The present invention relates to the use of boswellic acids
as well as to preparations containing boswellic acids for
human medical or veterinary prophylaxis and/or the treatment
of damage and/or inflammation of the islets of Langer
hans and/or damage of the B-cells of the islets of Langer
hans. In particular, the invention relates to the use of
boswellic acids as well as preparations containing boswel
lic acid(s) for the human medical or veterinary prophylaxis
and/or the treatment of damage and/or inflammation of the
islets of Langerhans and/or damage of B cells of the islets
of Langerhans, wherein the damage is accompanied by inflam
mation (insulitis) . Preferably, the damage and/or inflamma
tion of the islets of Langerhans and/or of the B-cells of
the islets of Langerhans is/are associated with type 1 dia
betes, type 2 diabetes or pancreatitis.
Basically, there are two types of diabetes. Type 1 diabetes
or juvenile diabetes is caused by an absolute insulin deficiency
as a result of damaged B cells or B cell death that
is frequently associated with insulitis. Type 2 diabetes or
adult onset diabetes is principally caused by an insulin
resistance of the tissue. This insulin resistance is accompanied
by relative insulin deficiency and increased glucose
production in the liver. In many cases, type 2 diabetes is
also accompanied by insulitis. Cellular damage or inflamma
tion of the islets of Langerhans of the pancreas can impair
the functioning of the insulin-producing B cells or lead to
a complete loss of function due to B cell death. This re
sults in an absolute insulin deficiency, which causes insu
lin-depending diabetes mellitus (= IDDM) . IDDM mainly oc
curs in children, youths or adolescents. However, it can
also demonstrate onset in advanced age. In this case, it is
called „latent autoimmune diabetes of the adult" (LADA) .
The most important aspect of an inflammation of the islets
of Langerhans is an infiltration by macrophages and
T-lymphocytes . During the activation of the TH1-
lymphocytes, B cells can be destroyed due to apoptosis re
sulting in the progression of the disease. The apoptosis
does not affect the A cells or D cells (the glucagon of the
A cells increases the blood glucose level, the somatostatin
of the D cells inhibits the secretion of insulin) .
Without insulin substitution, this condition eventually
leads to death due to diabetic coma. Previous attempts to
suppress the course of the diabetic disease, e.g. by administering
anti-inflammatory agents such as non-steroidal an
tiphlogistic agents, glucocorticoids (the latter even hav
ing a diabetogenous effect) , immunosuppressants, or by im
mune intervention and immune prevention, e.g. by adminis
tering cyclosporine A , have not led to a satisfactory solution
up to now. In fact, these therapeutic attempts have
rather considerable side effects. Other therapeutic ap
proaches such as the treatment with methotrexate, nicotina
mide, monoclonal antibodies, azothioprine etc. have not
proven to be suited either to influence damage of B-cells
in a way that is efficient for the diabetic person with
little side effects. Neither has the use of anti
inflammatory agents that act selectively such as COX2-
inhibitors (US 2003/0017148) to success.
Hence, in the state of the art there is a need for a causal
treatment for damage and/or inflammation of the islets of
Langerhans aiming at causal treatment or cure of a diabetic
condition. Furthermore, there is a need for an effective
prophylaxis against damage and/or inflammation of the is
lets of Langerhans as well as against damages of the Bcells
of the islets of Langerhans with the aim to prevent
the cause of a diabetic condition. The therapeutic concept
according to the invention is intended to be well tolerated
without significant side effects. Furthermore, according to
the invention, treatment is supposed to be possible before
the onset of diabetes, or, in case diabetes has already occured,
the treatment is supposed to prevent a deterioration
associated with further destruction of B cells.
Surprisingly, it has been found that a mixture of boswellic
acids or boswellic acids of a boswellic-acid containing
preparation, as well as individual boswellic acids, can
prevent damage and/or inflammation of the islets of Langerhans
(insulitis) or can stop the same, and can prevent or
cure damage, in particular inflammation-associated damage
of B cells of the islets of Langerhans. The effect of the
boswellic acids exhibits little side effects. The effect of
the boswellic acids not only makes them suitable for the
treatment, but also for the prophylaxis of damage and/or
inflammation of the islets of Langerhans as well as of the
B cells of the islets of Langerhans.
- A -
The invention relates to the use of acetyl-ll-keto- b-
boswellic acid, ll-keto- -boswellic acid, b-boswellic acid,
acetyl- -boswellic acid, 9 , ll-dehydro^-boswellic acid,
acetyl-9, ll-dehydro- b-boswellic acid, a-boswellic acid,
acetyl-a-boswellic acid, 11-dehydro-a-boswellic acid, ace
tyl-9, 11-dehydro-a-boswellic acid, lupeolic acid, acetyllupeolic
acid, 12-ursene-2-diketone, incensole, incensole
acetate, a derivative, in particular an ester thereof, a
physiologically tolerable salt thereof, a combination
thereof, or a preparation containing one or more of these
compounds for human medical or veterinary treatment and/or
prophylaxis of a ) damage and/or inflammation of the islets
of Langerhans and/or b ) damage of the B-cells of the islets
of Langerhans.
The invention also relates to a method for human medical or
veterinary treatment and/or prophylaxis of a ) damage and/or
inflammation of the islets of Langerhans and/or b ) damage
of B-cells of the islets of Langerhans by using the compounds
mentioned above.
Preferably, the use according to the invention or the
method according to the invention relates to the treatment
and/or the prophylaxis as set out above, wherein the damage
of the islets of Langerhans and their B-cells can be accom
panied by an inflammation (insulitis) . Frequently, the dam
age and/or inflammation of the islets of Langerhans and/or
the B-cells of the islets of Langerhans are associated in
patients with type 1 diabetes, type 2 diabetes, LADA type
diabetes or pancreatitis.
Damage to the islets of Langerhans and/or the B-cells com
prises preferably damage to the morphologic structure as
well as the physiological function. In this connection, the
extent of the damage can comprise all kinds and types of
damage, i.e. from minor damage to very severe damage. Such
damage is generally diagnosed by a malfunction of the is
lets of Langerhans, i.e. a disturbed secretion of the hormones
produced by the islets of Langerhans, i.e. insulin,
glucagon, or somatostatin. Damage can also be detected by
pancreas biopsy.
Boswellic acids are pentacyclic triterpenes and form the
main components of the resin of the Indian Boswellia tree
(Boswellia serrata) and other Boswellia species (Ammon,
HPT, Planta Med, 2006; 77: 1100-1116) .
The effect of orally administered preparations made of the
resin of different Boswellia species on the blood glucose
level in alloxan-induced diabetes has been investigated in
the state of the art. In the paper of Helal, Mostafa,
Ashour and Kawash (2005) („Effect of Boswellia Carterii
Birdw. on Carbohydrate Metabolism in Diabetic Male Albino
Rats", The Egyptian Journal of Hospital Medicine, 2005,
Vol. 20: 38-45) experiments were carried out with alloxandiabetic
rats. Alloxan leads directly to the destruction of
the insulin-producing B-cells by forming reactive oxygen
species (ROS) . In this study, only animals with a blood
glucose level (BG) of at least 180 - 250 mg/dl were further
examined. Due to the destruction of the B-cells the animals
were diabetic and were treated from that point on. They
were dosed orally with an aqueous extract (not containing
boswellic acids because they are not water-soluble) from
the resin of Boswellia carterii for 30 days. Beside a re
duction of the blood glucose level (BG) , a normalization of
the hypoinsulinemia and an increase in the glycogen in the
animals treated with alloxan, upon histophathologic exami
nation (H & E staining) the authors found a normal structure
of the islets of Langerhans after treatment with aque
ous boswellia extract. These authors state that a regenera
tion of the B-cells had taken place.
In a study by Helal and Abbas of 2006 („Effect of some
herbal medicine on some biochemical parameters in diabetic
rats", The Egyptian Journal of Hospital Medicine, 2006,
Vol. 22: 98-110) rats were given a single dose of alloxan.
After 48 hours the blood glucose level was measured. Again,
only those rats with a blood glucose level higher than 250
mg/dl, i.e. which were clearly diabetic, were further exam
ined. These animals were treated orally with an aqueous ex
tract from Boswellia carterii for 30 days. In this study,
the blood glucose levels decreased from 266.8 mg/dl to the
reference values. The same effect as with the aqueous ex
tract from Boswellia carterii was observed under the treat
ment with aqueous extracts from Nigella sativa, Aloe vera,
Ferula asa foetida and Commiphora myrrha. With all these
substances the insulin level in the blood increased.
A s far as the results obtained with Boswellia in this model
are concerned, the authors of the above-mentioned studies
attribute the decrease of the blood glucose level with the
increased insulin secretion, reduced insulin resistance and
increased glycogen synthesis due to the aqueous extract,
all a consequence of a stimulation of insulin secretion.
In a study by Kavitha et al . (2007) (hypoglycemic and c i¬
ther related effects of Boswellia glabra in Alloxan-induced
diabetes rats", Indian J Physiol Pharmacol 2007; 51 (1) :
29-39) diabetes was also induced by administering 200 mg/kg
of Alloxan. Only animals with a blood glucose level above
300 mg/dl 2 days after treatment with Alloxan were studied
further. Here, the oral administration of aqueous extracts
of leaves and roots of Boswellia glabra was tested with re
spect to their effect on blood glucose, cholesterol,
triglycerides, urea, creatinine in the blood and serum en
zymes over a period of 2 8 days. The blood parameters improved.
The authors of this study attribute this effect to
a repair of damaged B-cells.
None of the studies mentioned above, however, proves the
specific effect of boswellic acids as such for a use and/or
treatment and for the prophylaxis of damage or insulitis or
inflammation-induced damage to the B-cells of the islets of
Langerhans . Furthermore, these studies do not contain any
statement that by using boswellic acids the pathogenesis of
diabetes can be prevented or stopped.
By using the method of „multiple low dose - Streptozotocin"
(MLD-STZ) diabetes, which is an acknowledged animal model
for inducing diabetes that is associated with insulitis, it
has been shown that by using an extract of the resin from
Boswellia serrata that contains a mixture of boswellic ac
ids both damage/inflammation and apoptosis as well as the
shrinking of the cells of the islets of Langerhans can be
prevented or cured. Furthermore, by using this model it was
shown that both the boswellic-acid containing extract and
the ll-keto^-boswellic-acid as well as the acetyl-ll-keto-
b-boswellic acid that are contained in this extract per se
can prevent the increase of the pro-inflammatory cytokines
and, thus, damage/insulitis of the islets of Langerhans.
According to the invention, boswellic acids alone or in
combination with each other, as well as preparations con
taining boswellic acids, can be used. Preferably, the fol
lowing boswellic acids are used: acetyl-ll-keto^-boswellic
acid, ll-keto^-boswellic acid, b-boswellic acid, acetyl- b-
boswellic acid, 9 , ll-dehydro^-boswellic acid, acetyl-9,11-
dehydro^-boswellic acid, a-boswellic acid, acetyl-aboswellic
acid, 11-dehydro-a-boswellic acid, acetyl-9,11-
dehydro-a-boswellic acid as well as lupeolic acid, acetyllupeolic
acid as well as 12-ursene-2-diketone, incensole,
incensole acetate. Furthermore, derivatives of these bos
wellic acids as well as physiologically tolerable (pharma
ceutically acceptable) salts thereof can be used. Such de
rivatives of boswellic acids include esters, e.g. methyl-,
ethyl-, butyl-, allyl-esters as well as esters with other
physiologically tolerable alcohols. Examples of physiologi
cally tolerable salts of boswellic acids are Na, K , Mg or
ammonium salts.
Examples of boswellic-acid containing preparations are
preferably herbal preparations, such as extracts from parts
of plants, preferably from resins, from the plant family of
Burseraceae such as, for example, Boswellia carterii, Boswellia
sacra, Boswellia frereana, Boswellia bhau-da iana,
Boswellia papyfera, Boswellia neclecta, Boswellia odorata,
Boswellia dalzielli, Boswellia serrata among others. How
ever, other boswellic acid-containing preparations that are
pharmacologically and physiologically tolerable and that
are prepared by using a method that is known as such can be
used.
Preferably, an extract of Boswellia serrata is used. The
extract can be prepared from any part of boswellic acidcontaining
plants. Preferably, the extract is prepared from
the resin of boswellic acid-containing plants. Preferably,
the extract from the resin of Boswellia serrata is used.
The extract can be prepared from the plant parts to be ex
tracted in a manner known per se. Preferably, the extract
is prepared by extraction using an organic solvent. The organic
solvent is preferably selected from methanol, ethanol,
chloroform, carbon tetrachloride, ethyl acetate,
toluol, xylol, acetone, acetylacetone or dimethylf ormamide
or mixtures of these solvents. It is particularly preferred
to prepare the extract by methanolic extraction, e.g. pre
pared according to Singh et al . (G.B. Singh, Boswellic ac
ids, Drugs of the Future, 1993, 18: 307-309) .
According to a study by Biichele and Simmet (2003, J . Chromatogr.
B ; 791: 21-30) in incense extract the following
pentacyclic triterpenes have been found in the following
percentages :
a -boswellic acid 13,78%
acetyl - a -boswellic acid 3,37%
lupeolic acid 2,61%
acetyl lupeolic acid 1,10%
11-dehydro - a -boswellic acid 0,18%
acetyl-9, 11-dehydro - a -boswellic acid 0,06%
b-boswellic acid 19,20%
acetyl - -boswellic acid 10,04%
1l-keto - -boswellic acid 6 , 66%
acetyl-ll-keto - -boswellic acid 3,81%
9 , 1l-dehydro - -boswellic acid 0,83%
acetyl-9, ll-dehydro - -boswellic acid 0,52%
According to the invention, preferably an extraction method
is used in such a way that the compounds listed above are
extracted from the boswellic acid-containing plant to be
extracted.
According to the invention, boswellic acids as well as
preparations containing the same, preferably herbal prepa
rations, can be used per se or in combination with one or
more additional pharmaceutical substances. Examples of
pharmaceutical substances that can be combined with boswel
lic acids or with preparations containing the same are:
aqueous extracts from plant parts of Boswellia species and
other Burseraceae species, antiphlogistics , e.g. acetylsalicylic
acid, diflunisal, indometacin, acemetacin, diclofenac,
lonazolac, ibuprofen, dexibuprof en, flurbiprofen,
ketoprofen, dexaketoprof en, naproxen, tiaprofen acid, piroxicam,
meloxicam, lornoxicam, paracetamol, phenazon, propyphenazon,
metamizol, insulin, oral antidiabetics such as,
for example, sulfonylureas, glynides, metformin, imidazolidinone,
glitazone, alpha-glucosidase inhibitors (acarbose)
, dipeptidylpeptidase IV (DPP IV) inhibitors, cyc
losporin A , antioxidants, pentoxyphylline, isoxazoles, interferones,
gangliosides , alpha-adrenozeptorant agonists,
nicotinamide, dimethylurea . Furthermore, the boswellic acids
or preparations containing boswellic acids can also be
combined with additional preparations made from plants that
have a hypoglycaemic or hypolipidaemic effect, as well as
with statines, fibrates, nicotinic acid derivatives, ion
exchangers etc. Preferred examples of hypoglycaemically active
plants are Pterocarpus marsurpium, Stevia rebaudiana,
Momordica charantia.
The use according to the invention can be made by oral,
buccal, rectal, subcutaneous, intravenous or intraperitoneal
administration. For this purpose, the boswellic acids
or the preparations containing the same are formulated by a
known method that is suitable for the form of administra
tion concerned. Examples for corresponding pharmaceutical
dosage forms are tablets, powders, granulates, sugar-coated
tablets (dragees), capsules, solutions, emulsions, or sup
positories .
The dosage of the substances according to the invention or
the preparations concerning these substances respectively
depends on the extract preparation selected, the boswellic
acids selected, the severity of the condition as well as on
the relation of body surface to body weight of the individ
ual to be treated. The exact dosage can be ascertained by a
physician in a suitable way. A suitable standard dosage,
for example, is the administration of 400 to 500 mg of ex
tract three times a day (for example the product H15 of the
company Gufic Ltd. Mumbai) . A suitable dosage of ll-keto- b-
boswellic acid for humans ranges from 0.2 mg/kg to 4.0
mg/kg, preferably from 0.4 mg/kg to 8.0 mg/kg, three times
a day. A suitable dosage of acetyl-ll-keto^-boswellic acid
for humans ranges from 0.2 mg/kg to 4.0 mg/kg, preferably
from 0.5 mg/kg to 10.0 mg/kg, three times a day. A particu
larly preferred dosage is 1 mg/kg body weight for 11-keto-
b-boswellic acid and 2 mg/kg body weight for acetyl-11-
keto^-boswellic acid. These dosages refer to oral admini
stration. In a therapy over a longer period of time it has
to be taken into account that due to the long half life of
boswellic acids an accumulation of boswellic acid in the
blood over the time has to be expected. Due to that, only
after a longer period of time effective concentrations ac
cumulate in the blood. Preferably, boswellic acids or bos
wellic acid-containing preparations are administered to
gether with a meal, thus they are better resorbed.
The use according to the invention is particularly suited
for the treatment and/or prophylaxis of damage to the is
lets of Langerhans and/or damage to the B-cells of the is
lets of Langerhans. Frequently, the damage to the islets of
Langerhans and/or to their B-cells is accompanied by in
flammation (insulitis) . The inflammations or the inflamma
tion-induced damage can occur without diabetes or can be
associated with type 1 diabetes, type 2 diabetes or pan
creatitis. Examples for type 1 diabetes are type 1A diabe
tes, LADA diabetes and type IB diabetes.
Preferably, the use according to the invention is suited
for the following groups of persons:
i ) persons with a genetic predisposition for a type 1
diabetes with preceding diabetes-inducing diseases,
e.g. diseases caused by viruses, such as mumps vi
ruses, COX viruses, rubella viruses, measles viruses,
cytomegaloviruses, or influenza viruses, and/or
ii) persons, among whose first-degree relatives, e.g.
parents or siblings, type 1 diabetes has occurred, or
iii) persons having up-regulated diagnostic markers for
the development of diabetes. Such diagnostic markers
include glutamate decarboxylase (GAD) , tyrosin phos
phatase IA2, and islet cell antibodies (ICA) .
Frequently, a diabetes disease, in particular type 1 diabe
tes, is associated with an insulitis.
In LADA diabetes and in a number of type 2 diabetic persons
onset of insulitis occurs later. A s a consequence to dam
age, frequently accompanied/ followed by inflammation, Bcells
are damaged and/or destroyed, which results in an in
crease of the blood glucose level.
The use according to the invention in general has few side
effects. Side effects that may arise include epigastric
pain, hyperacidity and nausea.
The invention relates to the therapeutic and/or prophylac
tic treatment of damage of the islets of Langerhans and/or
a damage of the B-cells of the islets of Langerhans,
wherein the damage of the islets of Langerhans and/or their
B-cells is preferably accompanied by inflammation (insulitis)
. The above statements concerning the use according
to the invention apply accordingly.
The invention is explained in more detail by means of the
following figures. It is shown by
Figure 1 Influence of a 10-days' intraperitoneal admini
stration of 150 mg/kg of a mixture of different
boswellic acids obtained by an alcoholic ex
tract from the oleogum resin of Boswellia serrata
(BE) on the histologic image of the islets
of Langerhans in mice treated with STZ. Exami
nation on the 10th day of treatment with BE.
BK +/+: mouse strain used
n = 3-5
Staining: H&E, Anti-CD3, anti-activated caspase
3
Figure 2 Influence of a 10-days' intraperitoneal admini
stration of 150 mg/kg of a mixture of different
boswellic acids obtained by an alcoholic ex
tract from the oleogum resin of Boswellia serrata
(BE) on the histologic image of the islets
of Langerhans in mice treated with STZ. Examination
35 days after the first administration
of BE.
BK +/+: mouse strain used
Staining: H&E
n = 3 - 5
Figure 3 Influence of a 10-days' intraperitoneal admini
stration of 15.0 mg/kg AKBA on the histologic
image of the islets of Langerhans in mice
treated with STZ. Examination on the 10th day
of treatment with AKBA.
BK +/+: mouse strain used.
Staining as in Fig. 1
n = 4
Figure 4 Influence of a 10-days' intraperitoneal admini
stration of 7.5 mg/kg KBA on the histologic im
age of the islets of Langerhans in mice treated
with STZ. Examination on the 10th day of treat
ment with KBA.
BK +/+: mouse strain used
Staining as in Fig. 1
n = 3
Figure 5 Influence of a 5-, 10- and 21-days' intraperi
toneal administration of 150 mg/kg of a mixture
of different boswellic acids obtained by an al
coholic extract from the oleogum resin of Boswellia
serrata (BE) on the blood glucose level
of mice treated with STZ.
Mean +/- SE
Figure 6 Influence of a 7-days' peritoneal administra
tion of 150 mg/kg of a mixture consisting of
different boswellic acids obtained by an alco
holic extract from the oleogum resin of Boswellia
serrata (BE) as well as of the solvent
Tween 80 on the blood glucose level of mice
that were not treated with STZ.
Normal control
Mean +/- SE
n = 3
Figure 7 Influence on a 10-days' intraperitoneal admini
stration of 7.5 mg/kg of 1l-keto - -boswellic
acid (AKBA) on the blood glucose level of mice
treated with ST .
Mean +/- SE
n = 4
Figure 8 Influence of a 10-days' intraperitoneal admini
stration of 15.0 mg/kg acetyl-ll-keto -b-
boswellic acid (AKBA) on the blood glucose
level of mice treated with STC.
Mean +/- SE
n = 4
Figure 9 Influence of a 10-days' intraperitoneal admini
stration of 150 mg/kg of a mixture of different
boswellic acids obtained by an alcoholic ex
tract from the oleogum resin of Boswellia ser
rata (BE) on pro-inflammatory cytokines in the
serum of mice treated with STC.
C = untreated control
Mean +/- SE
n = 3-5
C = untreated control
Figure 10 Influence o f a 10-days' intraperitoneal admini
stration of 15.0 mg/kg acetyl-ll-keto - b -
boswellic acid (AKBA) on pro-inflammatory en
zymes in the serum of STC-treated mice.
C = untreated control group
Mean +/- SE
n = 3
Figure 11 Influence o f a 10-days' intraperitoneal admini
stration of 7.5 mg/kg 1l-keto - -boswellic acid
(KBA) on pro-inflammatory cytokines in the se
rum of STZ-treated mice.
C = untreated control group
Mean +/- SE
n = 3-5
The following examples are intended to further illustrate
the subject-matter of the invention.
Example 1 (reference example)
Effect o f acetyl-ll-keto - -boswellic acid (AKBA) on inflam
mation parameters in human type 1 diabetes and MLD-STZ in
duced diabetes in rodents (mouse, rat)
In in vitro experiments with mouse splenocytes, monocytes,
human thrombocytes and PML the effect of acetyl-ll-keto - b -
boswellic acid on typical inflammation markers was tested.
The experiments were carried out according to the review of
HPT Ammon, "Boswellic acids in chronic inflammatory dis
eases", Planta Medica 2006, 72: 1100-1116.
According to technical literature, the following parameters
are increased in splenocytes and PBMC in human type-1 dia
betes: IFN-g , IL-2, TNF-a, IL- I b, NF-kB . In MLD-STZ diabe
tes the following inflammation parameters in lymph node
cells and peritoneal macrophages are increased: IFN-g , IL-
2 , TNF-a. Beyond that an influx of macrophages into the
pancreatic islets is observed.
The results of the effects of AKBA on inflammation parame
ters as described in technical literature are contained in
the following Table 1 .
Consequently, it has been found that with acetyl-ll-keto- b-
boswellic acid a reduction of the relevant inflammation pa
rameters can be achieved.
Example 2
The effect of a mixture of a boswellic-acids containing ex
tract from the oleogum resin of Boswellia serrata (BE) on
streptozotocin diabetes
In this example, a methanolic extract from Boswellia ser
rata (BE) was investigated in accordance with G.B. Singh,
Boswellic acids, Drugs of the Future, 1993, 18: 307-309.
The boswellic acids identified there are b-boswellic acid,
acetyl - -boswellic acid, 1l-keto - -boswellic acid, acetyl-
1l-keto - -boswellic acid.
The use of "multiple low dose streptozotocin" (MDL-STZ diabetes)
is an acknowledged animal model for inducing diabe
tes that occurs frequently in association with insulitis,
which corresponds to IDDM in humans. In the pathogenesis
macrophages and T-lymphocytes infiltrate the islets of
Langerhans and the B-cells are destroyed. MLD-STZ induced
diabetes is very well suited for investigating the anti
diabetic and/or anti-inflammatory effect of drugs on the
pancreatic islets. For inducing MLD-STZ diabetes a mouse is
dosed with 40 mg/kg STZ per day intraperitoneally (i.p.)
over 5 days. During this time there is no B-cell destruction.
Only after 10 to 15 after the first injection of STZ
do signs of inflammation of the islets of Langerhans appear
when T-lmphocytes infiltrate and the B-cells are being de
stroyed. After about 16 days the symptoms of the inflamma
tion have disappeared again. Most B-cells have died. A s a
consequence, insulin secretion is reduced or no longer ex
istent (cf. McEvoy et al . 1984, "Multiple low-dose streptozotocin-
induced diabetes in the mouse", Evidence for stimu
lation of a cytotoxic cellular immune response against an
insulin-producing beta cell line.", J Clin Invest, 74:715-
22) . This animal model of experimental induction of diabe
tes mellitus essentially corresponds with the pathogenesis
of type 1 diabetes in young humans.
In order to investigate the effect of an extract containing
boswellic acids on the damage and/or inflammation of the
islets of Langerhans, a group of mice was dosed with streptozotocin
alone and another group of mice was dosed with
streptozotocin plus boswellic acid extract (a mixture of
boswellic acids with an overall concentration of all bos
wellic acids of 62%) . The aforesaid extract contained 5.51%
KBA and 4.96% AKBA. From the 1st to the 10th day, male mice
of strains bred in the own laboratory C3M/HeN and Bk +/+
were administered i.p with a dose of 150 mg/kg body weight.
Figure 1 shows histologic sections through a mouse pancreas
10 days after treatment with streptozotocin or streptozoto
cin plus boswellic acid extract. H&E staining was used, an
immunohistochemical detection of CD3-receptor complexes
(shows the presence of T-lymphocytes as inflammation mark
ers), as well as an immunohistochemical detection of the
activated caspase 3 enzyme (as marker for the existence of
apoptosis) .
The left column (A) shows histological sections of pancreata
of control mice with normal morphology in the endocrine
region of the pancreas without inflammation (normal H & E
staining, no T-lymphocytes and no signs of apoptosis) .
The middle column (B) shows histological sections of pancreata
of mice 10 days after treatment with streptozotocin.
An inflammation in the endocrine region of the pancreas
(H & E staining and detection of CD3 receptor complexes of
T-lymphocytes ) is shown. Moreover, apoptosis could be ob
served (caspase 3 activated) .
The right column (C) shows histological sections of pancreata
of mice that were treated with streptozotocin and boswellic
extract. Here, no signs of inflammation, neither
with H & E staining nor in an immunohistochemical detection
of T-lymphocytes, could be found. Furthermore, no signs of
apoptosis of cells were detected (no activated caspase 3 ) .
These immunohistochemical results show that the administra
tion of the boswellia extract both prevents the damage and
the inflammation of the islets of Langerhans caused by STZ
as well as the apoptosis of cells arising in this connection.
In Figure 2 histological sections from a mouse pancreas 35
days after the treatment with streptozotocin and boswellia
extract (B) or streptozotocin alone (A) are shown. In this
connection, what is worth noting are the different sizes of
the islets of Langerhans with the same magnification ap
plied. Animals that were only treated with streptozotocin
show shrinked endocrine regions in comparison to animals
treated with streptozotocin and boswellia extract (H&E
staining, 40-fold magnification) . This indicates that
streptozotocin alone in connection with damage/inflammation
(cf. Figure 1 ) has led to a shrinking of the islets of
Langerhans, this shrinking occurring as a consequence of a
massive death of B-cells. This was not the case when, additionally,
a mixture of boswellic acids was administered.
The results shown in Figures 1 and 2 unequivocally show
that an extract from the resin of Boswellia serrata that
contained a mixture of Boswellic acids prevented inflamma
tion, the death of B-cells as well as the shrinking of the
cells of the islets of Langerhans . This suggests that due
to the death of B-cells, insulin production/secretion is
considerably restricted in animals that have only been
treated with STZ, whereas this is not the case with respect
to the animals that have been treated at the same time with
Boswellia extract. The tests of the blood glucose levels
provide compelling evidence for this.
In Fig. 3 and 4 histological sections of mouse pancreas 10
days after the treatment with streptozotocin or streptozotocin
plus AKBA respectively (15 mg/kg, Fig. 2 ) or KBA
(7,5 mg/kg, Fig. 3 ) respectively is shown. The staining and
the immunohistochemical detection were carried out in ac
cordance Fig. 1 .
A s in Fig. 1 the left columns (A) show histological sec
tions of control animals with normal morphology in the en
docrine region of the pancreas without inflammation (normal
H&E staining, no T-lymphocytes and no signs of apoptosis) .
The middle columns (B) show histological pancreas sections
10 days after treatment with streptozotocin. Here, inflam
mations, T-lymphocytes and apoptosis have been observed as
well (cf . Fig . 1).
The right columns (C) show histological pancreas sections
of mice that have been treated with streptozotocin plus
AKBA or streptozotocin plus KBA. Here, after treatment with
AKBA, no signs of inflammation and only minor signs of
apoptosis were found. In the case of simultaneous treatment
with STZ plus KBA, neither signs of inflammation nor signs
of apoptosis were observed.
These immunohistochemical results show that, beside Boswellia
extract, two of its boswellic acids (AKBA and KBA) can
also prevent both STZ-induced damage and inflammation of
the islet of Langerhans and the apoptosis of cells.
Fig. 5 shows the effect of Boswellia extract (BE) on the
blood glucose level of MLD-STZ diabetic mice in relation to
the duration of the BE treatment.
For inducing MLD-STZ diabetes the animals were injected
i.p. 40 mg/kg STZ a day for a period of five days. In group
A the animals were additionally treated with 150 mg/kg BE
i.p. for 5 days, in group B for 10 days and in group C for
2 1 days.
In all three groups of the STZ-treated animals no increase
of the blood glucose level was observed after 5 days. An
increase could only be observed after 10 days, wherein the
increase continued.
A treatment with BE lasting only 5 days (A) only slightly
reduced the STZ-induced increase of the blood glucose
level. With BE treatment over 10 days, however, the in
crease of the blood glucose level was remarkably weaker.
The blood glucose level was around the normal value (group
B ) .
Group B clearly shows that the blood glucose did not sig
nificantly increase further even after the BE treatment was
discontinued. Similar results have been shown by group C .
These measurements show that, beside damage to B-cells and
inflammation, the BE has also prevented an increase in
blood glucose with the effect that the insulin-producing Bcells
mainly continue to be functional. It is of special
interest in this connection that after the treatment with
BE was discontinued the blood glucose did not increase fur
ther. This shows that the BE prevented another onset of the
disease.
It had to be ruled out that neither the extract nor the
solvent Tween 80 per se have a direct impact on the blood
glucose level.
Figure 6 shows the impact of the solubilizer for the ex
tract, Tween 80 (CAS No. 9005-65-6), as well as the impact
of the extract that is dissolved in this solubilizer on the
blood glucose in normal mice that have not been treated
with STZ. The animals were injected i.p. (A) 0.1 ml/kg
Tween 80 (1 % ) or (B) 150 mg/kg BE over 7 days. In both
cases no change in the blood glucose level was found. This
shows that neither the solvent alone nor the BE dissolved
in solvent have a direct impact on the blood glucose level
of the mouse.
According to Biichele et al . 2003 („Analysis of pentacyclic
triterpenic acids from Frankincense gum resins and related
phytopharmaceuticals by high-performance liquid chromatography.
Identification of lupeolic acid, a novel pentacyclic
triterpene", J . Chromatogr. B , 791: 21-30) it was shown
that an alcoholic extract from the resin of Boswellia serrata
contains a total of about 62% boswellic acids includ
ing acetylated and non-acetylated alpha and beta boswellic
acids. Of special interest among the Boswellic acids tested
up to now are acetyl-ll-keto^-boswellic acid (AKBA) and
ll-keto^-boswellic acid (KBA) . Therefore, it was investi
gated whether these two boswellic acids used individually
can prevent an increase in the blood glucose level in MLDSTZ
treated mice. The extract used according to the inven
tion contained 4.96% AKBA and 5.51% KBA.
The effect of 15 mg/kg AKBA as a single substance on the
blood glucose level in MLD-STZ diabetic mice is shown in
Figure 7 . The animals were treated for 5 days with STZ as
described above. AKBA in solution in Tween 80 was injected
i.p. daily for 10 days. A s is shown by Figure 5 , upon the
administration of 15 mg/kg AKBA a significant reduction of
the STZ-induced increase of the blood glucose level was ob
served .
After AKBA administration was discontinued after 10 days no
significant further increase of the blood glucose level was
observed.
Figure 8 shows the effect of 7.5 mg/kg KBA on the blood
glucose level in MLD-STZ diabetic mice. Like AKBA, KBA re
duced the STZ-induced increase of the blood glucose level.
Thus, Figures 7 and 8 show that the boswellic acids AKBA
and KBA contribute to the prevention of an increase of
blood glucose. Further boswellic acids that are contained
in the boswellia mixture contribute to this effect so that
the anti-diabetic effect of this group of substances is
shown .
Example 3
The effect of BE/KBA on pro-inflammatory cytokines in MLDSTZ
diabetic mice
Cytokines, which are released from the leukocytes, play an
important role in chronic inflammations. Among these cytokines,
the so-called pro-inflammatory cytokines, e.g. tumor
necrosis factor alpha (TNF - o ) , interferon gamma (IFN- g ) as
well as the interleukins IL-1A, IL-1B, IL-2 and IL-6 are
responsible for the induction of inflammation, onset of fever,
the permeability of the vessels, the proliferation and
activation of lymphocytes as well as the local destruction
of tissue etc. Insulitis is associated with an increase in
cytokines in the leukocytes - such as monocytes, macro
phages and T-lymphocytes - as well as in the blood.
Male mice were injected i.p. 40 mg/kg STZ for 5 days (STZ
group, group A ) . A second group was, in addition to STZ,
treated i.p. with 150 mg/kg BE for 10 days (group STZ + BE,
group B ) . A further group (group C ) remained untreated. After
10 days blood samples were taken.
In further tests, 15.0 mg/kg AKBA or 7.5 mg/kg KBA respec
tively were administered instead of 150 mg/kg BE.
10 days after a daily i.p. injection of 150 mg/kg of boswellia
extract of 15.0 mg/kg AKBA or 7.5 mg/kg KBA respec
tively in MLD-STZ animals (40 mg/kg i.p. for 5 days) the
presence of cytokines was determined using the commercially
available Multianalyte Array TM Kits (mouse-inflammatory
cytokines, SA Bioscience Corporation, USA) according to the
instructions on usage provided by the manufacturer. The cy
tokines IL-1A, IL-1B, IL-2, IFN- g , IL-6 and TNF - a were as
certained. The test results are shown in Figures 7 and 8 .
It is well-known that in inflammation first the pro
inflammatory cytokines increase in the tissue followed by
an infiltration of the inflammation cells into the tissue.
The test values shown in Figures 9 , 10, and 11 show that 10
days after the induction of MLD-STZ diabetes all cytokines
tested were significantly increased in the serum. The addi
tional i.p. administration of BE, AKBA or KBA reduced or
prevented the STZ-induced increase in TNF-a, IFN-g , IL-1A,
IL-1B, IL-2 and IL-6. The corresponding levels in the serum
of the animals tested no longer differed significantly from
those of the control group.
In line with the test values described above, one can as
sume that the prevention of leukocyte infiltration into the
islets of Langerhans, the prevention of apoptosis and the
prevention or reduction of hyperglycemia is due to the in
hibiting effect of BE, AKBA or KBA respectively on the STZinduced
increase of pro-inflammatory cytokines. Conse
quently, by the effect of the boswellic acids tested here
as well as by an extract containing the same damage of the
B-cells of the islets of Langerhans can be reduced or pre
vented .
In summary, the present data lead to the following conclu
sion :
STZ causes damage of the morphologic structure and the
functions of the islets of Langerhans and leads to the
death of B-cells. This leads to an increase in the blood
glucose level as a consequence of the insulin defi
ciency, e.g. Diabetes mellitus on the basis of damage of
the islets of Langerhans which may be associated with an
inflammatory process in the islets of Langerhans.
These processes can be prevented by administering a mix
ture of boswellic acids in a boswellia extract (BE) or
by administering individual boswellic acids.
The effect of the mixtures of boswellic acids is due to
the effect of one or more boswellic acids. This can be
deduced from the fact that two of the boswellic acids
contained in the aforesaid mixture, namely AKBA and KBA,
can prevent or reduce the increase in blood glucose in
response to the diabetogenic agent STZ also individu
ally.
C L A I M S
1 . A use of acetyl-ll-keto^-boswellic acid, ll-keto- b-
boswellic acid, b-boswellic acid, acetyl^-boswellic acid,
9 , ll-dehydro^-boswellic acid, acetyl-9, ll-dehydro- b-
boswellic acid, a-boswellic acid, acetyl-a-boswellic acid,
11-dehydro-a-boswellic acid, acetyl-9, 11-dehydro-aboswellic
acid, lupeolic acid, acetyl-lupeolic acid,
12-ursene-2-diketone, incensole, incensole acetate, a de
rivative, in particular an ester thereof, a physiologically
tolerable salt thereof, a combination thereof, or a prepa
ration containing one or more of these compounds for human
medical or veterinary prophylaxis and/or treatment of
a ) damage to/or inflammation of the islets of Langerhans
and/or
b ) damage to B-cells of the islets of Langerhans.
2 . The use according to claim 1 , wherein the damage to the
islets of Langerhans and/or their B-cells is accompanied by
inflammation (insulitis) .
3 . The use according to claim 1 or 2 , wherein the damage to
and/or the inflammation of the islets of Langerhans and/or
the damage to the B-cells is/are associated with type 1
diabetes, type 2 diabetes or pancreatitis.
4 . The use according to claim 3 , wherein the type 1 diabe
tes is type la diabetes, LADA diabetes or type lb diabetes.
5 . The use according to any of claims 1 to 4 , wherein the
combination consists of acetyl-ll-keto^-boswellic acid and
ll-keto^-boswellic acid and/or of physiologically toler
able salts thereof.
6 . The use according to claim 5 , wherein acetyl-ll-keto- b-
boswellic acid and ll-keto^-boswellic acid are contained
in a composition.
7 . The use according to any of claims 1 to 6 , wherein use
is made intraperitoneally, orally, buccally, rectally, intramuscularly,
subcutaneously or intravenously.
8 . The use according to any of claims 1 to 7 , wherein use
is made in the form of tablets, sugar coated tablets
(dragees), capsules, solutions, emulsions or suppositories.
9 . The use according to any of claims 1 to 8 , wherein use
is made together with at least one other pharmaceutical
substance .
10. The use according to claim 9 , wherein said pharmaceu
tical substance is selected from antiphlogistics , oral
antidiabetics, antioxidants, pentoxifylline, isoxazolene,
interf erones , gangliosides , a -adrenoceptor antagonists,
nicotinamide, dimethylurea, lipid-lowering agents and
herbal drugs.
11. The use according to claim 10, wherein the oral
antidiabetic is selected from sulfonylureas, glinides, met
formin, imidazolidinones , glitazones, a -glucosidase inhibitors,
and dipeptylpeptidase IV inhibitors.
12. The use according to any of claims 1 to 11, wherein
the person receiving prophylaxis and/or treatment is se
lected from:
i ) genetically predisposed persons with preceding diabetesinducing
diseases caused by viruses, said viruses selected
from mumps viruses, coxsackie B viruses, rubella viruses,
measles viruses, cytomegaloviruses, or influenza viruses,
and/or
ii) persons with at least one type 1 diabetic parent or
siblings, and/or
iii) persons with up-regulated diagnostic markers for inflamination
of the pancreas.
13. The use according to claim 12, wherein the diagnostic
marker is selected from glutamate decarboxylase (glutamic
acid decarboxylase), tyrosin phosphatase IA-2, oder islet
cell antibodies (ICA) .
14. The use of acetyl-ll-keto^-boswellic acid, 11-keto-
b-boswellic acid, b-boswellic acid, acetyl^-boswellic
acid, 9 , ll-dehydro^-boswellic acid, acetyl-9, ll-dehydro- b-
boswellic acid, a-boswellic acid, acetyl-a-boswellic acid,
11-dehydro-a-boswellic acid, acetyl-9, 11-dehydro-aboswellic
acid, lupeolic acid, acetyl-lupeolic acid,
12-ursene-2-diketone, incensole, incensole acetate, a de
rivative, in particular an ester thereof, a physiologically
tolerable salt thereof, a combination thereof, or a prepa
ration containing one or more of these compounds for the
preparation of a pharmaceutical drug for human medical or
veterinary prophylaxis and/or treatment of
a ) damage to and/or of the islets of Langerhans and/or
b ) damage to the B-cells of the islets of Langerhans.
15. The use according to claim 14, wherein the damage to
the islets of Langerhans and/or to their B-cells is accom
panied by inflammation (insulitis) .
16. The use according to any of claims 14 or 15, wherein
the damage to and/or the inflammation of the islets of
Langerhans and/or the damage to the B-cells of the islets
of Langerhans is/are associated with type 1 diabetes, type
2 diabetes or pancreatitis.
17. The use according to claim 16, wherein the type 1 di
abetes is type la diabetes, LADA diabetes or type lb diabe
tes .
18. The use according to any of claims 14 to 17, wherein
the combination consists of acetyl-ll-keto^-boswellic acid
and ll-keto^-boswellic acid or physiologically tolerable
salts thereof.
19. The use according to claim 18, wherein acetyl-11-
keto^-boswellic acid and ll-keto^-boswellic acid are con
tained in a preparation.
20. The use according to any of claims 14 to 19, wherein
use is made for the preparation of a pharmaceutical prepa
ration for intraperitoneal, oral, buccal, rectal, intramus
cular, subcutaneous or intravenous administration.
21. The use according to any of claims 14 to 20, wherein
use is made for the production of a pharmaceutical prepara
tion in the form of tablets, sugar-coated tablets (dragees),
capsules, solutions, emulsions, or suppositories.
22. The use according to any of claims 14 to 21, wherein
use is made together with at least one other pharmaceutical
substance .
23. The use according to claim 22, wherein the pharmceutical
substance is selected from antiphlogistics , oral
antidiabetics, antioxidants, pentoxifylline, isoxazolene,
interferons, gangliosides , a -adrenoceptor antagonists,
nicotinamide, dimethylurea, lipid-lowering agents and
herbal drugs.
24. The use according to any of claims 22 or 23, wherein
the oral antidiabetic is selected from sulfonylureas,
glinides, metformin, imidazolidinones , glitazones,
a -glucosidase inhibitors, and dipeptidylpeptidase IV in
hibitors .
25. The use according to any of claims 14 to 24, wherein
the pharmaceutical preparation is prepared for the prophylaxis
for and/or treatment of a person, selected from:
i ) genetically predisposed persons with preceding diabetesinducing
diseases caused by viruses, said viruses selected
from mumps viruses, coxsackie B viruses, rubella viruses,
measles viruses, cytomegaloviruses, or influenza viruses,
and/or
ii) persons with at least one type 1 diabetic parent or
siblings, and/or
iii) persons with up-regulated diagnostic markers for inflamination
of the pancreas.
26. The use according to claim 25, wherein said diagnos
tic marker is selected from glutamate decarboxylase, tyrosin
phosphatase IA-2, or islet cell antibodies (ICA) .
27. Acetyl-ll-keto^-boswellic acid, ll-keto^-boswellic
acid, b-boswellic acid, acetyl^-boswellic acid,
9 , ll-dehydro^-boswellic acid, acetyl-9, ll-dehydro- b-
boswellic acid, a-boswellic acid, acetyl-a-boswellic acid,
11-dehydro-a-boswellic acid, acetyl-9, 11-dehydro-aboswellic
acid, lupeolic acid, acetyl-lupeolic acid,
12-ursene-2-diketone, incensole, incensole acetate, a de
rivative, in particular an ester, a physiologically toler
able salt thereof, a combination thereof, or a preparation
containing one or more of these compounds for the human
medical or veterinary prophylaxis and/or treatment of
a ) damage to and/or inflammation of the islets of Langerhans
and/or
b ) damage to the B-cells of the islets of Langerhans .
28. Acetyl-ll-keto^-boswellic acid, ll-keto^-boswellic
acid, b-boswellic acid, acetyl^-boswellic acid,
9 , ll-dehydro^-boswellic acid, acetyl-9, ll-dehydro- b-
boswellic acid, a-boswellic acid, acetyl-a-boswellic acid,
11-dehydro-a-boswellic acid, acetyl-9, 11-dehydro-aboswellic
acid, lupeolic acid, acetyl lupeolic acid,
12-ursene-2-diketone, incensole, incensole acetate, a de
rivative, in particular an ester thereof, a physiologically
tolerable salt thereof, a combination thereof, or a preparation
containing one or more of these compounds for the
use according claim 27, wherein the damage to the islets of
Langerhans and/or their B-cells is accompanied by inflamma
tion (insulitis) .
29. Acetyl-ll-keto^-boswellic acid, ll-keto^-boswellic
acid, b-boswellic acid, acetyl^-boswellic acid,
9 , ll-dehydro^-boswellic acid, acetyl-9, ll-dehydro- b-
boswellic acid, a-boswellic acid, acetyl-a-boswellic acid,
11-dehydro-a-boswellic acid, acetyl-9, 11-dehydro-aboswellic
acid, lupeolic acid, acetyl lupeolic acid,
12-ursene-2-diketone, incensole, incensole acetate, a de
rivative, in particular an ester thereof, a physiologically
tolerable salt thereof, a combination thereof, or a preparation
containing one or more of these compounds for the
use according to claim 25, wherein the damage to and/or the
inflammation of the islets of Langerhans and/or the damage
to the B-cells of the islets of Langerhans is/are associ
ated with type 1 diabetes, type 2 diabetes, or pancreatitis
.
30. Acetyl-ll-keto^-boswellic acid, ll-keto^-boswellic
acid, b-boswellic acid, acetyl^-boswellic acid,
9 , ll-dehydro^-boswellic acid, acetyl-9, ll-dehydro- b-
boswellic acid, a-boswellic acid, acetyl-a-boswellic acid,
11-dehydro-a-boswellic acid, acetyl-9, 11-dehydro-aboswellic
acid, lupeolic acid, acetyl lupeolic acid,
12-ursene-2-diketone, incensole, incensole acetate, a de
rivative, in particular an ester thereof, a physiologically
tolerable salt thereof, a combination thereof, or a prepa
ration containing one or more of these compounds for the
use according to claim 29, wherein the type 1 diabetes is
type la diabetes, LADA diabetes or type lb diabetes.
31. Acetyl-ll-keto^-boswellic acid, ll-keto^-boswellic
acid, b-boswellic acid, acetyl^-boswellic acid,
9 , ll-dehydro^-boswellic acid, acetyl-9, ll-dehydro- b-
boswellic acid, a-boswellic acid, acetyl-a-boswellic acid,
11-dehydro-a-boswellic acid, acetyl-9, 11-dehydro-aboswellic
acid, lupeolic acid, acetyl lupeolic acid,
12-ursene-2-diketone, incensole, incensole acetate, a de
rivative, in particular an ester thereof, a physiologically
tolerable salt thereof, a combination thereof, or a preparation
containing one or more of these compounds for the
use according to any of claims 2 8 to 30, wherein said com
bination consists of acetyl-ll-keto^-boswellic acid and
11- keto^-boswellic acid and/or physiologically tolerable
salts thereof.
32. Acetyl-ll-keto^-boswellic acid, ll-keto^-boswellic
acid, b-boswellic acid, acetyl^-boswellic acid,
9 , ll-dehydro^-boswellic acid, acetyl-9, ll-dehydro- b-
boswellic acid, a-boswellic acid, acetyl-a-boswellic acid,
11-dehydro-a-boswellic acid, acetyl-9, 11-dehydro-aboswellic
acid, lupeolic acid, acetyl lupeolic acid,
12-ursene-2-diketone, incensole, incensole acetate, a de
rivative, in particular an ester thereof, a physiologically
tolerable salt thereof, a combination thereof, or a preparation
containing one or more of these compounds for the
use according to claim 31, wherein acetyl-ll-keto- b-
boswellic acid and ll-keto^-boswellic acid are contained
in a preparation.
33. Acetyl-ll-keto^-boswellic acid, ll-keto^-boswellic
acid, b-boswellic acid, acetyl- -boswellic acid,
9 , ll-dehydro^-boswellic acid, acetyl-9, ll-dehydro- b-
boswellic acid, a-boswellic acid, acetyl-a-boswellic acid,
11-dehydro-a-boswellic acid, acetyl-9, 11-dehydro-aboswellic
acid, lupeolic acid, acetyl lupeolic acid,
12-ursene-2-diketone, incensole, incensole acetate, a de
rivative, in particular an ester thereof, a physiologically
tolerable salt thereof, a combination thereof, or a preparation
containing one or more of these compounds for the
use according to any of claims 2 8 to 32, wherein the use is
made intraperitoneally, orally, buccally, rectally, intra
muscularly, subcutaneously or intravenously.
34. Acetyl-ll-keto^-boswellic acid, ll-keto^-boswellic
acid, b-boswellic acid, acetyl^-boswellic acid, 9,11-
dehydro^-boswellic acid, acetyl-9, ll-dehydro^-boswellic
acid, a-boswellic acid, acetyl-a-boswellic acid,
11-dehydro-a-boswellic acid, acetyl-9, 11-dehydro-aboswellic
acid, lupeolic acid, acetyl lupeolic acid,
12-ursene-2-diketone, incensole, incensole acetate, a de
rivative, in particular an ester thereof, a physiologically
tolerable salt thereof, a combination thereof, or a prepa
ration containing one or more of these compounds for the
use according to any of claims 2 8 to 33, wherein the use is
made in the form of tablets, sugar-coated tablets (dragees),
capsules, solutions, emulsions or suppositories.
35. Acetyl-ll-keto^-boswellic acid, ll-keto^-boswellic
acid, b-boswellic acid, acetyl^-boswellic acid,
9 , ll-dehydro^-boswellic acid, acetyl-9, ll-dehydro- b-
boswellic acid, a-boswellic acid, acetyl-a-boswellic acid,
11-dehydro-a-boswellic acid, acetyl-9, 11-dehydro-aboswellic
acid, lupeolic acid, acetyl lupeolic acid,
12-ursene-2-diketone, incensole, incensole acetate, a de
rivative, in particular an ester thereof, a physiologically
tolerable salt thereof, a combination thereof, or a prepa
ration containing one or more of these compounds for the
use according to any of claims 2 8 to 34, wherein use is
made together with at least one other pharmaceutical sub
stance .
36. Acetyl-ll-keto^-boswellic acid, ll-keto^-boswellic
acid, b-boswellic acid, acetyl^-boswellic acid,
9 , ll-dehydro^-boswellic acid, acetyl-9, ll-dehydro- b-
boswellic acid, a-boswellic acid, acetyl-a-boswellic acid,
11-dehydro-a-boswellic acid, acetyl-9, 11-dehydro-aboswellic
acid, lupeolic acid, acetyl lupeolic acid,
12-ursene-2-diketone, incensole, incensole acetate, a de
rivative, in particular an ester thereof, a physiologically
tolerable salt thereof, a combination thereof, or a prepa
ration containing one or more of these compounds for the
use according to claim 35, wherein the pharmaceutical substance
that is used at least is selected from antiphlogistics,
oral antidiabetics, antioxidants, pentoxifylline,
isoxazolene, interferons, gangliosides , a-adrenoceptor an
tagonists, nicotinamide, dimethylurea, lipid-lowering
agents and herbal drugs.
37. Acetyl-ll-keto^-boswellic acid, ll-keto^-boswellic
acid, b-boswellic acid, acetyl^-boswellic acid,
9 , ll-dehydro^-boswellic acid, acetyl-9, ll-dehydro- b-
boswellic acid, a-boswellic acid, acetyl-a-boswellic acid,
11-dehydro-a-boswellic acid, acetyl-9, 11-dehydro-aboswellic
acid, lupeolic acid, acetyl lupeolic acid, 12-
ursene-2-diketone, incensole, incensole acetate, a deriva
tive, in particular an ester thereof, a physiologically
tolerable salt thereof, a combination thereof, or a preparation
containing one or more of these compounds for the
use according to claim 36, wherein the oral antidiabetic is
selected from sulfonylureas, glinides, metformin, imidazolidinones
, glitazones, a-glucosidase inhibitors, and
dipeptylpeptidase IV inhibitors.
38. Acetyl-ll-keto^-boswellic acid, ll-keto^-boswellic
acid, b-boswellic acid, acetyl^-boswellic acid,
9 , ll-dehydro^-boswellic acid, acetyl-9, ll-dehydro- b-
boswellic acid, a-boswellic acid, acetyl-a-boswellic acid,
11-dehydro-a-boswellic acid, acetyl-9, 11-dehydro-aboswellic
acid, lupeolic acid, acetyl lupeolic acid,
12-ursene-2-diketone, incensole, incensole acetate, a de
rivative, in particular an ester thereof, a physiologically
tolerable salt thereof, a combination thereof, or a prepa
ration containing one or more of these compounds for the
use according to any of claims 27 to 37, wherein the person
receiving the prophylaxis and/or the treatment is selected
from:
i ) genetically predisposed persons with preceding diabetesinducing
diseases caused by viruses, said viruses selected
from mumps viruses, coxsackie B viruses, rubella viruses,
measles viruses, cytomegaloviruses, or influenza viruses,
and/or
ii) persons with at least one type 1 diabetic parent or
siblings, and/or
iii) persons with up-regulated diagnostic markers for in
flammation of the pancreas.
39. Acetyl-ll-keto^-boswellic acid, ll-keto^-boswellic
acid, b-boswellic acid, acetyl- -boswellic acid,
9 , ll-dehydro^-boswellic acid, acetyl-9, ll-dehydro- b-
boswellic acid, a-boswellic acid, acetyl-a-boswellic acid,
11-dehydro-a-boswellic acid, acetyl-9, 11-dehydro-aboswellic
acid, lupeolic acid, acetyl lupeolic acid,
12-ursene-2-diketone, incensole, incensole acetate, a de
rivative, in particular an ester thereof, a physiologically
tolerable salt thereof, a combination thereof, or a preparation
containing one or more of these compounds for the
use according to claim 38, wherein the diagnostic marker is
selected from glutamate decarboxylase, tyrosin phosphatase
IV-2 or islet cell antibodies (ICA) .