Method of treating mania in humans

Mania is treated by administering, to a patient in need thereof, galanthamine or a salt or derivative thereof or a functional equivalent of galanthamine, the functional equivalent being an acetylcholinesterase inhibitor which is active substantially selectively at nicotinic receptor sites.

Mania is a severe affective disorder which almost disables the patient in 
the manic phases and which in most patients recure with individual 
intervals. 
The medication used in practice until now in the treatment of affective 
disorders is, with respect to depression, to augment the noradrenergic 
and/or serotonergic activity in the brain. With respect to mania, the 
rationale behind the medication used in practice until now seems rather to 
be directed against the symptomatic relief of the psychotic behaviour of 
the manic patient in general, rather than against the supposed mechanism 
of the disease. 
Thus, mania is presently treated with, e.g. lithium salts and/or in certain 
cases benzodiazepines or neuroleptics. Lithium is mostly used in the 
prophylaxis of mania but in some cases is also used in the acute treatment 
of mania. The treatment with lithium salts has as the advantage that it 
prevent the outbreaks of the manic phases. However, lithium salts have a 
very slow onset of action, because they pass the blood-brain barrier only 
very slowly (2-4 days; Welner, Joseph et al., Psykiatri, 2nd edition, 
F.A.D.L., Copenhagen, 1985 (textbook)) and is therefore of limited use in 
the acute phases. Also, lithium salts have long term side effects, such as 
nephrotoxicity. Furthermore, the lithium concentration in plasma has to be 
monitored closely to avoid intoxication: lithium is excreted through the 
kidneys, and just a small deviation from the normal lithium clearance 
increases the risk of intoxication; such small deviations can occur in 
connection with slimming diets, in combination with medication with 
diuretics, and in connection with administration of NSAID and ACE 
inhibitors. Also, many patients feel that they are slowed down more than 
wanted both motoric and psychic and it could be due to a mental side 
effect of lithium. Benzodiazepines such as rivotril are not used 
prophylactically, and do not alleviate the basic condition, but only give 
a symptomatic damping of some of the symptoms in mania, such as the motor 
and verbal activity and the voice and noise level. 
Neuroleptics such as haloperidol preparations are also used in the 
treatment of the acute phases of mania but some people are hypersensitive 
to neuroleptics and reveal extrapyrimidal side effects such as symptoms 
like in Parkinson's disease. 
Janowsky D. S., El-Yousef M. K., Davis J. M., et al. A Cholinergic 
adrenergic hypothesis of mania and depression. Lancet 1972:2:6732-6735, 
proposed an adrenergic-cholinergic balance hypothesis of affective 
disorders, depression being a disease of cholinergic predominance, and 
mania being a disease of cholinergic deficiency. Janowsky et al. found 
that physostigmine, a centrally active cholinesterase inhibitor, rapidly 
converted mania to a syndrome consistent with a psychomotor retardation. 
Having received physostigmine, manics became significantly less talkative, 
euphoric, active, cheerful, happy, friendly or grandiose and showed a 
decrease in flight of ideas. Patients also reported that they felt 
drained, being without energy, becoming apathetic and having no thoughts, 
Also, physostigmine has been found to cause a depressed mood in a group of 
euthymic bipolar patients maintained on lithium. Risch S. C. et al. 
(1983): Psychopharmacol. Bull, 19:696-698, have shown that some normals 
become depressed after receiving physostigmine. 
EP 311 303 discloses novel 4-aminopyridine derivatives which are stated to 
be acetylcholinesterase inhibitors and are stated to be active against 
Alzheimer's disease. It is also stated that the derivatives exhibit 
antidepressant activities. 
EP 413 667 discloses halogenalkylphenylalcohols, -ketones and their 
hydrates and states that these compounds show selective central 
acetylcholinesterase inhibiting effect on homogenized rat brain tissue, 
and that, in such experiment, enzyme from various brain regions are 
significantly inhibited, whereas enzyme from peripheral organs is affected 
only to a small degree, and that one of the compounds, in this experiment, 
has a strong inhibiting effect on Cortex, Hippocampus, Striatum, and 
Pons/medulla, whereas enzyme from the heart is not affected. It is stated 
that the compounds are useful as selective acetylcholinesterase 
inhibitors, e.g. for treatment of Alzheimer's disease, Huntingtons chorea, 
tardive Dyskinesia, Hyperkinesia, mania, acute panic reactions, Down's 
syndrome, Myasthenia gravis, Friedrich's ataxia, and pain. 
EP 383 318 discloses novel aralkylamine compounds and discloses that a 
number of the compounds show acetylcholinesterase inhibitor activity in 
homogenated cerebral cortex from Wistar rats. It is stated that the 
compounds are indicated for senile demantia, Alzheimer's disease, 
Huntington's chorea, hyperkinesia and mania. 
EP 412 822 discloses novel 4,4-disubstituted piperidine derivatives which 
have central nervous system activity as shown by inhibition of 
tetrabenazine-induced catalepsy, inhibition of pentylenetetrazole-induced 
seizure, and analgesic effect in mouse writhing tests. The compounds are 
stated to show an antidepressive effect which is higher than that of 
imipramine or nomifensine. The compounds are stated to have 
anticholinergic effect and are suggested for treatment of psychotic 
disorders, such as insomnia, mania, agitation, depression, anxiety, 
emesis, pains, and dementia. 
According to the present invention, it has been found that mania in humans 
can be effectively treated by administration of galanthamine, and that 
galanthamine seems to not only mask the symptoms, but to provide real 
improvement and disappearance of symptoms faster than the usual treatment, 
without the severe side effects and disadvantages associated with the 
above-mentioned lithium, benzodiazepine and neuroleptic treatment which 
are the hitherto used treatments in humans. 
Galanthamine is a well-known acetylcholinesterase inhibitor which is active 
substantially selectively at nicotinic receptor sites and has 
substantially no effect on muscarinic receptor sides, is capable of 
passing the blood-brain barrier in humans, and presents no severe side 
effects in therapeutically necessary dosages. 
Galanthamine and acid addition salts thereof have, for many years, been 
known to have anticholinesterase properties. 
Galanthamine, a tertiary alkaloid, has been isolated form the bulbs of the 
Caucasian snowdrops Galantanus woronowi (Proskurnina, N. F. and Yakoleva, 
A. P. 1952, Alkaloids of Galanthus woronowi. II. Isolation of a new 
alkaloid. (In Russian.) Zh. Obschchei Khim. (J.Gen.Chem.) 22, 1899-1902. 
Chem.abs. 47,6959, 1953. It has also been isolated from the common 
snowdrop Galanthus Nivalis (Boit, 1954). 
Galanthamine has been used extensively as a curare reversal agent in 
anaesthetic practice in Eastern bloc countries (cf. review by Paskow, 
1986) and also experimentally in the West (cf. Bretagne and Valetta, 1965: 
Wislicki, 1967; Conzanitis, 1971). 
Pharmacokinetic studies have recently been made by Thomsen, T. and H. 
Kewitz. (Selective Inhibition of Human Acetylcholinesterase by 
Galanthamine in vitro and in vivo. Life Sciences, Vol 46, pp. 1553-1558 
(1990), and, by the same authors, Galanthamine Hydrobromide in a Long-Term 
Treatment of Alzheimer's Disease. Dementia 1990, 1:46-51). 
The findings according to the present invention seem to be in accordance 
with the above-mentioned 1973 findings by Janowski et al., the only prior 
art reference reporting treatment, in that galanthamine is an 
acetylcholinesterase inhibitor, such as is physostigmine, and thus 
counteracts cholinergic deficiency. On the other hand, physostigmine, used 
by Janowsky, has a profile of properties which is basically different from 
the profile of galanthamine. Thus, physostigmine, contrary to 
galanthamine, has a considerable effect at muscarinic receptor sites, and 
has a very fast onset of activity and a very short half life, of the order 
of minutes and at least less than an hour. 
It is believed that the excellent and suprising effect against mania 
possessed by galanthamine is due to its specific profile of properties, 
the most important of the known ones of which can be summarized as 
follows: 
capability to pass the blood brain barrier in humans, 
a high selectivity for acetylcholinesterase as opposed to 
butyrylcholinesterase (about 50-fold when measured by the in vitro method 
by Thomsen et al., see below), 
a sufficient elimination half life to warrant duration of an effective 
concentration of at least 4 hours, probably at least 6 hours, 
a relatively low toxicity in therapeutical concentrations, 
capability of being effective in doses which are sufficiently low to keep 
peripheral side effects low 
Galanthamine must be considered as being a very desirable drug for the 
treatment according to the invention: The elimination half life of 
galanthamine hydrobromide is over four hours; it shows a practically 
complete renal elimination; its two metabolites, epigalanthamine and 
galanthaminone are both probably inactive. A complete elimination of 
metabolites and galanthamine takes place in 72 hours. Galanthamine has 
been used in Eastern Block countries since around 1958 as an anticurare 
agent in anesthesiology, and a considerably number of patients have been 
treated with galanthamine without any reported case of liver toxicity or 
serious side effects. Galanthamine hydrobromide, being a tertiary amine 
and lipid soluble, is absorbed rapidly from the gut and transverses the 
blood brain barrier easily. The common side effects, other than the ones 
related to cholinergic crisis, are either nausea or vomiting, and a slight 
headache. However, these side effects are rare, especially when care is 
taken to start medication in low doses such as mentioned above. 
With most patients, mania is a recurring disease, starting with hypomanic 
stages developing into mania, but it is difficult even within the same 
patient to predict the onset of a new hypomanic/manic phase or the 
duration thereof. This means that it is of great importance to have a 
drug, like galanthamine, which has an onset of action of as little as a 
few minutes. 
Accordingly, a central aspect of the present invention relates to a method 
for the treatment of mania in humans, comprising administering, to a human 
patient in need thereof, an effective amount of galanthamine. 
The galanthamine can suitably be administered orally in the form of an acid 
addition salt, e.g. the hydrobromide, but other administration forms are 
possible and realistic, such as is described below. 
The effective amount will normally be referred to as a therapeutically 
effective amount, but the invention also comprises the cases where 
treatment is started before the symptoms have fully developed, e.g. 
prophylactically in hypomanic stages. "Prophylaxis" in the classical 
meaning of this term, e.g. such as lithium is administered for 
prophylacting mania, would normally not come into consideration because 
galanthamine and functional equivalents have a fast onset of action. 
Because galanthamine has substantially no effect on the activity at 
muscarinic receptor sites, as apparent from its high selectivity for 
acetylcholinesterase as opposed to butyrylcholinesterase, it will not give 
rise to the often severe side effects on the heart which are associated 
with cholinesterase inhibitors which have a low selectivity for 
acetylcholinesterase as opposed to butyrylcholinesterase. Galanthamine has 
a selectivity for acetylcholinesterase opposed the effect on 
butyrylcholinesterase of 60 to 1. 
The amount of galanthamine is preferably adjusted individually based upon 
observation of the effect of initially very low dosages. There is as 
considerable difference with respect to how sensitive individuals are to 
acetylcholinesterase inhibitors. Thus, the amount of galanthamine is 
suitably adjusted by means of a regimen starting at low dosages, e.g. 1 
mg, preferably at 5 mg, per day, but, if appropriate, even as low as 0.1 
mg per day, if the dosage is well tolerated by the patient within the 
first two hours the dosages is increased to, e.g. 10 mg per dosage dosed 3 
to 4 times per day or in some severe cases to 60 mg or more per day dosed 
over 3 or 4 times. The increase of the dosages is suitably discontinued 
when the dosage of galanthamine 
1) positions the affective mood of the patient in a condition of at the 
most hypomania, that is, a score of at the most 14 on Bech's Mania Scales 
described by Bech et al. Acta Scand. Psych. 1986, suppl. pp 29-31, 
preferably at the most 12, more preferably at the most 10, still more 
preferably at the most 8, and most preferably at the most 5, 
2) augments the quantity and quality of the sleep in the patient (an 
increase in the quality of the sleep is an increase in the proportion of 
REM sleep), 
but 
3) still gives substantially no heart side effects, and 
4) is lower than the amount which will give rise to a cholinergic crisis. 
Because cholinergic crisis, a life-threatening dose-dependant side effect 
of all kinds of acetylcholinesterase inhibitors, should, by all means, be 
avoided, it is recommended to start with the low dosages as mentioned 
above and furthermore not to exceed 150 mg per day and preferably not to 
exceed dosages above 60 mg per day, unless the patient shows a very low 
sensitivity to acetylcholinesterase inhibitor, in which case higher doses, 
such as 200 mg per day, could be used. 
The effect of the galanthamine against the patient's mania is suitably 
measured by scoring the symptoms of the patients in accordance with the 
guidelines in Bech's mania Scales as described in Example 2. Referring to 
that scale, the patient's point score should preferably, where possible, 
be reduced to at the most 14, which is the limit between manic and 
hypomanic stages, more preferably at the most 5 which is the limit between 
hypomanic and normal stages. 
The treatment according to the invention should preferably be continued 
until the manic phase is over. As a measure that the manic phase is over 
can be used the daily and later in the treatment weekly by scoring the 
patients according to Bech's mania Scale. When the patients have reached a 
score below 6, they are kept on galanthamine medication for about another 
two months to be sure that the patient is properly treated. 
As far as is known, galanthamine is the only acetylcholinesterase inhibitor 
with the above-defined profile of properties which has been tested against 
mania in humans. While galanthamine has, indeed, given remarkable results, 
such as appears from the clinical data given in the examples, it is 
justified to presume that other acetylcholinesterase inhibitors which are 
functional equivalents to galanthamine with respect to its combination of 
high selectivity with respect to nicotinic receptor sites and capability 
of passing the blood brain barrier in humans in vivo, will also show a 
useful combination of effect against mania and acceptability in the 
clinic, although it cannot be ruled out that galanthamine, galanthamine 
salts and galanthamine derivatives, due to the special conformation of the 
gelanthamine ring system, have specific properties which are decisive for 
the remarkable effect on mania. 
In accordance with the above, compounds which are functional equivalents of 
galanthamine are defined herein as compounds which 
a) possess an at least 10-fold selectivity, preferably an at least 20-fold 
selectivity, more preferably an at least 40-fold selectivity, and most 
preferably an at least 50-60 fold selectivity, for acetylcholinesterase as 
opposed to butyrylcholinesterase, when measured by the in vitro method by 
Thomsen et al., see below, 
b) are capable of passing the blood brain barrier in humans in vivo. 
A useful drug for the treatment of mania in accordance with the present 
invention has a pharmaceutically acceptable, low toxicity in therapeutical 
concentrations, and is capable of reducing the point score, on Bech's 
Mania Scales (see below), to at the most 14, preferably at the most 5 in a 
randomly selected group of human mania patients in a double blind test, in 
doses which are sufficiently low to keep peripheral side effects 
acceptably low and to avoid cholinergic crisis. 
As will be understood from the above definition, a compound can be 
subjected to well-defined and relatively short-lasting tests (see below) 
to determine whether it fulfills criterion a) above. Then, the likelihood 
whether the compound will pass the blood brain barrier in humans in vivo 
(criterion b)) can be assessed in a model. One such model is a whole rat 
brain model in which rats are given the acetylcholine esterase in vivo and 
are then killed whereupon homogenate of the rat brain is examined with 
respect to the acetylcholinesterase activity; the result is then compared 
to the acetylcholinesterase activity in rat brains not treated with 
acetylcholinesterase inhibitors. Another rat model could be the 
measurement and comparison of acetylcholinesterase activity in 
cerebrospinal fluid in vivo in the same rat before and after treatment. If 
the compound fulfills criterion a), and its likelihood of passing the 
blood brain barrier has been established in one of the above-described rat 
brain models, it will be a candidate drug. An initial determination of 
toxicity is necessary in cases before any effect in humans can be 
assessed; such initial determination of toxicity can be performed by 
pharmacologic tests in a manner known per se. After the pharmacological 
tests, the capability of the candidate drug of passing the blood brain 
barrier in humans in vivo can be determined by the method described below. 
If the candidate drug has been found to possess this capability, it can be 
passed to the mania testing proper. Optionally, the candidate drug can be 
subjected to additional short-lasting tests, such as the in vivo 
selectivity test described by Thomsen et al., and a test to determine 
whether it increases cortisol level in humans. Both of these tests give 
further indication of whether the candidate drug has a spectrum of 
properties equivalent to galanthamine with respect to what must be 
presumed to be essential properties. Peripheral side effects will be 
assessable when the effect is tested clinically, which is acceptable from 
an experimental and ethical point of view, provided the toxicity has first 
been assessed by the above-mentioned pharmacological tests. With respect 
to the final assessment of the candidate drug's effect on mania, it is 
evident that a rational and efficient design of the assessment will 
involve an initial test on one or a few patients and, provided the initial 
test is positive, the above-mentioned conclusive double blind test. 
Because of the well-defined and brief character of all of the tests, and 
especially the well-defined in vitro character of the initial screening, 
the test series for identifying useful functional equivalents of 
galanthamine is a reasonable an not burdensome routine which is within the 
realm of the person skilled in the art. 
Functional equivalents and derivatives of galanthamine which are useful in 
the method of the invention will be employed in the same manner as stated 
herein for galanthamine. Whenever quantities of such a functional 
equivalent or derivative are referred to herein, the quantities are given 
as the equipotent quantity of galanthamine hydrobromide with respect to 
inhibition of acetylcholinesterase, that is, as the quantity of 
galanthamine hydrobromide which result in the same inhibition of 
acetylcholine esterase in the above-mentioned in vitro test according to 
Thomsen et al as does the functional derivative or derivative. 
The selectivity of the acetylcholinesterase inhibitor for 
acetylcholinesterase as opposed to butyrylcholinesterase can be determined 
by in vitro and in vivo tests as described by Thomsen and Kewitz in the 
above mentioned paper Selective Inhibition of Human Acetylcholinesterase 
by Galanthamine in vitro and in vivo, Life Sciences, Vol 46, pp. 1553-1558 
(1990), and T. Thomsen, H. Kewitz and O. Pleul, J. Clin. Chem. Clin. 
Biochem. 26 469-475 (1988). This in vivo test is the one referred to above 
in connection with criterion a). Thus, with reference to this 
determination method, a preferred acetylcholinesterase inhibitor is one 
which in the in vitro method described has an at least 10-fold selectivity 
for acetylcholinesterase as opposed to butyrylcholinesterase, such as an 
at least 20-fold selectivity for acetylcholinesterase as opposed to 
butyrylcholinesterase, e.g. an at least 40-fold selectivity for 
acetylcholinesterase as opposed to butyrycholinesterase. For galanthamine, 
these authors found a 50-fold to 60-fold selectivity for 
acetylcholinesterase as opposed to butyrylcholinesterase. 
The capability to pass the blood brain barrier in vivo in humans can be 
assessed by either by a test which could be called "Auditory brain stem 
response" or by a test which is based on the measurement of CRH, ACTH and 
cortisol. The rationale behind these tests, and the way they are 
performed, is explained in the following: 
The auditory brain stem response test is based on the observation that 
manio-depressive patients are hypersensitive to cholinergic influences, 
one manifestation hereof being hypersensitivity to auditory signals as 
assessed by the increase of amplitude of auditory evoked potentials in the 
nuclei of the auditory system in the brain stem, i.e. on the "brain side" 
of the blood brain barrier. This hypersensitivity manifests itself in a 
lower amplitude than in normal humans when the person is not treated with 
a cholinergic agent such as acetylcholinesterase inhibitor; and a very 
significantly increase of the amplitude when the person has received a 
cholinergic agent, provided, of course, that the cholinergic agent is able 
to pass the blood brain barrier and thus enter the nuclei of the auditory 
system in the brain stem. See also example 3. 
The other test based on the measurement of CRH (corticotropic-hormone 
releasing hormone released from the hypothalamus in the brain, and which 
releases both ACTH from the adenohypophysis and cortisol from the adrenal 
medulla) and ACTH (corticotropic hormone, which releases cortisol from the 
adrenal medulla) is carried out by measuring the CRH, ACTH and cortisol 
concentration in the blood in healthy persons before and after medication 
with acetylcholinesterase. If the concentration of all three hormone are 
increased after medication or at least CRH and cortisol are increased it 
is proven that the acetylcholinesterase has effect in the central nervous 
system, and since it is an in vivo experiment it is further proven that 
the acetylcholinesterase has passed the blood brain barrier. 
As mentioned above, the selectivity of the acetylcholinesterase inhibitor 
can, as an additional characterization, optionally be expressed with 
reference to the in vivo determinations performed by Thomsen and Kewitz on 
galanthamine and described in the above-mentioned paper Selective 
Inhibition of Human Acetylcholinesterase by Galanthamine in vitro and in 
vivo, Life Sciences, Vol 46, pp. 1553-1558 (1990). With reference to this 
determination, a preferred acetylcholinesterase inhibitor is one which, 
upon adminisration in an amount of 10 mg to a healthy adult, results in 
inhibition of at least 40% of the acetylcholinesterase activity in 
erythrocytes from the adult within about 2-5 minutes and no substantial 
inhibition of butyrylcholinesterase therein, such as an 
acetylcholinesterase inhibitor which, when administered in an amount of 10 
mg to a healthy adult, results in inhibition of at least 50% of the 
acetylcholinesterase activity in erythrocytes from the adult within about 
2-5 minutes. For galanthamine, Thomsen and Kewitz found 65% inhibition of 
acetylcholinesterase in the erythrocytes within 2 minutes after 
administration of 10 mg of galanthamine i.v. in a healthy volunteer, 
whereas no inhibition of butyrycholinesterase in plasma was seen. 
Compounds which are contemplated to be valuable functional equivalents of 
galanthamine and useful in the treatment according to the invention are 
the galanthamine derivatives having the formula I (formula I also 
represent galanthamine itself) 
##STR1## 
wherein R.sup.1 and R.sup.2 which may be the same or different each 
represents a hydrogen atom or an acyl group, such as a lower alkanoyl 
group, e.g. an acetyl group or a straight-chained or branched alkyl group, 
e.g. methyl, ethyl, propyl, or isopropyl; R.sup.3 is a straight or 
branched chain alkyl, alkenyl or alkaryl group which is optionally 
substituted by a halogen atom or a cycloalkyl, hydroxy, alkoxy, nitro, 
amino, aminoalkyl, acylamino, heteroaryl, heteroaryl-alkyl, aroyl, 
aroylakyl or cyano group; and R.sup.4 represents a hydrogen or halogen 
atom attached to at least one of the ring carbons of the tetracyclic 
skeleton, and salts thereof, such as a hydrobromide, hydrochloride, 
methylsulfate or methiodide. 
In the compounds of formula I, alkyl moieties preferably contain 1 to 8 
carbon atoms, halogen atoms are preferably fluorine, chlorine, or bromine, 
especially fluorine or chlorine, aryl moieties are preferably phenyl, 
cycloalkyl groups are preferably 3- to 7-membered rings, especially 
cyclopropyl or cyclobutyl, and heteroaryl moieties are preferably 5- to 
8-membered rings, e.g., thienyl, furyl, pyridyl, pyrrolyl, or pyrizanyl. 
Among the compounds of the formula I are those described in EP-A-236684. 
The compounds of formula I may be prepared according to conventional 
techniques, including those described in EP-A-236684. 
Other compounds which are contemplated to be valuable functional 
equivalents useful in the method of the invention are galanthamine 
derivatives of the general formula II 
##STR2## 
wherein the broken line represents an optionally present double bond in 
one or the two of the positions shown, R.sub.1 and R.sub.2 are each 
selected independently from the group consisting of hydrogen, hydroxyl, 
amino or alkylamino, cyano, sulfhydryl, alkoxy of 1-6 carbon atoms, 
alkylthic, aryloxy, arylthio, R.sub.5 -substituted aryloxy, R.sub.5 
-substituted arylthio, aralkoxy, an aliphatic or aryl carbamyl group 
wherein the aliphatic or aryl moiety may be R.sub.5 substituted or 
unsubstituted, aralkylthio, R.sub.5 -substituted aralkoxy, R.sub.5 
-substituted aralkylthio, aryloxymethyl, R.sub.5 -substituted 
aryloxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, benzoyloxy, 
R.sub.5 -substituted benzoyloxy, aryloxycarbonyl and R.sub.5 -substituted 
aryloxycarbonyl, R.sub.1 may also be alkyl of up to 14 carbon atoms, or 
hydroxymethyl, R.sub.2 may also be carboxymethyl, provided that at least 
one of R.sub.1 and R.sub.2 is hydroxy, amino or alkylamino unless R.sub.8 
is hydroxymethyl, 
R.sub.3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, 
cycloalkylmethyl, phenyl, R.sub.5 -substituted phenyl, alkylphenyl, 
R.sub.5 -substituted alkylphenyl, heterocyclyl selected from .alpha.- or 
.beta.-furyl, .alpha.- or .beta.-thienyl, thenyl, pyridyl, pyrazinyl, and 
pyrimidyl, alkyl-heterocyclyl or R'-substituted heterocyclyl, where R' is 
alkyl or alkoxy, 
each R.sub.4 is independently selected from hydrogen, hydroxyl, sulfhydryl, 
alkyl, aryl, aralkyl, alkoxy, mercaptoalkyl, aryloxy, thiaryloxy, 
alkaryloxy, mercaptoalkaryl, nitro, amino, N-alkylamino, N-arylamino, 
N-alkarylamino, fluoro, chloro, bromo, iodo, and trifluoromethyl, 
R.sub.5 is selected from the same groups as R.sub.4, 
R.sub.6 is hydrogen, halo, trifluoromethyl or alkyl of 1 to 4 carbon atoms, 
R.sub.8 is hydrogen or hydroxymethyl, 
R.sub.9 is hydrogen or alkyl of 1 to 6 carbon atoms, or when R.sub.2 is 
hydroxyl, R.sub.9 may be a moiety of formula I wherein R.sub.9 is hydrogen 
and R.sub.2 is a linking bond; or 
R.sub.2 and R.sub.9 may jointly form semicarbazone, 
X is oxygen or NR.sub.5, 
Y is nitrogen or phosphorus, 
and methylenedioxy derivatives thereof with the proviso that when X is o, 
R.sub.3 is not methyl when R.sub.1 is methoxy, R.sub.2 is hydroxy, and all 
R.sub.4 are hydrogen, 
or a pharmaceutically acceptable acid addition salt thereof. 
Examples of subclasses and specific compounds of the formula II are given 
in WO 88/08708, which also discloses methods for preparing the compounds 
II. 
Galanthamine, galanthamine derivatives and galanthamine functional 
equivalents, when suited therefor, may be administered orally at a dosage 
of e.g. 5-150 mg per day, such as 10-60 mg per day, e.g. 10-50 mg, such as 
10-40 mg, per day, the dosage being adapted to the patient and the 
patient's response. As mentioned above, the treatment should often be 
started with a low dosage and then increased until the suitable dosage has 
been established. The dosage of galanthamine functional equivalents is 
expressed as the equipotent amount of galanthamine hydrobromide, the 
reference basis being the capability of inhibiting acetylcholinesterase in 
the Thomsen et al. in vitro test mentioned above. 
For the oral administration, galanthamine or a galanthamine salt or 
derivative or a functional equivalent may be formulated, for example, as 
an aqueous suspension or a solution in aqueous ethanol or as a solid 
composition such as a tablet or capsule. Suspensions or solutions for oral 
administration are typically of a concentration of 1-50 mg/ml, more 
commonly 5-40 mg/ml, for example, 10-40 mg/ml, typically 20-30 mg/ml of 
galanthamine. Divided doses in the range 0.1-3 mg/kg body weight per day 
may prove useful. Typically, one might administer a dosage of 20-100 mg 
per day to a patient of a body weight of 40-100 kg, although in 
appropriate cases such dosages may prove useful for patients having a body 
weight outside this range. In other cases, dosages as low as 10 mg and as 
high as 200 mg may be appropriate for persons in this body weight range. 
Galanthamine and its acid addition salts form crystals. They are generally 
only sparingly soluble in water at room temperature; therefore, injectable 
compositions are normally in the form of an aqueous suspension. If 
necessary, pharmaceutically-acceptable suspension aids may be employed. 
Typically, such a suspension will be employed at a concentration of 0.1-30 
mg/ml, more commonly 1-30 mg/ml, for example, 5-30 mg/ml, such as 10-30 
mg/ml of galanthamine. As mentioned above, typical dosage rates when 
administering galanthamine by injection are the range 0.01-20 mg per day 
depending upon the patient. For example, divided doses in the range 0.5-5 
mg/kg body weight per day may prove useful. Typically, one might 
administer a dosage of 5-50, mg per day to a patient of a body weight of 
40-100 kg, although in appropriate cases such dosages may prove useful for 
patients having a body weight outside this range. In other cases, dosages 
as low as 5 mg and as high as 200 mg per day may be appropriate for 
persons in this body weight range. 
Galanthamine and its pharmaceutically acceptable acid addition salts, and 
its derivatives and functional equivalents, when suited therefor, may be 
administered by subcutaneous, intravenous or intramuscular injection. 
The parenteral dosage rate of galanthamine can also be expressed by 
reference to the body weight of the patient; in this case, a normal dosage 
rate will often be 0.1 to 4 mg/kg body weight. Depot compositions will 
often deliver a dosage rate of 0.01 to 5.0 mg/kg per day. 
In preparing tablets or capsules, standard tablet or capsule-making 
techniques may be employed. If desired, a pharmaceutically acceptable 
carrier such as starch or lactose may be used in preparing galanthamine or 
galanthamine equivalent tablets. Capsules may be prepared using soft 
gelatine as the encapsulating agent. If desired, such capsules may be in 
the form of sustained release capsules wherein the main capsule contains 
microcapsules of galanthamine or functional equivalents thereof which 
release the contents over a period of several hours thereby maintaining a 
constant level of galanthamine or its functional equivalent in the 
patient's blood. 
The following specific formulations may find use in the treatment of mania: 
Tablets or capsules containing 0.1, 1, 2, 5, 10 and 25 mg galantahamine 
hydrobromide or functional equivalent to be taken four times a day, or a 
sustained-release preparation delivering an equivalent daily dose. 
Liquid formulation for oral administration available in 5 mg/ml and 25 
mg/ml concentration. 
Other interesting administration forms of galanthamine and functional 
equivalents are suppositories, a slow-release plaster, and other depot 
compositions. 
All of the above-mentioned administration forms are prepared in manners 
known per se. 
Although galanthamine must be considered as having a high degree of safety, 
there have been certain side effects in a few of the patients treated. 
These have been slight nausea in about 30% of the cases (the nausea, 
however, disappearing after about one week of treatment), vomiting and 
dizziness in 5-10% of the patients (also disappearing after about one week 
of treatment in most cases), and more severe side effects in 4-6% of the 
patients. These more severe side effects must be considered acceptable in 
view of the effect of the drug; however, in patients who are suspected of 
developing arrhythmia, it should be considered to administer, e.g., 
atropin in combination with the treatment according to the invention.

EXAMPLE 1 
Formulation of tablets containing galanthamine 
______________________________________ 
Composition of 1 tablet containing 1 mg galanthamine 
______________________________________ 
Galanthamine hydrobromide 
0.001 g 
Calcium phosphate 0.032 g 
Lactose 0.005 g 
Wheat Starch 0.0056 g 
Microcrystalline Cellulose 
0.015 g 
Talc 0.0007 g 
Magnesium Stearate 0.0007 g 
______________________________________ 
______________________________________ 
Composition of 1 tablet containing 5 mg galanthamine 
______________________________________ 
Galanthamine hydrobromide 
0.005 g 
Calcium phosphate 0.024 g 
Lactose 0.004 g 
Wheat Starch 0.004 g 
Microcrystalline Cellulose 
0.04 g 
Talc 0.002 g 
Magnesium Stearate 0.001 g 
______________________________________ 
______________________________________ 
Composition of 1 tablet containing 10 mg galanthamine 
______________________________________ 
Galanthamine hydrobromide 
0.010 g 
Lactose 0.040 g 
Wheat Starch 0.0234 g 
Microcrystalline Cellulose 
0.0374 g 
Talc 0.0036 g 
Magnesium Stearate 0.0012 g 
Gelatin 0.0044 g 
______________________________________ 
Preparation 
All the tablets are prepared according to routine tabletting procedures. 
EXAMPLE 2 
Clinical trials of the effect of galanthamine on manic patients 
Methods and materials 
Drug 
Nivalin tablets containing 5 mg galanthamine, obtained from Waldheim Ltd., 
Vienna, Austria, were used in this example. 
Patients 
5 persons suffering from mania with a score above 5 on the Bech's Mania 
Scale for whom the symptoms could not be ascribed to any disease of 
organic origin. 
Bech's Mania Scale 
To evaluate the stage of mania in the patient to be treated Bech's Mania 
Scale was used. 
All cases were evaluated before, under and after Nivalin treatment. 
Bech's Mania Scale consists of 11 items: 
1. Activity (motor), score from 
0 (normal activity) up to 
4 (constantly active, restlessly energetic. Even if urged the patient 
cannot sit still). 
2. Activity (verbal), score from 
0 (normal verbal activity) up to 
4 (impossible to interrupt, dominates completely the conversation). 
3. Flights of thoughts, score from 
0 (no flight of thoughts) up to 
4 (it is difficult to impossible to follow the patient's line of thoughts 
as the patient constantly jumps from one topic to another). 
4. Voice/Noise level, score from 
0 (natural volume of voice) up to 
4 (shouting, screaming, or using other sources of noise due to hoarseness). 
5. Hostility/Destructiveness, score from 
0 (no signs of impatience or hostility) up to 
4 (overt physical violence, physically destructive). 
6. Mood (feeling of well-being), score from 
0 (neutral mood) up to 
4 (extremely elevated mood, quite irrelevant to situation). 
7. Self-Esteem, score from 
0 (normal self-esteem) up to 
4 (grandiose ideas which cannot be corrected). 
8. Contact (intrusiveness), score from 
0 (normal contact) up to 
4 (extremely dominating and manipulating without context with the setting). 
9. Sleep (average of last 3 nights), score from 
0 (habitual duration of sleep) up to 
4 (no sleep). 
10. Sexual interest, score from 
0 (normal sexual interest and activity) up to 
4 (completely and inadequately occupied by sexuality). 
11. Work, 
A: At first rating of the patient, score from 
0 (normal work activity, up to 
4 (the patient is or ought to be hospitalized and unable to participate in 
ward activities). 
b: At weekly ratings, score from 
0 (the patient has resumed work at his/hers normal activity level, up to 
4 (the patient is still fully hospitalized and generally unable to 
participate in ward activities). 
The criteria for mania scored in the Bech's Mania Scale are: 
A total scale score of 0-5 means that the patient is not manic. 
A total scale score of 6-14 means that the patient is hypomanic. 
A total scale score of 15 or more means that the patient is definitely 
suffering from mania. 
Laboratory tests 
Blood samples from all patients were examined before the start of the 
treatment with respect to: 
Haemoglobin concentration (Hgl) 
White cell count (WCc) 
Differentiated white cell count (DWCc) 
Mean corpuscular volume (MCV) 
Mean corpuscular haemoglobin concentration (MCHC) 
Packed red cells volume per 100 ml blood (PCV) 
Platelets 
ERS 
Electrolytes (N.sup.a +, K.sup.+, Cl.sup.-, Ca.sup.++, Phos.sup.++) 
Liver tests (bilirubin, ALT (alaninamino transaminase), AST (aspartatamino 
transaminase), and GOT (glutamine-oxaloacetic transaminase) 
Se-glucose 
Se-oreatine 
Thyroidstimulating hormone (TSH) 
Thyroida hormones (T3 and T4) 
These tests were performed before the treatment to exclude patients with 
mania-like symptoms caused by a disease of organic origin from the 
treatment with galanthamine and were also performed during the treatment 
in order to document any alterations of the parameters during the 
treatment with Nivalin. 
Other measurements 
Blood pressure and ECG were measured before the start of the treatment and 
regularly during the treatment. 
Results 
With respect to the blood measurements and the blood pressure and ECG, no 
observable changes in the results were found during the treatment. 
The following case examples are demonstrative of the effects of Nivalin on 
manic symptoms. 
Case No. 1: 
HO, a 74 year old woman with a bipolar affective disorder for over 30 
years. She was hospitalized from 1988 six times. For the last year she was 
hospitalized three times with initially depression that evolved in three 
months to mania. The mania was at least of degree II according to Carlson 
et al. 1973. She was given T. Haldol and evolved a malignant neuroleptic 
syndrome in the spring 1990. (with a total white cell count over 
28.00.times.10 9/1, temperature over 40 C, muscle rigidity, elevated 
Creatine kinase.) 
With the cessation of the neuroleptic drug she recovered and became 
euthymic for a short while and them became depressive again. Later that 
year, 1990, when she evolved into a manic state again the only possible 
medication was a benzodiazepine in high doses. She became heavily sedated 
without a diminution of her manic symptoms. She had to be guarded day and 
night and there was also the danger of this frail woman to break her leg 
as she became very unsteady on her feet. 
Her manic symptoms lasted usually about three months and at the time of 
this case her mania had lasted about three weeks and was steadily 
increasing, at that time definitely manic with 29 points on the Bech's 
Mania Score. It was decided to give her T. Nivalin 5 mg initially in the 
morning. She tolerated well the first 5 mg and was given T. Nivalin 5 
mg.times.2 in the afternoon. An hour after she had taken 10 mg of T. 
Nivalin her behaviors had markedly changed to everybody's surprise. The 
next day she had 14 points on the scale, i.e. slightly hypomanic. 
The biggest change was in activity (motor and verbal), and flight of 
thoughts. Her sleep improved slightly. But what was remarked mostly was 
her change in concentration. She was able to look at TV and read. Also she 
managed an hour long game of chess, which, incidentally, she won. But she 
had not been able to perform a sustained activity of any sort for days. 
Two days later the Nivalin treatment was stopped and she practically 
immediately became psychotic again. 
Once started on Nivalin treatment 30 mg per day she became visibly more 
manageable and resumed a more normal behaviour although according to the 
nurses slightly hypomanic. This was repeated once again with the same 
result. It was decided that she should continue on T. Nivalin 30 mg a day 
and the benzodiazepine treatment was stopped. 
HO continued on T. Nivalin 5 mg.times.3 for three months; then the 
medication was stopped and she could manage her affairs at home. A month 
later she developed her usual depressive episode and was then hospitalized 
in a depressive mood. 
Case No. 2: 
HAS a 47 year old woman who had been hospitalized seven time since 1984. 
She was mostly hospitalized when she was in a manic state but could stay 
at her home while depressed which always preceded her mania. She had taken 
an overdose of lithium just prior to her stay at the hospital and was in a 
lithium intoxicated state with nystagmus and ataxia. 
It was considered that she would not tolerate neuroleptic medication and 
was put on T. Nivalin 5 mg 2.times.3 a day. She stayed in the hospital for 
a month and left practically euthymic. On the Mania Scale she dropped from 
initially 24 to 10 points in two days. Her activity and flight of ideas 
normalized the most. She was also clearly more able to concentrate and 
sustain a commenced activity than before the medication. 
Case No. 3: 
SA a 33 year old woman which had been hospitalized fourteen time since 1982 
with the diagnosis bipolar affective disorder. Last winter she had been 
hospitalized because of a heavy depression. And in the spring she left 
hospital slightly hypomanic and stayed that way most of the last summer. 
Last December she was hospitalized with state III mania or with the 
maximal score on the Mania Scale which is 44 points. She was considered 
very sensitive to neuroleptic medication and developed always very soon 
extrapyramidal signs that took weeks to disappear after medication. 
She was consequently very hostile to the usual medication in her manic 
state. She was given T. Nivalin 5 mg 2.times.3, and the next day she was 
slightly hypomanic with 11 points on the Mania Scale. This was considered 
as a dramatic reduction in her manic symptoms, especially by her husband 
that knew her well, and it was decided to try to treat her at home 
especially that she had developed a very hostile attitude towards the 
hospital and its staff and to hospitalize her would have demanded a legal 
step to be taken, which her husband was against. She went to her home and 
stayed there for over a month always slightly hypomanic. She started to 
neglect her medication and was later hospitalized with her will. She was 
given a more conventional therapy and left the hospital two months later 
slightly hypomanic but on lithium and a weak neuroleptic. 
The initial effect was without doubt no psychomotor retardation nor anergy, 
but a substantial alleviation of her manic symptoms. 
Case No. 4: 
BS a 42 year old male that had been hospitalized since 1981 over fourteen 
times. He had received the diagnosis bipolar affective disorder, but also 
schizoaffective disorder. He was constantly on some neuroleptic 
medication. In his last hospitalization he did develop some simile of a 
manic episode and was put on T. Nivalin 5 mg 2.times.3 or 30 mg a day. His 
behaviour normalized quickly and he became visibly quite euthymic. He had 
been rated with 17 points on the mania scale and became within normal 
range as mentioned. He told the nurses that he was afraid that Nivalin 
made him too normal and that his social assistance would therefore be 
withdrawn. He was somewhat reluctant to continue the medication when he 
left hospital. 
Case No. 5: 
KS six times hospitalized since 1988 because of bipolar affective disorder. 
From February to May 1990 he had been hospitalized because of depression. 
In the spring he developed a hypomanic state that lasted practically all 
summer 1990. He refused to be hospitalized and in November 1990 was he by 
police forced to be internalized then in a highly manic state and a 
constant embarrassment to his environment. He was given T. Haldol and T. 
Rivotril and developed rapidly extrapyramidal signs, a Morbus 
Parkinsonlike mimic and stance even with low doses of the neuroleptic and 
accompanied with T. Artane (benzhexol). Then the neuroleptic was totally 
withdrawn and he was given 30 mg of T. Nivalin a day. He maintained that 
T. Nivalin made him a little bit depressive and empty in the head. The 
manic symptoms were manageable. He told the nurses later that the energy 
and augmented depression disappeared later although he continued on the 
Nivalin treatment. And he felt that the Nivalin treatment improved his 
memory which he had felt were failing him. 
Conclusion 
The above-mentioned five cases are all chronically ill patients with 
advanced affective disorder. The cases show the value of the treatment of 
galanthamine in manic patients. 
EXAMPLE 3 
Auditory brain stem response 
Methods 
Electrical potentials caused by click-stimulation in the ears are measured 
with electrodes positioned outside on the head of the examined parson. In 
the configuration of the potentials are components from the brain stem and 
the brain. 
Persons 
A patient suffering from bipolar manio-depression in the depressive state 
and a healthy person, respectively. 
Drug 
Tablet containing 10 mg galanthamine 
BRIEF DESCRIPTION OF THE FIGURES 
Results are shown in FIGS. 1A, 1B, 2A and 2B and show the potentials from a 
depressive patient and a healthy person, both treated and untreated. 
FIGS. 1A, and 2A show that in the depressed patient, the auditory brain 
stem response without treatment has a much smaller, almost half, amplitude 
of the potential compared to the amplitude of the untreated healthy 
person. 
Furthermore, FIGS. 1A and 1B show a dramatically increase of the amplitude 
in the treated depressive patient compared to untreated persons. 
Also, from FIGS. 2A and 2B it is seen that the potentials do not change 
from the untreated person to the treated person. 
CONCLUSION. 
From the results in the depressed person it is seen that the potentials 
change after treatment with galanthamine, such as explained above. This 
means that galanthamine must be able to cross the blood-brain barrier, 
since it is possible to inhibit in synapsis in the brain stem, which is 
positioned on the "brain side" of the blood-brain barrier. 
LEGENDS TO FIGURES 
FIG. 1A shows the auditory evoked response of a depressed patient (a manio 
depressed patient in the depressed state) without treatment with 
galanthamine. 
FIG. 1B shows the auditory evoked response of a depressed patient (the same 
as in FIG. 1A) 2 hours after treatment with 10 mg of galanthamine. 
FIG. 2A shows the auditory evoked response of a healthy person without 
treatment with galanthamine. 
FIG. 2B shows the auditory evoked response of a healthy person (the same as 
in FIG. 2A) 2 hours after treatment with 10 mg of galanthamine.