some puzzling pharmacological effects of monoamine oxidase inhibitors. In: Advances in Biochemical

Psychopharmacology, Vol.5. (Eds. E. Costa and M. Sandier), Raven Press, New York, pp.393-408.

Sandier, M. and Glover, V. (1989). Monoamine oxidase inhibitors in

Parkinson's disease. In: Drugs for the Treatment of Parkinson's Disease, (Ed. D.B. Calne), Vol.88, Handbook of Experimental Pharmacology,

Springer, Berlin, pp.411-431.

Sandier, M., Stern, G.M. (1982). Deprenyl in Parkinson's disease. In: Neurology 2. Movement Disorders. Eds. CD. Marsden, S. Fahn.

Butterworth Scientific, London, pp.166-173.

Tetrud, J.W. and Langston, J.W. (1989). The effect of deprenyl

(selegiline) on the natural history of Parkinson's disease. Science, 245, 519-522.

The Parkinson Study Group (1989). Effect of deprenyl on the progression of disability in early Parkinson's disease. New Eng/.J.Med., 321,

1364-1371.

Yahr, M.D. and Kaufman, H. (1989). Clinical action of L-deprenyl in

Parkinson's disease. In: Drugs for the Treatment of Parkinson's

Disease. (Ed. D.B. Calne), Springer, Berlin, pp.433-441. Coppen A, Abou-Saleh MT. Lithium therapy: from clinical trials to practical management. Acta Psychiatr Scand 1988; 78: 754-762.

Guze SB, Robins E. Suicide and primary affective

disorders. Br J Psychiatry 1970;117:437-8.

Lee AS, Murray RM. The long-term outcome of

Maudsley depressives. Br J Psychiatry 1988;

153 : 741 - 751.

Lehmann HE, Fenton FR, Deutsch M, Feldman S,

Engelsmann F. An 11 -year follow-up study of 110

depressed patients. Acta Psychiatr Scand 1988;78:57-65

Kiloh LG, Andrews G, Neilson M. The long-term outcome of depressive illness. Br J Psychiatry 1988;153 :752-7.

Angst J, Stassen HH, Huber G, Gross G, Stone MH.

Suicides in affective and schizoaffective, schisophrenic and borderline disorders. In: A Marnerous, M T Tsuang ed.

Affective and schizoaffective disorders: similarities and differences. Springer Verlag: Berlin, 1989 in print.

Black DW, Winokur G, Nasrallah A. Is death from natural causes still excessive in psychiatric patients? J Nervous and Mental Disease 1987;175:674-680.

Eastwood MR, Stiasny S, Meier HMR, Woogh CM.

Mental illness and mortality. Comprehensive Psychiatry.

1982;23 :377-385.

Coleman M, Douglas A, Hermon C, Peto J. Cohort study analysis with a Fortran program. Int J Epidemiol 1986;

15: 134-7.

Liddell FDK. Simple exact analysis of the standardized mortality ratio. J Epidemiol. Community Health 1984; 38:85-8.

Claims

1. A method for increasing the life expectancy of a human, or animal subject, comprising administering lithium in a pharmaceutically acceptable form to the subject.

2. A method as claimed in claim 1 further

including the simultaneous, separate or sequential administration to the subject of a pharmaceutically acceptable form of a L-phenyl isopropyleunine derivative of formula I:

in which R₁ is an alkyl group having 1 to 5 carbon atoms, R₂ is a propyl, propenyl or propynyl group which may be substituted by a hydrogen group or a halogen atom or, if R₃ or R₄ is not hydrogen, R₂ can be

hydrogen, and R₃ and R₄ are each hydrogen, halogen or a nitro, amino or diazonium group, or a pharmaceutically acceptable acid addition salt thereof.

3. A method as claimed in either claim 1 or claim 2, wherein the lithium and/or the L-phenyl isopropylamine derivative is administered to the subject at a regular rate.

4. A method as claimed in claim 2, or 3, wherein the L-phenyl isopropylamine derivative is L-deprenyl or its hydrochloride.

5. A method as claimed in any of the preceding claims, wherein the lithium is administered in the form of a pharmaceutically acceptable salt, preferably as lithium carbonate.

6. A method as claimed in any of the preceding claims, wherein the lithium and/or compound of formula I is administered at regular intervals over a prolonged period of time, preferably of at least one year's duration.

7. A method as claimed in any of claims 2-6, wherein L-deprenyl is administered to a human subject at a daily dose of between 5 and 50 milligrams.

8. A method as claimed in any of the preceding claims, wherein the lithium is administered at a rate which provides a blood plasma level of about 0.6mmol/l.

9. A method as claimed in claim 8, wherein lithium carbonate is administered to a human subject at a rate of 400-800mg per day.

10. A composition comprising lithium in a

pharmaceutically acceptable form, for use in a method of increasing the life expectemcy of a human or animal subject.

11. A composition as claimed in claim 10 further comprising a pharmaceutically acceptable form of an L-phenyl isopropylamine derivative of the general formula I:

in which R₁ is an alkyl group having 1 to 5 carbon atoms, R₂ is a propyl, propenyl or propynyl group which may be substituted by a hydroxy group or a halogen atom or, if R₃ or R₄ is not hydrogen, R₂ can be hydrogen, and R₃ and R₄ are each hydrogen, halogen or a nitro, amino or diazonium group, or a pharmaceutically acceptable salt thereof.

12. A composition as claimed in either claim 10 or 11, wherein the lithium is in the form of a lithium salt, preferably lithium carbonate.

13. A composition as claimed in any of claims 11-12, wherein the L-phenyl isopropylamine derivative is L-deprenyl or its hydrochloride.

14. A composition as claimed in either claim 12 or claim 13 further comprising acceptable pharmaceutical carriers or excipients, such as lubricating and filling agents.

15. A composition as claimed in claim 14 in the form of a tablet, coated pill, pill; suppository, capsule, solution, powder mixture, emulsion or

injectable solution.

16. A packaged pharmaceutical for use in a method of increasing the life expectancy of a human or animal subject, comprising a pharmaceutically acceptable form of lithium together with a pharmaceutically acceptable form of an L-phenyl isopropylamine derivative of the general formula I:

in which R₁ is an alkyl group having 1 to 5 carbon atoms, R₂ is a propyl, propenyl or propynyl group which may be substituted by a hydroxy group or a halogen atom or, if R₃ or R₄ is not hydrogen, R₂ can be hydrogen, and R₃ and R₄ are each hydrogen, halogen or a nitro, amino or diazonium group, or a pharmaceutically acceptable acid addition salt thereof, arranged for simultaneous, separate or sequential use.

17. A packaged pharmaceutical as claimed in claim 16, wherein the lithium is in the form of a lithium salt, preferably lithium carbonate and the L-phenyl isopropylamine derivative is L-deprenyl or its

hydrochloride.

18. A packaged pharmaceutical as claimed in claim 16, wherein the lithium salt and the L-deprenyl or its hydrochloride are each admixed with suitable

pharmaceutical carriers or excipients, such a

lubricating and filling agents.

19. A packaged pharmaceutical as claimed in claim 18, wherein, the lithium salt and L-deprenyl fire each present in the form of tablets, coated pills, pills, suppositories, capsules, solutions, powder mixtures, emulsions or injectable solutions.

20. A packaged pharmaceutical as claimed in claim 18, wherein the L-deprenyl is arranged to be

administered to a human subject in a daily dose of between 5 and 15 milligrams and the lithium is arranged to be administered at a rate sufficient to provide a twelve hour blood plasma level of about 0.6mmol/l.

21. The use of lithium, or a pharmaceutically acceptable form of lithium, for the manufacture of a composition for use in a method as claimed in any of claims 1-9.

22. The use of lithium, or a pharmaceutically acceptable form of lithium, and/or a L-phenyl

isopropylamine derivative of formula I, or a

pharmaceutically acceptable salt thereof, for the manufacture of a composition as claimed in any of claims 10-15 or a packaged pharmaceutical as claimed in any of claims 16-20.