Note: Descriptions are shown in the official language in which they were submitted.
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A SYNERGISTIC PHARMACEUTICAL COMBINATION COMPRISING CICLETANINE FOR THE
PREVENTION OR TREATMENT OF DIABETES
The invention refers to a synergistic pharmaceutical
combination suitable for the prevention or treatment of a
prediabetic state, metabolic X-syndrome or diabetes mellitus
as well as disorders which are associated with the states listed
above, namely endogenic metabolic disorders, insulin
resistance, dislipidemia, alopecia, diffuse effluvium, polycystic
ovary syndrome and/or other diabetic complications.
In the industrially developed countries more and more
human being suffers from diabetes. The frequency of the
disease is growing especially rapidly in the population above
50 of age. For example, the development of type 2 diabetes
(i.e. non-insulin-dependent diabetes mellitus, NIDDM) is
promoted by the defects in both the production and use of
insulin. Genetic and environmental factors equally contribute to
the formation of this wide-spread serious disease accompanied
by significant mortality. The patient treated with insulin or
another antidiabetic or anti-hyperlipidemic agent obtains, as a
matter of fact, only a palliative treatment that improves the life
quality, however, the complications which accompany the
diabetes appear unavoidably. A significant part of the
antidiabetic agents only enhances the production of insulin in
the organism.
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The aim of the invention is to provide a pharmaceutical
combination which is suitable for the prevention of the
development of diabetes or at least the complications that
accompany diabetes, or, if such prevention is not possible
anymore, for the efficient treatment of said complications.
It has been found that cicletanine [chemical name (~)-3-(4-
chlorophenyl)-1,3-dihydro-6-methylfuro-[3,4.-c]pyridin-7-of], a
known active agent having blood pressure lowering activity [US
Patent No. 4,383,998 ], exerts an insulin sensitizing effect. For
example, in cases when insulin is produced by the organism in
a decreased amount, this available amount becomes sufficient
to bring about the required physiological effect in the presence
of cicletanine. Also in patients suffering from insulin resistance,
the administration of cycletanine enhances the sensitivity of
insulin. Consequently, a lower dosage of insulin or an
antidiabetic or anti-hyperlipidemic active agent administered to
the patient is sufficient to produce the therapeutical efFect.
Thus, a first object of the invention is to provide a
synergistic pharmaceutical combination suitable for the
prevention or treatment of a prediabetic state, metabolic X-
syndrome or diabetes mellitus as well as disorders which are
associated with the states listed above, namely endogenic
metabolic disorders, insulin resistance, dislipidemia, alopecia,
diffuse effluvium, polycystic ovary syndrome and/or other
diabetic complications.
A second object of the invention is to provide the use of
cicletanine for the preparation of a pharmaceutical composition
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having insulin sensitising effect.
A third object of the invention is to provide a method for
treating a patient suffering from or threatened by a prediabetic
state, metabolic X-syndrome or diabetes mellitus as well as
disorders which are associated with the states listed above,
namely endogenic metabolic disorders, insulin resistance,
dislipidemia, alopecia, diffuse effluvium, polycystic ovary
syndrome and/or other diabetic complications with cicletanine.
The synergistic pharmaceutical combination of the invention
comprises
(a) a first pharmaceutical composition containing"cicletanine
or a pharmaceutically suitable acid addition salt thereof and
one or more conventional carrier(s), and
(b) a second pharmaceutical composition containing an
antidiabetic or anti-hyperlipidemic active agent or, if desired
and chemically possible, a pharmaceutically suitable acid
addition salt or a salt formed with a pharmaceutically suitable
base thereof and one or more conventional carrier(s).
Definition of expressions used in the description and claims
A pharmaceutical combination is an association of two
pharmaceutically active agents in which
- either each of the active agents has been converted, one by
one, to separate pharmaceutical compositions using one or
more conventional carriers) and any of the usual processes of
drug manufacture, and in this case the two sorts of
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pharmaceutical composition obtained are administered fio the
patient simulfianeously or one after the other following an
interval; or
- the two active agents have been converfied to one single
pharmaceutical composition that can be administered to the
patient being in need fihereof. In the latter case, the
pharmaceutical composition may contain a mixiure of the two
active agents, or each of the active agents may be present at a
different site in the pharmaceutical composition, e.g. one of
them in the tablet core and the other in a coating of the tablet
core. Of course, one or more conventional carriers) and any of
the usual processes of drug manufacture are used to prepare
this single pharmaceutical composition.
Under an antidiabetic active agent (b~) any of the
pharmacologically active agents conventionally used in the
therapy for the treatment of diabetes is meant. These are
mainly the following:
- insulin,
- insulin sensitizing active agents,
- active agents that enhance the production of insulin,
- sulfonamides,
- biguanidine derivatives and
- a-glucosidase inhibitors.
As insulin, in the first place, human insulin prepared by
recombinant technology is employed, which is administered, in
general, parenterally.
The insulin sensitizing active agents enhance the effect of
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insulin. The most important sorts of them are the PP~R
(peroxisome proliferator-activated receptor) y-agonists, for
example the thiazolidinedione derivatives such as pioglitazone
[(~)-5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-
5 thiazolidinedione], troglitazone [(~)-5-[[4-[(3,4-dihydro-6-
hydroxy-2,5,7,3-tetramethyl-2H-1-benzopyran-2-yl)methoxy]-
phenyl]methyl]-2,4-thiazolidinedione], ciglitazone [5-[[4-[(1-
methylcyclohexyl)methoxy]phenyl]methyl]-2,4-thiazolidine-
dione, rosiglitazone [(~)-5-[4-[2-[N-methyl-N-(2-pyridyl)amino]-
ethoxy]benzyl]-2,4-thiazolidinedione] and other 2,4-
thiazolidinedione derivatives as well as pharmaceutically
suitable acid addition salts thereof.
The active agents that enhance the production of insulin
are, for example, as follows: mitiglinide [(ocS,3aR,7aS)-
octahydro-y-oxo-a-(phenylmethyl)-2H-isoindole-2-butanoic
acid), repaglinide [(S)-2-ethoxy-4-[2-[[3-methyl-1-[2-(1-
piperidinyl)phenyl]butyl]amino]-2-oxoethyl]benzoic acid],
senaglinide (i.e. nateglinide) [N-[[(trans-4-(1-methylethyl)-
cyclohexyl]carbonyl]-D-phenylalanine] or pharmaceutically
suitable acid addition salts or pharmaceutically suitable salts
thereof.
Out of the sulfonamides, the most important ones are the
sulfonylurea derivatives e.g. tolbutamide [N-[(butylamino)-
carbonyl]-4-methylbenzenesulfonamide], chlorpropamide [4-
chloro-N-[(propylamino)carbonyl]benzenesulfonamide],
fiolazamide [N-[[(hexahydro-1 H-azepin-1-yl)amino]carbonyl]-4-
methylbenzenesulfonamide], acetohexamide [4-acetyl-N-
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[(cyclohexyfamino)carbonyl]benzenesulfonamide] etca as first
generation sulfonylureas or, for example, glyburide
(glibenclamide) [5-chloro-N-[2-[4-[[[(cyclohexylamino)carbonyl]_
amino]sulfonyl]phenyl)ethyl]-2-methoxybenzamide], glipizide
[N-[2-[4-[[[(cyclohexyl-amino)carbonyl]amino]sulfonyl]phenyl]-
ethyl]-5-methylpyrazine-carboxamide], gliclazide [N-[[(hexa-
hydrocyclopenta[c]pyrrol-2(1 H)-yl)amino]carbonyl]-4-methyl-
- benzenesulfonamide], glimepiride [traps-3-ethyl-2,5-dihydro-4-
methyl-N-[2-[4-[[[[(4-methylcyclohexyl)amino]carbonyl]amino]-
sulfonyl]phenyl]ethyl]-2-oxo-1 H-pyrrole-1-carboxamide],
gfiquidone [N-[(cyclohexyl-amino)carbonyl]-4-[2-(3,4-dihydro-7-
methoxy-4,4-dimethyl-1,3-dioxo-2(1 H)-isoquinolinyl)ethyl]-
benzenesulfonamide], glibornuride [N-[[(3-hydroxy-4,7,7-
trimethylbicyclo[2.2.1]hept-2-yl)amino]carbonyl]-4-methyl-
benzenesulfonamide], glisoxepid [N-[2-[4-[[[[(hexahydro-1 H-
azepin-1-yl)amino]carbonyl]amino]-sulfonyl]phenyl]ethyl]-5-
methyl-3-isoxazolecarboxamide], glisentide [N-[2-[4-[[[(cyclo-
pentylamino)-carbonyl]amino]sulfonyl]phenyl]-ethyl]-2-
methoxybenzamide], glisolamide [N-[2-[4[[[(cyclohexyl-
amino)carbonyl]amino]-sulfonyl]phenyl]ethyl]-5-methyl-3-
isoxazolecarboxamide], glybuzole [N-[5-(1,1-dimethylethyl)-
1,3,4-thiadiazol-2-yl]benzenesulfonamide], glyclopyramide [4-
chloro-N-[(1-pyrrolidinylamino)carbonyl]benzenesulfonamide]
etc. as second generation sulfonylureas and pharmaceutically
suitable acid addition salts thereof.
The most important biguanidine derivatives can be
characterized by the formula
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~1 ~3
2 ~~ ~~ \ ~
I~ N H ~l H (~
wherein
R~, R2, R3 and R4 represent, independently, a hydrogen atom,
a C~_~o alkyl group, a naphthyl group, a phenyl group or a
phenyl(C~_4 alkyl) group, wherein in both former cases the
phenyl group is optionally substituted by 1-3 substituents
which can be, independently, a halo atom, a C~_4 alkyl group
or a C~_4 alkoxy group,
with the proviso that one of R~, R2, R3 and R4 is other than a
hydrogen atom, or
R~ and R2 together with the adjacent nitrogen atom and/or R3
and R4 together with the adjacent nitrogen atom form a 5-
or 6-membered, saturated, unsaturated or aromatic ring that
can be fused with a further 5- or 6-membered saturated,
unsaturated or aromatic ring optionally containing also a
nitrogen atom,
and pharmaceutically suitable acid addition salts thereof.
Especially preferred biguanidine derivatives are metformin
[N,N-dimethylimidocarbonimidic diamide], buformin [N-
butylimidodicarbonimidic diamide] and phenformin [N-(2-
phenylethyl)imidodicarbonimidic diamide].
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The ~:-glucosidase inhibitors inhibit the enzyme a-
glucosidase. Important representants thereof are, for example,
miglitol [1,5-dideoxy-1,5-[(2-hydroxyethyl)imino]-D-glucitol],
acarbose [O-4.,6-dideoxy-4-[[[1 S-(1 a,4cc,5(3,6a,)]-4,5,6-
trihydroxy-(3-hydroxymethyl)-2-cyclohexen-1-yl]amino]-a,-D-
g1 ucopyranosyl-( 1-~4)-O-a.-D-glucopyranosyl-( 1-~4.)-D-
glucose], voglibose [3,4-dideoxy-4-[[2-hydroxy-1-
(hydroxymethyl)ethyl]amino]-2-C-(hydroxymethyl)-D-epiinositol]
etc.
Under an anti-hyperlipidemic active agent (b2) any of the
pharmacologically active agents conventionally used in the
therapy for the treatment of high blood-lipid level is meant.
These are compounds that can be classified mainly as follows:
aryloxyalkanoic acid derivatives,
HMG coenzyme reductase inhibitors,
nicotinic acid derivatives,
antacids for bile acids.
Out of the aryloxyalkanoic acid derivatives, preferred active
agents are e.g. clofibrate [2-(4-chlorophenoxy)-2-methyl=
propanoic acid ethyl ester], gemfibrozil [5-(2,5-dimethyl-
phenoxy)-2,2-dimethylpentanoic acid], sirnfibrate [2-(4-chloro-
phenoxy)-2-methylpropanoic acid 1,3-propanediyl ester],
etofibrate [3-pyridinecarboxylic acid 2-[2-(4-chlorophenoxy)-2-
methyl-1-oxopropoxy]ethyl ester], ciprofibrate [2-[4-(2,2-
dichlorocyclopropyl)phenoxy]-2-methylpropanoic acid],
ronifibrate [3-pyridinecarboxylic acid 3-[2-(4-chlorophenoxy)-2-
methyl-1-oxopropoxy]propyl ester] etc.
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Out of the HMG coenzyme reductase inhibitors, the most
important active agents are the following: lovastatin [[1 S-
[1a(R''),3a,7~,8[i(2S*,4S~'),8a[i]]-2-methylbutanoic acid
1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4.-
hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl ester],
fluvastatin [[R*,S*-(E)]-(~)-7-[3-(4.-fluorophenyl)-1-(1-methyl-
ethyl)-1 H-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid],
pravastatin [[1 S-[1 a(aS*,8S*),2a,6a,8~(R*),8aa]]-1,2,6,7,8,8a-
hexahydro-[i,b,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-
1-naphthaleneheptanoic acid monosodium salt], simvastatin
[[1 S-[1 a,3a,7[i,8[i(2S*,4S*),8a[i]]-2,2-dimethylbutanoic acid
1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-
hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl ester],
atorvastatin [[R-(R*,R*)]-2-(4-fluorophenyl)-[3,8-dihydroxy-5-(1-
methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1 H-pyrrole-1-
heptanoic acid] etc.
Out of the nicotinic acid derivatives, for example, the
following ones are used: acipimox [5-methylpyrazinecarboxylic
acid 4-oxide], niceritrol [3-pyridinecarboxylic acid 2,2-bis[[(3-
pyridinylcarbonyl)oxy]methyl]-1,3-propanediyl ester], nicomol
[3-pyridinecarboxylic acid (2-hydroxy-1,3-cyclohexane-
diylidene)-tetrakis(methylene) ester], nicoclonate [3-pyridine-
carboxylic acid 1-(4-chlorophenyl)-2-methylpropyl ester] etc.
Out of the antacids that bind the bile acids, important ones
are the following: colestipol [a basic anion exchange resin: N-
(2-aminoethyl)-N'-[2-[(2-aminoethyl)amino]-ethyl]-1,2-ethane-
diamine polymer with (chloromethyl)oxirane], cholestyramine [a
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synthetic, strongly basic anion exchange resin containing
quaternary ammonium functional groups which are attached to
a styrene-divinylben~ene copolymer], polidexide [an anion
exchange resin containing quaternary ammonium groups
5 which bind the bile acids in the intestine] etc.
The antidiabefic and anti-hyperlipidemic active agents are
known from the literature. If desired and chemically possible,
these active agents can be used in the form of the
pharmaceutically suitable acid addition salts thereof or in the
10 form of the salts formed with pharmaceutically suitable bases.
Under a pharmaceutically suitable acid addition salt, an acid
addition salt formed with a pharmaceutically suitable inorganic
acid such as hydrogen chloride or sulfuric acid and the like, or
with a pharmaceutically suitable organic acid such as acetic
acid, fumaric acid, lactic acid and the like is meant.
When the antidiabetic or anti-hyperlipidemic active agent
has a chemical structure that can form a salt with a base, also
the salt of the active agent formed with a pharmaceutically
suitable inorganic or organic base can be used. When said
active agent can form an acid addition salt with an acid, a
pharmaceutically suitable acid addition salt of the active agent
can be employed, too.
In formula I, the C~_4 alkyl group can ~be a methyl, ethyl, n-
propyl, isopropyl, n-butyl, sec,-butyl, tert.-butyl, or isobutyl
group. The C~_~o alkyl group may be, in addition to the ones
listed above, for example, a pentyl, hexyl, heptyl, octyl, nonyl
or decyl group, too. A C~_4 alkoxy group can be, for example, a
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methoxy, ethoxy, n-propoxy or n-butoxy group. A halo atom is,
for example, a fluoro, chloro, bromo or iodo atom. A 5- or 6-
membered, saturated, unsaturated or aromatic ring containing
a nitrogen atom is, for example, a pyrrole, isopyrrole, dihydro-
pyrrole, pyrrolidine, pyridine, piperidine, dihydropyridine, tetra-
hydropyridine ring or the like.
In the synergistic pharmaceutical combination of the
invention, the mass (or weight) ratio of the,cicletanine or a
pharmaceutically suitable acid addition salt thereof and the
antidiabetic or anti-hyperlipidemic active agent or, if desired
and chemically possible, a pharmaceutically suitable acid
addition salt or a salt formed with a pharmaceutically suitable
base thereof is, in general, (1-100):(100-1). In general, the one
or two pharmaceutical compositions) of the pharmaceutical
combination is/are suitable for peroral or parenteral
administration and is/are solid or liquid composition(s). The
suitable dosage forms and manufacture thereof as well as the
useful carriers are known from the literature e.g. Remington's
Pharmaceutical Sciences, Mack Publishing Co., Easton, USA.
In the synergistic pharmaceutical combination of the
invention, each active agent can be present in a separate
pharmaceutical composition or both cicletanine and the
antidiabetic or anti-hyperlipidemic active agent are present in a
single common pharmaceutical composition. The antidiabetic
or anti-hyperlipidemic active agent can be, for example, one of
the species listed above. Thus, the preferred synergistic
pharmaceutical combination of the invention may contain
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cicletanine or a pharmaceutically suitable acid addition salt
thereof such as the hydrochloride as well as (b~) an anti-
diabetic active agent e.g. insulin, or an insulin sensitizing active
agent such as a thiazolidinedione derivative, for example,
pioglitazone, troglitazone, ciglitazone, rosiglitazone, or an
active agent that enhances the production of insulin such as
mitiglinide, repaglinide, senaglinide, or a sulfonamide such as
tolbutamide, chlorpropamide, tolazamide, acetohexamide,
glyburide, glipizide, gliclazide, glimepiride, gliquidone,
glibornuride, glisoxepid, glisentide, glisolamide, glybuzole,
glyclopyramide, or a biguanidine derivative of the formula I,
preferably metformin, buformin, phenformin, or an a-
glucosidase inhibitor such as miglitol, acarbose or voglibose, or
(b2) an anti-hyperlipidemic active agent e.g. an aryloxyalkanoic
acid derivative such as clofibrate, gemfibrozil, simfibrate,
etofibrate, ciprofibrate, ronifibrate, or a HMG coenzyme
reductase inhibitor such as lovastatin, fluvastatin, pravastatin,
simvastatin, atorvastatin, or a nicotinic acid derivative such as
acipimox, niceritrol, nicomol, nicoclonate, or an antacid for bile
acids such as colestipol, cholestyramine, polidexide, or, if
desired and chemically possible, a pharmaceutically suitable
acid addition salt or a salt formed with a pharmaceutically
suitable base of the species given under (b~) and (b2).
The influence of the combination of the invention on the
glucose sensitivity was studied using the following tests. All
experiments performed conform to the European Community
guiding principles for the care and use of experimental
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animals.
Adult male New Zealand white rabbits weighing 3-3.2 kg,
housed in an animal room (12-hour light/darl< periods a day,
temperature of 22-25 °C, relative humidity of 50-70 %) with one
animal per pen, fed commercial laboratory chow and tap water
ad libitum, were used throughout. The animals underwent
surgery after a two-week adaptation period [Szilvassy Z. et al.,
Br. J. Pharmacol., 112, 999-1001 (1994)].
Surgery was performed under aseptic conditions. The
rabbits were anaesthetized with an intravenous bolus of 10
mg/kg diazepam (Sigma, St. Louis, MO, USA) and 5 mg/kg
ketamine (EGIS Pharmaceuticals Ltd., Budapest, Hungary).
Lidocaine (EGIS Pharmaceuticals Ltd., Budapest, Hungary)
was administered subcutaneously for local pain relief. Poly-
ethylene catheters were inserted into two major branches of
the jugular vein and the left carotid artery. The catheters were
exteriorised through the back of the neck. These lines were
kept patent by filling with sodium heparin solution (100 IU/ml).
Human regular insulin was infused at a constant rate (13
mU/kg, NOVO Nordisk, Copenhagen) via one of the venous
catheters over 120 min. This insulin infusion yielded plasma
insulin immunoreactivity of 100~5 p,U/ml in the steady state.
This value corresponds to five times the value of the normal
upper limit. Blood samples (0.3 ml) were taken from the arterial
cannula for blood glucose concentration at 10 min intervals.
Blood glucose concentration was maintained constant (5.5. i-0.5
mmol/litre) by a variable rate of glucose infusion via the second
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venous cannula. When blood glucose had stabilized for at least
30 min, we defined this condition as steady state. In the steady
state, additional blood samples (0.5 ml) were taken for plasma
insulin determination at 10-min intervals. The glucose infusion
rate (mg/kg/min) during steady state was used to characterise
insulin sensitivity [DeFronzo R.A. et al., Am. J. Of Physiol.,
237, E214-223 (1979)]. The test compound (s) was/were
administered to healthy and hypercholesterolaemic animals,
respectively, perorally, in a single dose, daily, for five days, and
the glucose infusion rates determined on the 6t" day were
averaged within each test group consisting of 6 animals. One
group of the healthy and one of the hypercholesterolaemic
animals was used as the control. The results obtained are
shown in Tables 1, 2, and 3. ,
Table 1
Insulin sensitivity as characterized by the glucose infusion rate
in mg/kg/min during steady state
Group Control CicletanineMetforminCicletanine
of (30 mg/kg)(100 (30 mg/kg)
animals p.o. mg/kg) +
p.o. metformin
(100 mg/kg)
p.o.
normal 13,81,11 16,21,35 14,41,03 19,41,32
7,91,3 14,21,31 10,71,01 15,61,12
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normal = healthy animals were used in the test;
HC = hypercholesterolaemic animals were used in the test.
Table 2
5 Insulin sensitivity as characterized by the glucose infusion rate
in mg/kg/min during steady state
Group Control CicletanineTroglitazoneCicletanine
of (30 mg/kg)(75 mg/kg) (30 mg/kg)
animals p.o. p.o. +
troglitazone
(75 mg/kg)
p.o.
normal 13,20,9816,91,13 14,30,08 19,82,00
...._....................._...........__..._..........................._.......
._.._....._........._.._.........._...._...M.__...._..._......_...._.......__..
.................__............._............._._..._............_.............
_.._..................._.............._......_............
HC 8,20,76 13,51,41 13,21,06 15,70,99
normal = healthy animals were used in the test;
10 HC = hypercholesterolaemic animals were used in the test.
Table 3
Insulin sensitivity as characterized by the glucose infusion rate
in mg/kg/min during steady state
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Gr~uia ~~ntr~I Cicletanine ~aride Ci~lefanirre
~f (30 mg/kg) (1 mg/kg) (30 mg/kg)
anirr~als p.o. p.o. +
glyburide
(1 mg/kg)
p.o.
normal 13,44~0,86 15,9~0,89 11,8~1,3g 16,4.~2,22
HC 8,4~1,09 12,9~1,06 7,0~1,00 14,91~0,78
normal = healthy animals were used in the test;
HC = hypercholesterolaemic animals were used in the test.
As a matter of fact, the amount of glucose infused to obtain
constant blood glucose level has been measured in the above
tests. It is favourable that a higher amount of glucose should
be needed at the given constant blood glucose level which
indicates the enhanced effect of insulin. Consequently, the
higher glucose infusion rate is measured, the higher efficiency
is obtained with the compound tested.
As seen in Table 1, in healthy animals, of course, higher
values are obtained than in hypercholesterolaemic ones. In the
control groups, lower glucose infusion rates are experienced
than in the groups treated with either cicletanine or metformin.
Anyway, in both healthy and cholesterolaemic animals, the
glucose infusion rates are significantly higher when the animals
has been treated with both cicletanine and metformin than in
the case when only one of the test compounds has been
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administered. Thus, synergism is observed between
cicletanine and metformin.
The situation is the same with cicletanine and troglitazone
as well as cicletanine and glyburide as shown by Table 2 and
Table 3, respectively.
Thus, the especially preferred synergistic pharmaceutical
combination of the invention contains (a) cicletanine or a
pharmaceutically suitable acid addition salt thereof and (b) a
biguanidine derivative of the formula I, suitably metformin, or a
pharmaceutically suitable acid addition salt thereof, or a
sulfonylurea, suitably glyburide, or a pharmaceutically suitable
acid addition salt thereof, or a thiazolidinedione derivative,
suitably troglitazone, or a pharmaceutically suitable acid
addition salt thereof, wherein the active agents are present in
separate pharmaceutical compositions or in a single
pharmaceutical composition.
The invention includes also the use of cicletanine or a
pharmaceutically suitable acid addition salt thereof for the
preparation of a pharmaceutical composition having insulin
sensitizing effect. Preferably, the pharmaceutical composition
is a unit dosage form, in general, suitable for peroral or '
parenteral administration, and contains 30 to 100 mg of
cicletanine or cicletanine hydrochloride. The suitable dosage
forms and manufacture thereof as well as the useful carriers
are known from the literature e.g. Remington's Pharmaceutical
Sciences, Mack Publishing Co., Easton, USA.
The insulin sensitizing effect of various doses of cicletanine
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was studied using similar tests employed in the study of
glucose sensitivity of the synergistic pharmaceutical
combination of the invention. The animals were treated with 10
mg/kg, 30 mg/kg or 100 mg/kg of cicletanine, perorally, once
daily, for 5 days. The glucose infusion rate was determined on
the 6~h day. The results obtained are shown in Table 4.
Table 4
Insulin sensitivity as characterized by the glucose infusion rate
in mg/kg/min during steady state
Group Control CicletanineCicle Cicletanine
of (10 mg/kg) (30 mglkg)(100 mg/kg)
animalsp.o. p.o. p.o.
normal 13,440,86 14, 91,1116, 81, 15, 90,83
52
HC 8,41,09 11,21,21 13,51,41 14,261,16
normal = healthy animals were used in the test;
HC = hypercholesterolaemic animals were used in the test.
As a matter of fact, in the latter test the influence of various
doses of cicletanine on the utilization of insulin produced by the
pancreas was studied. From tha data of Table 4 it can be seen
that, relative to the control group, even a peroral dosage of as
low as 10 mg/kg of cicletanine enhances the utilization of
insulin produced by the organism in both healthy and hyper-
cholesterolaemic animals. (The control data indicate the
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19
amount of glucose to be administered by infusion which
amount is required to produce an euglycaemic state in hyper-
insulinaemic animals.) Of course, the higher doses of
cicletanine produced still favourable utilizations of insulin.
The invention includes also a method for the treatment or
the prevention of a prediabetic state, metabolic ?~-syndrome or
diabetes mellitus as well as disorders which are associated
with the states listed above, namely endogenic metabolic
disorders, insulin resistance, dislipidemia, alopecia, diffuse
effluvium, polycystic ovary syndrome andlor other diabetic
complications, in which the patient suffering from or threatened
by said states is treated with a therapeutically effective amount
of cicletanine or a pharmaceutically suitable acid addition salt
thereof. The therapeutically effective amount of cicletanine is
an amount that produces insulin sensitizing effect.
In addition to cicletanine or a pharmaceutically suitable acid
addition salt thereof, if desired, also an antidiabetic or anti-
hyperlipidaemic active agent can be administered to the patient
suffering from or threatened by the states listed above. In this
case the antidiabetic or anti-hyperlipidemic active agent and
the cicletanine or a pharmaceutically suitable acid addition salt
thereof can be administered simultaneously or one after the
other following a shorter interval lasting for e.g. some seconds
or minutes or a longer interval lasting for e.g. 10-30 minutes.
Since the cicletanine synergistically enhances the
therapeutical effect of the antidiabetic or anti-hyperlipidemic
active agent, the daily dose of the antidiabetic or anti-
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hyperlipidemic agent is lower than the usual daily dose thereof
employed in the conventional treatment when no cicletanine is
administered.
The daily dose of cicletanine is, in general 30 to 100 mg,
5 preferably about 50 mg for an adult person having a body
weight of 70 kg.
Using the process of the invention, the development of
especially the following clinical patterns can be prevented, or,
when once developed, they can be influenced advantageously:
10 - prediabetic state such as glucose intolerance or insulin
resistance,
- metabolic X-syndrome,
- both types of diabetes (IDDM and NIDDM),
- diabetic complications with special regards to retinopathy,
15 neuropathy, nephropathy, polycystic ovary syndrome
(PCOS), alopecia, diffuse effluvium, gestation diabetes
mellitus (GDM), arterial hypertonia, dislipidemia, arterio-
sclerosis, obesitas, cardial ischemia associated with diabetes
etc.
20 Thus, a pharmaceutical composition containing cicletanine
or a pharmaceutically suitable acid addition salt thereof can be
administered to a patient that is treated or conventionally
should be treated with an antidiabetic or anti-hyperlipidemic
active agent in order to prevent or treat a prediabetic state,
metabolic X-syndrome or diabetes mellitus as well as disorders
which are associated with the states listed above, namely
endogenic metabolic disorders, insulin resistance, dislipidemia,
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21
alopecia, diffuse effluvium, polycystic ovary syndrome and/or
other diabetic complications. As a result of the administration
of the pharmaceutical composition containing cicletanine or a
pharmaceutically suitable acid addition salt thereof, either no
further treatment with an antidiabetic or anti-hyperlipidemic
active agent is required, or a lower dosage of the antidiabetic
or anti-hyperlipidemic active agent is sufficient. When a
pharmaceutical composition containing cicletanine or a
pharmaceutically suitable acid addition salt thereof as the
active agent is administered to a patient suffering from
diabetes and obtaining a regular insulin treatment, then the
daily insulin dose can be reduced, thus, avoiding the
development of insulin resistance.
20
