U.S. patent application number 09/991650 was filed with the patent office on 2002-05-09 for composition for treatment of diabetes and treatment of diabetes.
Invention is credited to Niizato, Tetsutaro, Shiotani, Masaharu, Shoji, Yoko.
Application Number | 20020055491 09/991650 |
Document ID | / |
Family ID | 17496822 |
Filed Date | 2002-05-09 |
United States Patent
Application |
20020055491 |
Kind Code |
A1 |
Niizato, Tetsutaro ; et
al. |
May 9, 2002 |
Composition for treatment of diabetes and treatment of diabetes
Abstract
Fosfomycin or a pharmaceutically acceptable salt thereof has
been found to have an action of lowering the serum glucose level
and is recognized to be useful as an orally administrable remedy
for treating diabetes. It has further been found that the serum
glucose level-lowering action of fosfomycin or its salt can be
enhanced synergistically and significantly when forfomycin is
administered in association with vanadyl sulfate and the like.
Therefore, the composition comprising fosfomycin or its salt and
vanadyl sulfate or the like is useful as an orally administrable
remedy for treating diabetes.
Inventors: |
Niizato, Tetsutaro;
(Yokohama-shi, JP) ; Shiotani, Masaharu;
(Yokohama-shi, JP) ; Shoji, Yoko; (Yokohama-shi,
JP) |
Correspondence
Address: |
LARSON & TAYLOR, PLC
1199 NORTH FAIRFAX STREET
SUITE 900
ALEXANDRIA
VA
22314
US
|
Family ID: |
17496822 |
Appl. No.: |
09/991650 |
Filed: |
November 26, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09991650 |
Nov 26, 2001 |
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09509664 |
Mar 31, 2000 |
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09509664 |
Mar 31, 2000 |
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PCT/JP98/04470 |
Oct 2, 1998 |
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Current U.S.
Class: |
514/99 |
Current CPC
Class: |
A61K 31/665 20130101;
A61K 33/24 20130101; Y10S 514/866 20130101; A61K 33/24 20130101;
A61K 31/665 20130101; A61K 33/24 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
514/99 |
International
Class: |
A61K 031/665 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 3, 1997 |
JP |
9-271205 |
Claims
1. A method for treating a diabetic patient, which comprises
administering orally or parenterally to the patient who shows a
symptom of an unusually high serum glucose level, an amount of
fosfomycin or a pharmaceutically acceptable salt thereof in an
effective dose to lower the serum glucose level in blood.
Description
TECHNICAL FIELD
[0001] This invention relates to a novel composition for
therapeutically treating diabetes, which comprises as an active
ingredient fosfomycin, a known antibiotic, or a pharmaceutically
acceptable salt thereof. This invention also relates to a novel
composition for therapeutically treating diabetes, which comprises
fosfomycin or a pharmaceutically acceptable salt thereof and also a
vanadyl compound (or a vanadyl salt) containing vanadyl group
(VO.sup.2+) as active ingredients. This invention further relates
to a novel method for treating diabetes by administration of
fosfomycin or a salt thereof.
[0002] Furthermore, this invention includes the use of fosfomycin
or a salt thereof or the use of a mixture of fosfomycin or a salt
thereof with a vanadyl compound, in the preparation of a remedy of
diabetes.
BACKGROUND ART
[0003] Diabetes are one of typical diseases incident to old adults,
similarly to cancers, brain infarction, cardiac infarction,
Alzheimer's disease and the like. There are numerous latent
diabetes, too. Diabetes are diseases caused by occurrence of
abnormal metabolisms of glucose, protein and lipid due to a
deficiency or insufficiency of the actions of insulin. Typical
signs of diabetes include an abnormal increase in the serum glucose
level over the normal range of the glucose level and an excretion
of glucose in the urine.
[0004] Insulin is one of hormones in pancreas and has such
functions to promote the permeability of glucose through the cell
membranes in liver, muscles and adipose tissues and thereby to
increase the uptake of glucose by the cells, and further to promote
the combustion of glucose in the glycolysis step and oxidation step
of glucose in the muscles and also to elevate the activity of the
enzyme system for synthesizing glycogen from glucose. It is known
that by exhibiting the above biological functions, insulin has such
action "in vivo" as to keep the serum glucose level at the normal
levels.
[0005] In 1985, the classification of diabetes was proposed by The
World Health Organization (WHO). Diabetes are classified into two
large groups, namely, the insulin-dependent diabetes mellitus (Type
I, IDDM) where the patients do not produce insulin ; and the
non-insulin-dependent diabetes mellitus (Type II, NIDDM) where the
patients cause an insulin resistance. For the treatment of the type
II diabetes, some orally administrable remedies are used. Under the
present situation, however, the treatment of the type I diabetes
has to resort on the injection of insulin. It has therefore been
required worldwide to develope such novel oral remedies which are
effective for treating the diabetes by oral administration.
[0006] It has been known from about 1960's that "ouabain" which has
a digitalis-like cardiac action is effective as a strong inhibitor
to Na,K-ATPase. Further, ouabain is known to have an insulin-like
action in view of the fact that the action of inhibiting Na,
K-ATPase can participate in the transportation and metabolism of
glucose "in vivo". in 1977, Cantley et al, found that sodium
orthovanadate which is a penta-valent vanadium compound and which
was accidentally mixed in ATP can strongly inhibit Na,K-ATPase (L.
C.Cantley et al., "J.Biol.Chem." Vol. 252, No.21, 7421-7423
(1977)). Judging from the fact that ouabain inhibits Na,K-ATPase
and possesses the insulin-like action, many researchers then
anticipated that the penta-valent vanadium compound, which was
already admitted as an inhibitor to Na,K-ATPase similarly to
ouabain, would also exhibit the insulin-like action (refer to
Hiroshi Sakurai, "Gendai Kagaku" Current Chemistry in English,
July, 1996,14-20). As a result of many subsequent researches
relating to the action of penta-valent vanadium on the uptake of
glucose into cells, there is reported that some vanadates which are
penta-valent vanadium compounds possess the insulin-like actions
(see, for example, Degani et al, "Biochemistry" Vol. 20, p.5795
(1981)).
[0007] Further, streptozotocin is known to be an antibiotic which
is produced by actinimycetes. It is known that streptozotocin, if
administered to animals, can specifically destroy .beta.-cells of
the islets of Langerhans in pancreas to stop the secretion of
insulin and thus involve occurrence of experimental diabetes in the
animals. In 1985, Heyliger et al, reported that when the diabatic
rats which were made diabatic by administration of streptozotocin
(abbreviated as STZ), namely the rats called as STZ diabatic rats,
are given sodium metha-vanadate (NaVO.sub.3) in the form of an
aqueous saline solution as drinking water, the so treated rats
showed such a decrease in the glucose level in blood serum that the
glucose level was returned to the normal level at 6th week after
the administration of the vanadate. Heylinger et al also reported
that a vanadate showed the insulin-like action with respect to the
glucose metabolism (see C. B.Heyliger et al., "Science"
Vol.27,p.1474-1477 (1985)).
[0008] Further, Japanese Patent Application Laid Open Publication,
KOKAI-Hei 2-292217 specification (issued on Dec. 3, 1990) discloses
that several vanadium complexes of the following
formulae(A).about.(G) possess a function of lowering the serum
glucose level and that vanadyl sulfate (VOSO.sub.4) also possesses
the function of lowering the serum glucose level.
[0009] Vanadium (VI) complex having the following formula (A) 1
[0010] Salicylaldehyde-vanadium (VI) complex having the following
formula (B) 2
[0011] Gluconic acid- or L-lactic acid-vanadium (VI) complex having
the following formula (C) 3
[0012] wherein R.sup.1 stands for a group
--CH(OH)CH(OH)CH(OH)CH.sub.2OH, or a methyl group.
[0013] L-Cystein methyl ester- or L-cysteamine-vanadium (VI)
complex having the following formula (D) 4
[0014] wherein R.sup.2 stands for a hydrogen atom or a
methoxycarbonyl group.
[0015] L-(+)-Tartaric acid -vanadium (VI) complex having the
following formula (E) 5
[0016] Oxalic acid-vanadium (VI) complex having the following
formula (F) 6
[0017] Malonic acid-vanadium (VI) complex having the following
formula (G) 7
[0018] While, Hiroshi Sakurai et al, report that vanadyl sulfate
possesses the action of lowering the serum glucose level, and they
report that comparisons are made between various vanadium
compounds, including vanadium oxide, meta-vanadic acid,
orthovanadic acid, vanadyl sulfate, potassium vanadate, sodium
vanadate and the like, with remarking that the toxicity of sodium
metavanadate (NaVO.sub.3) which is a penta-valent vanadium
compound, when orally administered, was about 10 times higher than
the toxicity of vanadyl sulfate(VOSO.sub.4) which is a tetra-valent
vanadium compound (see Hiroshi Sakurai et al, "Trace Elements in
vivo" published by Hirokawa Book Company, 1994).
[0019] Up to date, there have been synthesized a variety of
vanadium compounds which are of a low toxicity and are orally
administrable. Peroxo-vanadium compounds thus synthesized were
studied on their function of lowering the serum glucose level, and
further investigations were made to estimate whether a combined use
of the penta-valent vanadium compounds synthesized and hydrogen
peroxide can give rise to a synergistic effect on the action of
lowering the serum glucose level. However, there is found no report
to show that said combined use would have any synergistic effect in
the action of lowering the serum glucose level (see B. I.Poner et
al., "J.Biol.Chem.", Vol.269, No.6, 4596-4604 (1994)).
[0020] Specifically, fosfomycin is a known antibiotic having an
antibiotic activity. Fosfomycin or a pharmaceutically acceptable
salt thereof has the structure represented by the following general
formula (I) 8
[0021] wherein R and R' are each a hydrogen atom or a
pharmaceutically acceptable monovalent metal atom, for example, an
alkali metal atom, preferably sodium, potassium or ammonium
radical, or R and R' are combined together to show a divalent metal
atom pharmaceutically acceptable, for example, an alkaline earth
metal atom, preferably calcium or magnesium.
[0022] Fosfomycin and a salt thereof are useful as an
antibiological agent and are also useful as a relieving or
preventing agent for nephro-toxicity of aminoglycoside antibiotics
(see Japanese Patent Publication Sho-64-5574) and are further
useful as an agent for reducing the adverse side-effects of
anticancer agents (Japanese Patent Publication Hei-5- 2649). As far
as we, the inventors of this invention know, however, such fact has
never been known that fosfomycin has any action for lowering the
serum glucose level of the diabetic rats.
DISCLOSURE OF THE INVENTION
[0023] An object of this invention is to provide a novel remedy for
treating diabetes, which is capable of administering either orally
or parenterally. Another object of this invention is to provide
such a novel, orally administrable drug preparation for treating
diabetes, which contains as an active ingredient a vanadium
compound having an action capable of lowering an unusually high
serum glucose level by the diabetes to the normal serum glucose
level, and which further contains as another active ingredient such
a second compound capable of enhancing the action of lowering the
serum glucose level shown by the said vanadium compound and also
possessing by itself the action of lowering the serum glucose
level. A further object of this invention is to provide a novel
method for treating diabetes. Other objects of this invention will
become apparent from the undermentioned explanation.
[0024] We, the inventors of this invention, have made extensive
investigations in order to achieve the objects of this invention as
above-mentioned. As a part of our investigations, we have first
carried out experimental studies on the oral administration of
vanadyl sulfate [molecular formula VOSO.sub.4; called also as
vanadium oxysulfate (VI)] to the STZ diabetic rats which were
experimentally induced by the administration of streptozotocin
(STZ) (hereinafter sometimes abbreviated as "STZ diabetic rats").
Said vanadyl sulfate used here is already known to possess the
action capable of lowering such an unusually high serum glucose
level of the experimental diabetic rats to the normal serum glucose
level. Our experimental studies in question have now been made to
estimate how the dosage of vanadyl sulfate orally administered can
influence on the strength of the action of vanadyl sulfate for
lowering the serum glucose level, the strength of the action
thereof for lowering the urea type nitrogen level in the serum, the
strength of the action thereof for lowering the creatinine level in
the serum etc., as well as on the strength of the action thereof
for lowering the urinary glucose (urinary sugar) level, the
strength of the action thereof for lowering the urinary total
protein level, and the strength of the action thereof for lowering
the urinary creatinine level. Then, we have further proceeded our
experimental studies to carry out the oral administration of
vanadyl sulfate in combination with various additional compounds to
the STZ diabetic rats, in order to detect what are such certain
compounds which can exhibit a synergistically enhancing effect on
the serum glucose level-lowering action of vanadyl sulfate.
[0025] As a result of these investigations, we have found for the
first time that when disodium salt or calcium salt of fosfomycin is
administered orally to the STZ diabetic rats, it can show such
activity that the fosfomycin salt does not exhibit any action of
lowering the serum glucose level at a low dosage of administration
of it, but it can exhibit a significant action of lowering the
serum glucose level at a high dosage of administration of it, even
when it is administered by itself. Thus, we have now found, quite
unexpectedly, that fosfomycin or a pharmaceutically acceptable salt
thereof, only when administered at a high dosage, can have the
action of lowering the serum glucose level and then is useful as a
remedy for treating diabetes.
[0026] Furthermore, we have now found that fosfomycin or a salt
thereof possesses such a function that fosfomycin or its salt is
capable of synergistically enhancing the action of lowering the
serum glucose level as shown by the vanadyl sulfate which is
exhibited upon the administration of vanadyl sulfate to the STZ
diabetic rats. We have further found that as similar as the vanadyl
sulfate, vanadyl dichloride (VI) of formula VOCl.sub.2 and vanadyl
dibromide (VI) of formula VOBr.sub.2 are also expectable to have
the action of lowering the serum glucose level, and also that
fosfomycin or a salt thereof is expectable to be able to enhance
the serum glucose level-lowering action of vanadyl dichloride and
vanadyl dibromide. This invention has been completed on the basis
of these findings.
[0027] According to a first aspect of this invention, therefore,
there is provided a composition for treating diabetes, which
comprises as an active ingredient fosfomycin or a pharmaceutically
acceptable salt thereof, in combination with a pharmaceutically
acceptable solid or liquid carrier or carriers for the active
ingredient.
[0028] In the composition for treating diabetes according to the
first aspect of this invention, fosfomycin may preferably be in the
form of its salt, and it may suitably be in the form of monosodium
salt or disodium salt or calcium salt. The toxicity of fosfomycin
itself is extremely low (see Japanese Journal of Antibiotics,
January, 1979). Fosfomycin or its salt may be orally administered,
and the dosage of fosfomycin for the oral administration may be in
the range of 0.05-5 g/day. Fosfomycin or its salt may also be
parenterally administered. The parenteral administration may be
effected by intravenous administration, intra-muscular or
subcutaneous injection, intraperitoneal administration, intrarectal
administration, percutaneous administration or intra-mucosal
administration.
[0029] In the composition according to the first aspect of this
invention, the carrier to be incorporated may be any of solid or
liquid carriers conventionally used in the art. The solid carrier
may, for example, be starch, lactose, crystalline cellulose and
calcium phosphate. The liquid carrier may, for example, be water,
aqueous common salt solution and ethanol. The content of fosfomycin
as active ingredient in the composition of this invention may, for
example, be in the range of 5-80% based on the total weight of the
composition. The composition according to the first aspect of this
invention may be formulated in the form of a preparation suitable
for oral administration or parenteral administration.
[0030] In general, the composition according to the first aspect of
this invention may be formulated in the form of usual preparations.
The preparations may additionally contain one or more of filler,
extender, binder, moistening agent, disintegrator, surface active
agent and lubricant. The preparations may be in the form of
tablets, pills, powder, liquid, suspension, emulsion, granules,
capsules, suppository, injection (solution or suspension) or
ointment. When the composition is prepared in the form of tablets,
there may be incorporated therein as the carrier a solid carrier
such as lactose, sodium chloride, starch, calcium carbonate,
kaolin, crystalline cellulose, silica, etc.; a binder such as
water, ethanol, propanol, simple syrup, starch liquor, gelatin
solution, carboxymethyl cellulose, shellac, methyl cellulose,
potassium phosphate, polyvinylpyrrolidone, etc.; a disintegrator
such as dry starch, sodium alginate, agar powder, laminaran powder,
sodium hydrogen carbonate, polyoxyethylene sorbitan fatty acid
esters, sodium lauryl sulfate, stearic acid monoglyceride, etc.; a
disintegration inhibitor such as stearin, cacao butter,
hydrogenated oil, etc.; an absorption promotor such as quaternary
ammonium salts, sodium lauryl sulfate, etc.; a humectant such as
glycerin, starch, etc.; an adsorbent such as bentonite, colloidal
silica, etc.; and a lubricant such as purified talc, stearic acid
salts, boric acid powder, polyethyleneglycol, etc. If necessary,
tablets may also take a form of tablets coated with a usual
coating, for example, sugar-coated tablets, gelatin-coated tablets,
film-coated tablets or two-layered or multi-layered tablets.
[0031] In cases where the composition according to the first aspect
of this invention is prepared in the form of pills, there may be
incorporated as the carrier an excipient such as lactose, starch,
cacao butter, hydrogenated vegetable oils, kaolin, talc, etc.; a
binder such as powdery gum arabic, powdery tragacanth, gelatin,
ethanol, etc.; a disintegrator such as laminaran, agar, etc. In
cases where the composition is prepared in the form of
suppositories, there may be incorporated as the carrier
polyethyleneglycol, cacao butter, higher alcohols, higher alcohol
esters, gelatin, semi-synthesized glycerides, etc.
[0032] When the composition according to the first aspect of this
invention is used as a preparation for oral administration, it is
preferred to formulate the composition in the form of tablets,
pills, granules, etc. by incorporating known pharmaceutically
acceptable excipient(s), for example, lactose, crystalline
cellulose, starch, calcium phosphate; binder(s), for example,
starch, sodium caraelose, hydroxypropyl cellulose; disintegrator,
for example, calcium caramelose, calcium carbonate; lubricant(s),
for example, magnesium stearate, talc, etc. It is also possible to
formulate the composition in the form of a dry syrup or a syrup in
a usual manner. Further, by applying a known retarted release
formulation technique to these various types of preparations, there
may be formulated a sustained preparation.
[0033] Other types of the preparations include sublingual tablet,
suppository, collunarium, ophthalmic solution or endermic absorbent
preparation in the form of plaster, ointment or cream.
[0034] In cases where the composition of this invention is in the
form of orally administrable preparations, sublingual tablets or
suppository, fosfomycin or its salt of general formula (I) may be
administered at a daily dosage of 0.05-5 g, preferably 0.1-1 g,
once a day or twice or three times a day dividedly. For the other
preparation forms, the dosage of fosfomycin may suitably vary
depending upon the purpose of treatment.
[0035] In cases where the composition according to the first aspect
of this invention is formulated in the form of capsules, the
capsules are prepared by mixing the active ingredient with various
carriers as exemplified above and by filling the mixture in hard
gelatin capsules or soft capsules. Further, when the composition is
formulated in the form of injections, it is preferred that the
composition is first prepared in the form of liquid, emulsion or
suspension, which is then sterilized and is made isotonic with
blood. When the composition is formulated in the form of
injections, there may be incorporated as the diluent water, aqueous
lactic acid solution, ethyl alcohol, propylene glycol or
polyoxyethylene sorbitan fatty acid esters. In this case, common
salt or glycerin may be added to the injections in an amount
sufficient to give an isotonic solution. Further, there may be
added solubilizer, buffering agent or antipaining agent which is
conventionally used.
[0036] When the composition according to the first aspect of this
invention is orally administered for the purpose of treating
diabetes, fosfomycin disodium salt as the active ingredient may be
orally administered consecutively. The consecutive administration
may be effected for 2-30 days, preferably for 5 days, and it may
dividedly be made in two or three times a day. The dose of
fosfomycin disodium salt is 32-3000 mg/kg, preferably 320-1000
mg/kg. We have found that oral administration of fosfomycin
disodium salt at a dose of 160 mg/kg showed a tendency to improve
the serum glucose level in blood. We have further confirmed that
the oral administration of fosfomycin disodium salt or calcium salt
at a dose of 320 mg/kg twice a day for 5 consecutive days can
evidently ameliorate an unusually high serum glucose level or some
other symptoms of diabetes mullitus to get a good effect of the
treatment of diabetes.
[0037] Further, according to a second aspect of this invention,
there is provided a method for treating diabetic patient, which
comprises administering orally or parenterally to the patient who
shows a symptom of unusually high serum glucose level, an amount of
fosfomycin or a pharmaceutically acceptable salt thereof in an
effective dose to lower the serum glucose level in blood.
[0038] According to a third aspect of this invention, there is
provided the use of fosfomycin or a pharmaceutically acceptable
salt thereof, in the preparation of a composition for treating
diabetes.
[0039] Further, according to a fourth aspect of this invention,
there is provided a composition for treating diabetes, which
comprises fosfomycin or a pharmaceutically acceptable salt thereof
as a first active ingredient, and a vanadyl compound (or a vanadyl
salt) represented by the following general formula (II)
O=V(X).sub.n (II)
[0040] wherein V stands for tetravalent vanadium, X stands for a
sulfate group --SO.sub.4 or a chlorine atom or bromine atom, and n
is 1 when X is the sulfate group --SO.sub.4 and n is 2 when X is
the chlorine or bromine atom, as a second active ingredient, in
combination with a pharmaceutically acceptable solid or liquid
carrier or carriers for these active ingredients.
[0041] In the composition according to the fourth aspect of this
invention, fosfomycin is preferably in the form of its disodium
salt or calcium salt. The vanadyl compound of general formula (II)
(i.e. vanadyl salt) is preferably vanadyl sulfate VOSO.sub.4. The
vanadyl sulfate may also be in the form of its tri-hydrate or
tetra-hydrate.
[0042] Fosfomycin or its salt and the vanadyl compound of general
formula (II), which are used as the active ingredients in the
composition according to the fourth aspect of this invention, may
be administered orally or parenterally, similarly to the
composition according to the first aspect of this invention. The
carrier incorporated in this composition may be of the same kinds
as those used in the composition according to the first aspect of
this invention. Further, the composition according to the fourth
aspect of this invention may be formulated in the form of orally or
parenterally administrable preparations, similarly to the
composition according to the first aspect of this invention.
[0043] When the composition of the fourth aspect of this invention
is orally administered for the treatment of diabetes, fosfomycin
disodium salt as an active ingredient may be administered for 2-30
consecutive days, preferably 5 consecutive days. In parallel
therewith, vanadyl compound of formula (II) may also be
administered consecutively. The single dose for oral administration
of fosfomycin disodium salt is 32-3000 mg/kg, whereas the single
oral dose of the vanadium compound of formula (II), particularly
vanadyl sulfate, is 1-100 mg/kg. We have confirmed by our
experiments that oral administration of fosfomycin sodium salt and
vanadyl sulfate concurrently by the administration of the
composition of the fourth aspect of this invention can remarkably
ameliorate the various symptoms of diabetes, with involving a
synergistic effect of the treatment over the single administration
of fosfomycin by itself.
[0044] In the composition of the fourth aspect of this invention,
it is preferable that fosfomycin or its salt and vanadyl compound
of general formula (II) are contained in a molar ratio in the range
of 1:0.01 to 1:10, preferably in the range of 1:0.1 to 1:3. The
composition preferably contains fosfomycin disodium salt or calcium
salt and also contains, as the vanadyl compound of general formula
(II), vanadyl sulfate of formula VOSO.sub.4, vanadyl dichloride of
formula VOCl.sub.2 or vanadyl dibromide of formula VOBr.sub.2 or a
hydrate thereof.
[0045] Further, according to a fifth aspect of this invention,
there is provided a method for treating a diabetic patient, which
comprises administering orally or parenterally to the patient who
shows a symptom of an unusually high serum glucose level, a mixture
of fosfomycin or pharmaceutically acceptable salt thereof with a
vanadyl compound (or a vanadyl salt) represented by the following
general formula (II)
O=V(X).sub.n (II)
[0046] wherein V stands for tetravalent vanadium, X stands for a
sulfate group --SO.sub.4 or a chlorine atom or bromine atom, and n
is 1 when X is the sulfate group --SO.sub.4 and n is 2 when X is
the chlorine or bromine atom or a hydrate thereof, in an effective
dose of said mexture to lower the serum glucose level in the
blood.
[0047] In the method according to the fifth aspect of this
invention, fosfomycin disodium salt or calcium salt may be
administered at a dosage of it effective to lower the serum glucose
level, and also vanadyl sulfate VOSO.sub.4 or vanadyl dichloride
VOCl.sub.2 or vanadyl dibromide VOBr.sub.2 or a hydrate thereof may
be administered at a dosage thereof effective to lower the serum
glucose level. Further, it is preferred to set that the proportions
of the fosfomycin salt and the vanadyl compound to be administered
are corresponding to a molar ratio in the range of 1:0.01 to 1:10.
In this method, fosfomycin or its salt and the vanadyl compound of
general formula (II) or a hydrate thereof may be orally
administered, simultaneously, for 2-30 consecutive days.
[0048] Furthermore, according to a sixth aspect of this invention,
there is included the use of a mixture of fosfomycin or a
pharmaceutically acceptable salt thereof with a vanadyl compound of
general formula (II) hereinbefore defined or a hydrate thereof.
[0049] In addition, with respect to the toxicity, LD.sub.50 value
in rats of fosfomycin calcium salt is not lower than 3.5 g/kg at
its oral administration and vanadyl sulfate showed no toxicity in
rats at its oral administration of 50 mg/kg.
BEST MODE FOR CARRYING OUT THE INVENTION
[0050] This invention is now illustrated more concretely with
reference to the following Examples.
EXAMPLE 1
[0051] In this Example, as animals to be tested, the STZ diabetic
rats were prepared from normal Wistar rats having an average body
weight of 250 g (male, 6 weeks of age). For this purpose, the
normal Wistar rats were made diabetic by a single administration of
a dose of 60 mg/kg of STZ intravenously. The normal Wistar rats
(male) which are to be subjected to the STZ administration, when
they were given 20 g/day of feed and 36 g/day of water, had have
such body conditions that average values each of their urine volume
output, serum glucose level, serum urea nitrogen level, serum
creatinine level, serum total protein level and serum albumin level
of the rats are amounting to 18 ml, 152 mg/dl, 18.0 mg/dl, 0.5
mg/dl, 5.63 g/dl and 4.2 g/dl, respectively.
[0052] The STZ diabetic rats as prepared and used in this Example
are such those rats (7 weeks of age, 6 rats per group) which had
received an intravenous administration of a single dose of 60 mg/kg
of STZ and which were confirmed to have been made diabetic with
their showing such symptom that their serum glucose level was not
less than 400 (mg/dl), when measured by sampling their blood at 1
week lapse from the STZ administration. These STZ diabetic rats
showed such disease symptoms which are characterized by unusually
much increased values of their taken amounts of water and the urine
volume output, serum glucose level and urinary glucose level, and
which are also characterized by abnormal increase in the urea
nitrogen (BUN)level and creatinine level in their serum, as well as
an unusual decrease in the serum total protein level and an
increase in the urinary creatinine level.
[0053] One week after the intravenous administration of single dose
60 mg/kg of STZ, to the male 7-week-old Wistar rats (6 rats per
group), which have been confirmed to have the symptoms of diabetes,
were orally administered either one or both of vanadyl sulfate
VOSO.sub.4 at a single dose of 50 mg/kg and fosfomycin disodium
salt (abbreviated as FOM-Na) at a single dose of 160 mg/kg, twice a
day for 5 consecutive days, by administration of the test
compounds) in the form of the aqueous solutions The body weight,
amounts (volumes) of feed taken, water taken and urine volume
output of the rats under test were measured with lapse of time.
Further, sampling of blood from the rats was effected at a time of
24 hours after the final administration of the compound(s) tested.
Samplings of the urine from the rats were effected over 12 hours
after the final administration of the compound(s) tested, and the
blood sample and the urine samples as collected were subjected to
the following biochemical tests.
[0054] In the biological tests of the blood sample above-mentioned,
there were measured the serum glucose level, serum urea nitrogen
level, serum creatinine level, serum total protein level and serum
albumin level. In the biochemical tests of the urine sample, there
were measured the collected amounts of the glucose, total protein
and creatinine present in the urine. As the animals to be used for
control tests (untreated), there were used such male 7-week-old
Wistar rats (6 rats per group) which were made to be the STZ
diabetic conditions, but which did not receive the administration
of the test compound(s). These rats for the comparative purpose
were tested similarly to the above tests.
[0055] The measured values (average values) of the body weight, the
volumes of feed taken and water taken and the urine volume output
shown by the test rats are summarized in Table 1 below for
exhibiting the general observation of the body conditions of the
rats under test. The measured values (average values) of the
biochemical tests of the serum (blood) sample are shown in Table 2
below. The measured values (average values) of the biochemical
tests of the urine sample are shown in Table 3 below.
1 TABLE 1 Body weight Feed volume Water volume Urine volume (g)
taken (g) taken (g) output (ml) Test compound The day of
measurement (Day) and its dose 0 5 0 5 0 5 0 5 Control group 239
.+-. 4 247 .+-. 7 35 .+-. 1 34 .+-. 3 115 .+-. 20 139 .+-. 15 115
.+-. 6 113 .+-. 11 (Untreated) VOSO.sub.4 50 mg/kg 226 .+-. 8 239
.+-. 9 35 .+-. 2 29 .+-. 4 140 .+-. 12 99 .+-. 24 111 .+-. 10 82
.+-. 21 FOM-Na 160 mg/kg 235 .+-. 4 282 .+-. 3 36 .+-. 1 37 .+-. 1
153 .+-. 5 142 .+-. 16 115 .+-. 5 106 .+-. 7 FOM-Na 160 mg/kg + 237
.+-. 7 251 .+-. 7 35 .+-. 2 21 .+-. 5 139 .+-. 6 53 .+-. 11 110
.+-. 4 29 .+-. 9 VOSO.sub.4 50 mg/kg * * *# Mark* shows a
significant difference of the measured value from the control group
(untreated). : P < 0.05 Mark# shows a significant difference of
the measured value from the treated rat group to which VOSO.sub.4
alone was administered. : P < 0.05
[0056]
2TABLE 2 Biochemical Test of Serum sample Urea Total nitrogen
Creatinine protein Albumin Glucose level level level level level
(mg/dl) (mg/dl) (mg/dl) (g/dl) (g/dl) Test compound The day of
measurement (Day) and its dose 0 5 5 5 5 5 Control group 418 .+-. 5
424 .+-. 22 30 .+-. 1 0.6 .+-. 0.02 5.2 .+-. 0.1 3.9 .+-. 0.1
(Untreated) VOSO.sub.4 50 mg/kg 416 .+-. 13 339 .+-.0 70 23 .+-. 2
0.6 .+-. 0.02 5.2 .+-. 0.1 3.8 .+-. 0.1 FOM-Na 160 mg/kg 418 .+-.
16 365 .+-. 21 31 .+-. 2 0.6 .+-. 0.02 5.5 .+-. 0.1 4.2 .+-. 0.1 *#
FOM-Na 160 mg/kg + 416 .+-. 15 175 .+-. 40 20 .+-. 1 0.5 .+-. 0.02
5.7 .+-. 0.1 4.1 .+-. 0.1 VOSO.sub.4 50 mg/kg *# * *# *# *# Mark*
shows the significant difference from the control group
(untreated). : P < 0.05 Mark# shows the significant difference
from the treated rat group to which VOSO.sub.4 alone was
administered. : P < 0.05
[0057]
3TABLE 3 Biochemical Test of Urine sample Glucose Total protein
Creatinine (g/12 hr) (g/12 hr) (mg/12 hr) Test compound and The day
of measurement (Day) its dose 0 5 0 5 0 5 Control group 8.8 .+-.
1.1 9.7 .+-. 2.1 4.5 .+-. 2.6 7.4 .+-. 3.8 11.3 .+-. 1.4 13.0 .+-.
0.9 (Untreated) VOSO.sub.4 50 mg/kg 9.1 .+-. 1.4 6.8 .+-. 3.2 7.2
.+-. 8.2 3.9 .+-. 0.8 12.5 .+-. 1.8 12.1 .+-. 2.5 FOM-Na 160 mg/kg
9.2 .+-. 0.9 8.9 .+-. 1.3 4.2 .+-. 1.1 5.6 .+-. 2.2 12.5 .+-. 0.7
12.5 .+-. 0.8 FOM-Na 160 mg/kg + 8.9 .+-. 0.6 1.5 .+-. 2.1 4.4 .+-.
2.2 2.5 .+-. 1.4 12.8 .+-. 1.3 8.4 .+-. 2.5 VOSO.sub.4 50 mg/kg **
* ** ## ## Mark* and mark** show the significant difference from
the control group (untreated). *: P < 0.05 **: P < 0.01 Mark#
and mark## show the significant difference from the treated rat
group to which VOSO.sub.4 alone was administered. #: P < 0.05
##: P < 0.01
[0058] As is clear from the test results shown in Table 1, Table 2
and Table 3 above, both of the single administration of fosfomycin
diaodium salt alone at a dose of 160 mg/kg and of the single
administration of vanadyl sulfate alone at a dose of 50 mg/kg can
evidently be shown to have the action of lowering an unusually high
serum glucose level and urinary glucose level in the STZ diabetic
rats under test.
[0059] On the other hand, when fosfomycin disodium salt was
administered in combination with vanadyl sulfate, there has been
recognized that ameliorations can be achieved not only to
remarkably decrease the abnormally high serum glucose level and
high urinary glucose level, but also to lower the high urea
nitrogen level and high creatinine level in the serum and to make
better the reduced total protein level and reduced albumin level in
the serum and also to suppress the high creatinine content in the
urine.
EXAMPLE 2
[0060] To male Wistar 7-week-old rats (7 rats per group), which
were intravenously administered with a single dose of 60 mg/kg of
STZ and which were confirmed to have been made diabetic after the
lapse of 1 week from the STZ administration, fosfomycin disodium
salt or fosfomycin calcium salt (FOM-Ca) was orally administered at
a dose of 320 mg/kg, twice a day for 5 consecitive days. Then,
sample of the blood of each test rat was taken and subjected to the
biochemical tests. The test results obtained are shown in Table 4
below.
[0061] The test results of Table 4 indicate that fosfomycin
disodium salt and fosfomycin calcium salt both can clearly
ameliorate the symptoms of diabetes, particularly the unusually
high serum glucose level. Thus, it has been confirmed that
fosfomycin or its salt is effective for the therapeutic treatment
of diabetes.
4 TABLE 4 Glucose Triglyceride Creatinine Total protein Albumin
(mg/dl) (mg/dl) (mg/dl) (g/dl) (g/dl) Test compound The day of
measurement (Day) and its dose 0 5 0 5 5 5 5 Control group 431 .+-.
8 413 .+-. 17 169 .+-. 29 115 .+-. 23 0.56 .+-. 0.02 4.89 .+-. 0.06
3.7 .+-. 0.0 FOM-Na 432 .+-. 6 345 .+-. 23 211 .+-. 30 65 .+-. 3
0.50 .+-. 0.00 5.26 .+-. 0.06 4.0 .+-. 0.1 320 mg/kg * * * * *
FOM-Ca 431 .+-. 5 336 .+-. 23 178 .+-. 18 59 .+-. 7 0.51 .+-. 0.01
5.37 .+-. 0.07 4.1 .+-. 0.1 320 mg/kg * * * * Control group shows
the groups of rats which were the STZ-administered diabetic rats
having received an administration of distilled water only. Mark*
shows the significant difference from the control group. : P <
0.05
Industrial Applicability
[0062] According to this invention, fosfomycin or its salt has been
found to have an action capable of lowering the serum glucose level
and to be effective as an orally administrable drug for treating
the diabetes. Further, it has been recognized that the serum
glucose level-lowering action of fosfomycin or its salt can be
synergistically and remarkably enhanced, if it is administered in
combination with vanadyl sulfate or its equivalent vanadyl
compound. Therefore, a composition comprising fosfomycin or its
salt in combination with vanadyl sulfate or its equivalent vanadyl
compound is useful as an orally administrable drug for treating the
diabetes.
* * * * *