Note: Descriptions are shown in the official language in which they were submitted.
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ENANTIOMERIC COMPOSITIONS OF CICLETANINE, ALONE AND IN
COMBINATION WITH OTHER AGENTS, FOR THE TREATMENT OF DISEASE
RELATED APPLICATIONS
[0001] This present application is a continuation in part of U.S. Patent
Application
10/929,108 of Fong and Cornett, filed on August 27, 2004, which claims the
benefit of
U.S. Provisional Patent Application No. 60/498,916, filed Aug. 29, 2003, and
which then
appeared as U.S. Published Application 2005/013314 on May 26, 2005. This
present
application is also a continuation in part of U.S. Patent Application
10/892,601 of Fong
and Cornett, filed on July 16, 2004, which claims the benefit of U.S.
Provisional Patent
Application No. 60/488,040, filed July. 17, 2003, and which then appeared as
U.S.
Published Application 2005/0043391 on February 24, 2005. The patent
application
further claims benefit of U.S. Patent Applications No. 11/035,231, No.
11/035,308 of
Cornet et al., and 11/035,328, of Cornett et al, all three filed on January
13, 2005; and
U.S. Patent Application No. 60/684,684 of Cornett, filed on May 26, 2005. The
present
application still further claims the benefit of U.S. Provisional Patent
Application Nos.
60/612323 and 60/612369, each of Cornett, and each filed on September 22,
2004.
Each of these aforementioned patent applications is expressly incorporated
herein by
reference, in its entirety. Finally, this application claims benefit of the
U.S. Patent
Application of the same title, filed on September 21, 2005.
FIELD OF THE INVENTION
[0002] Embodiments of the present invention are related to using compositions
of
cicietanine, either alone, or in combination with other agents, for the
treatment of
diseases such as diabetes, metabolic syndrome, and hypertension, as well as
associated complications of these diseases..
BACKGROUND OF THE INVENTION
[0003] Diabetes is a chronic metabolic disorder which afflicts 14 million
people in the
United States, over two million of whom have its most severe form, childhood
diabetes
(also called juvenile, Type I or insulin-dependent diabetes). Type II Diabetes
(DM II)
makes up more than 85-90% of all diabetics, and is likely to be the next
epidemic.
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[0004] Patients with diabetes of all types have considerable morbidity and
mortality
from microvascular (retinopathy, neuropathy, nephropathy) and macrovascular
(heart
attacks, stroke, peripheral vascular disease) pathology, all of which carry an
enormous
cost. For example: a) Proliferative retinopathy (the leading cause of
blindness for people
under 65 years of age in the United States) and/or macular edema occur in
about 50%
of patients with type 2 diabetes, as do peripheral and/or autonomic
neuropathy. b) The
incidence of diabetic renal disease is 10% to 50% depending on ethnicity. c)
Diabetics
have heart attacks, strokes and peripheral vascular disease at about triple
the rate of
non-diabetics. The cost of treating diabetes and its complications exceeds
$100 billion
annually.
[0005] Non-insulin dependent diabetes mellitus develops especially in subjects
with
insulin resistance and a cluster of cardiovascular risk factors such as
obesity,
hypertension and dyslipidemia, a syndrome which first recently has been
recognized
and is named "The metabolic syndrome" (Alberti K. G., & Zimmet P. Z. 1998
Diabet
Med 7:539-53).
[0006] In accordance with the WHO definition, a patient has metabolic syndrome
if
insulin resistance and/or glucose intolerance is present together with two or
more of the
following conditions: 1) reduced glucose tolerance or diabetes; 2) reduced
insulin
sensitivity (under hyperinsulinemic, euglycemic conditions corresponding to a
glucose
uptake below the lower quartile for the background population); 3) increased
blood
pressure ( 0140/90 mmHg); 4) increased plasma triglyceride (g1.7 mmol/I)
and/or low
HDL cholesterol (<0.9 mmol/I for men; <1.0 mmol/I for women); 5) central
adipositas
(waist/hip ratio for men: >0.90 and for women >0.85) and/or Body Mass Index
>30
kg/M2); 6) micro albuminuria (urine albumin excretion: 020 pg min-1
or
albumin/creatinine ratio.02.0 mg/mmol.
[0007] In the chronological sequence of impaired glucose tolerance, followed
by early
and late phases of type 2 diabetes, it is desirable to start early with
nonpharmacologic
therapy, including physical activity, diet, and weight reduction. In addition,
to reduce the
incidence of macrovascular complications of diabetes, pharmacotherapy for
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disturbances in lipid metabolism and for hypertension is also desirable
(Goldberg, R. et
a/. 1998 Circulation 98:2513-2519; Pyorala, K. et al. 1997 Diabetes Care
20:614-620).
Therefore, it is believed that the treatment should aim at simultaneously
normalizing
blood glucose, blood pressure, lipids and body weight to reduce the morbidity
and
mortality.
[0008] In general, there are three pharmacotherapeutic approaches typically
relevant
to the management of metabolic syndrome (insulin resistance syndrome, syndrome
X).
These include the use of 1) hypoglycemic agents, such as oral antidiabetics
(OADs);
and insulin; 2) antihypertensive agents; and 3) lipid-lowering agents.
[0009] Drug toxicity is one consideration in the treatment of humans and
animals.
Toxic side effects resulting from the administration of drugs include a
variety of .
conditions that range from low-grade fever to death. Drug therapy is typically
conducted
when the benefits of the treatment protocol outweigh the potential risks
associated with
the treatment. The factors balanced by the practitioner include the
qualitative and
quantitative impact of the drug to- be used as well as the resulting outcome
if the drug is
not provided to the individual. Other factors considered include the physical
condition of
the patient, the disease stage and its history of progression, and any known
adverse
effects associated with a drug.
[0010] Holman and Turner (Textbook of Diabetes, Pickup, J. C., Williams, G.,
Eds.;
Blackwell Scientific Publ. London, pp. 462-476, 1991) report that
sulfonylureas can
cause life threatening hypoglycemia, due to their continuous action while
present in the
bloodstream. Such an action may affect the myocytes in the heart increasing
the risk of
cardiac arrhythmias. On the other hand, metformin is known'to cause stomach-
malfunction and toxicity which can cause death by excessive dose of
administration to a
patient for a prolonged time (Innerfield, R. J. 1996 New Engi J Med 334:1611-
1613).
Glitazones (e.g., Actos , Avandia@, Rezulin ; also known as the
thiazolidinediones)
tend to increase lipids. Troglitazone is known to have side effects, such as
anemia,
nausea, and hepatic toxicity (Eung-Jin'Lee et al. 1998 Diabetes Science, Korea
Medicine, 345-359; Ishii, S. et al. 1996 Diabetes 45: (Suppl. 2), 141A
(abstracts)
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Watking, P. B. et al. 1998 N Engl J Med 338:916-917). Other reported adverse
events
include dyspnea, headache, thirst, gastrointestinal distress, insomnia,
dizziness,
incoordination, confusion, fatigue, pruritus, rash, alterations in blood cell
counts,
changes in serum lipids, acute renal insufficiency, and dryness of the mouth.
Additional
symptoms that have been reported, for which the relationship to troglitazone
is
unknown, include palpitations, sensations of hot and cold, swelling of body
parts, skin
eruption, stroke, and hyperglycemia.
SUMMARY OF THE INVENTION
[0011] In accordance with present invention, various embodiments of
therapeutically
beneficial formulations, such as oral formulations, are disclosed, comprising
a
therapeutically effective amount of cicletanine alone, or in combination with
one or more
second agent, for the treatment of diabetes, metabolic syndrome, and
hypertension, as
well as complications that arise from these diseases. For the purposes herein,
metabolic syndromes may also include those syndromes possessing a set or
subset of
phenomena associated with poor metabolic health, usually involving some
aspects of
the maladies of hypertension, obesity, impaired glucose tolerance, and lipid
(cholesterol, triglyceride) disorders. For example, recent US.NIH guidelines
define
metabolic syndrome as a state of meeting 3 or more of the following criteria:
abdominal
obesity (waist circumference >40 inches in men or >35 inches in women);
glucose
intolerance (fasting glucose >110 mg/dL); blood pressure >130/85 mmHg; high
triglycerides (>150 mg/dL); and/or low HDL (<40 mg/dL in men or <50 mg/dL in
women). Therapeutic benefits to patients with any of these aforementioned
diseases or
conditions from such treatment include, but are not limited to, lowering blood
glucose,
improving glucose tolerance, improving the blood lipid profile, lowering blood
pressure,
and/or treating any complications associated with these diseases.
[0012] The cicletanine compositions of the present invention may take any of
several
forms. In some embodiments, the cicietanine of the therapeutic formulation may
consist
solely of the negative (-) enantiomer, or alternatively, solely as the
positive (+)
enantiomer, In other alternative embodiments, cicletanine may comprise a non-
racemic
mixture of the (-) and a(+) enantiomers of cicletanine. Such non-racemic
mixtures may
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vary in relative proportions of the respective enantiomer. For example, the
cicletanine
proportions may vary from a ratio of about 999 parts (-) enantiomer to about 1
part (+)
enantiomer to a ratio of about 1 part (-) enantiomer to about 999 parts (+)
enantiomer.
[0013] The present invention follows from the proposal of the inventors that
the (+) and
(-) enantiomers of cicletanine possess different prophylactic and therapeutic
properties.
The (+) enantiomer is proposed to possesses a predominantly diuretic effect,
in fact, a
cicletanine composition with a high proportion of the (+) enantiomer (and a
low
proportion of the (-) enantiomer) is proposed to have several advantages over
the
racemic mixture. Administration of the high (+) enantiomer non-racemic
mixture, for
example, causes a more pronounced diuretic and potassium lowering effect with
a
greater salutary effect on blood glucose and/or lipids (e.g., triglycerides
and cholesterol)
than that of a preparation containing a racemic combination, or the (+) and (-
)
enantiomers of cicletanine alone. Additionally, the high (+) enantiomer non-
racemic
mixture results in a less-pronounced potassium-lowering effect than that of a
preparation containing only the (+) enantiomer of cicietanine. In contrast,
the (-)
enantiomer possesses a predominantly vasorelaxant effect. Administration of a
cicletanine composition containing a high proportion of the (-) enantiomer and
a low
proportion of the (+) enantiomer has a more pronounced vasorelaxant effect
than that of
the racemic mixture. Consistent with the practice of this invention,
therefore, the (-)
enantiomer offers organ-protective, glucose-lowering, and lipid-lowering
benefits that
are superior to those supported by the racemic mixture.
[0014] In some embodiments of the invention, the various cicletanine
compositions
may be the sole therapeutic agent of the formulation, in other embodiments, a
second
agent or agents may be included along with the cicietanine composition.
"Second
agent", as used herein, refers to any agent other than the cicletanine
compositions;
"second agent", as such is a generic term that may include a plurality of
agents that are
members of this non-cicletanine class. Such second agents may be, by
themselves,
effective agents for lowering blood glucose, improving the blood lipid
profile, lowering
blood pressure, and/or treating any complications associated with these
diseases. In
general, the range of diseases and associated complications or sequelae that
receive
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therapeutic benefit from formulations consisting only of cicietanine
compositions are the
same as those that receive benefit from formulations that include both
cicletanine, of
varying enantiomeric composition, and a second therapeutic agent.
[0015] In one embodiment of the invention, a second agent is selected from the
group
of glucose-lowering agents, also referred to as oral diabetic agents,
including, but not
limited to, sulfonureas, biguanines, alpha-glucosidase inhibitors,
triazolidinediones and
meglitinides. Where the second agent is a sulfonurea, it is may be selected
from a
group including glimel, glibenclamide; chlorpropamide, tolbutamide, melizide,
glipizide
and gliciazide. Where the second agent is a biguanine, it may be selected from
a group
including metformin and diaformin. Where the second agent is an alpha-
glucosidase
inhibitor, it may be selected from a group including voglibose; acarbose and
miglitol.
Where the second agent is a thiazolidinedione, it may be selected from a group
including pioglitazone, rosiglitazone and troglitazone. Where the second agent
is a
meglitinide, it may be selected from a group including repaglinide and
nateglinide.
[0016] In accordance with other embodiments of the present invention, an oral
formulation is disclosed, comprising a therapeutically effective amount of
cicletanine in
combination with a second agent that improves the blood lipid profile, for
example by
lowering blood cholesterol. In one specific embodiment, the second agent
is.selected
from the group including bile acid binding resins, HMGCoA reductase
inhibitors,
nicotinic acid and probucol.
[0017] In yet a further embodiment, a method for treating and/or preventing
complications of diabetes or metabolic syndrome in a mammal is also disclosed,
where
the method comprises administering an oral formulation comprising a
therapeutically
effective amount of cicletanine and a blood glucose lowering amount of a
second agent.
For example, the second agent is selected from the group of oral treatment
agents,
including sulfonureas, biguanines, alpha-glucosidase inhibitors,
triazolidinediones and
meglitinides. In other embodiments, the method is also adapted to treat and/or
prevent
diabetes complications that may include retinopathy, neuropathy, nephropathy,
microalbuminuria, claudication, macular degeneration, and erectile
dysfunction.
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[0018] In an example of a variation of the method, the therapeutically
effective amount
of cicletanine is sufficient to mitigate a side effect of said second agent.
In another
exemplary variation, the therapeutically effective amount of cicletanine is
sufficient to
enhance an effect or the effectiveness of another agent, such as, for example,
the
tissue sensitivity to insulin. In other embodiments, where cicletanine and a
second
agent exert similar effects, the therapeutically effective amount of
cicletanine and the
blood glucose lowering amount of the second agent are may be sufficient to
produce a
synergistic effect, whereby the result is greater than the apparent
contributions of either
agent alone.
[0019] In another embodiment, a method is disclosed for treating and/or
preventing a
condition or complication associated with elevated cholesterol in a mammal.
The
method, for example, comprises administering an oral formulation comprising a
therapeutically effective amount of cicletanine and a lipid lowering amount of
a second
agent. By way of more specific example, the second agent is selected from a
group
including bile acid binding resins, HMGCoA reductase inhibitors, nicotinic
acid and
probucol. Conditions or complications associated with elevated cholesterol
include, for
example, atherosclerosis, hypertension, retinopathy, neuropathy, nephropathy,
microalbuminuria, claudication, macular degeneration, and erectile
dysfunction.
[0020] In another embodiment, the present invention is directed toward
treatment of
hypertension and its complications, in addition to diabetes and metabolic
syndrome. For
example, as described above, therapeutic formulations may comprise either
cicietanine
compositions without a second therapeutic agent, or a second agent may be
included.
Cicletanine compositions may take various enantiomeric forms, for example,
cicletanine
may be a non-racemic mixture, or it may be purely either the (+) or (-)
enantiomer.
Cicletanine, without a second agent, constitutes a therapeutic with
effectiveness at
treating hypertension by various mechanisms.
[0021] In one embodiment, the present invention relates to an oral therapeutic
formulation, comprising an amount of cicletanine, a prostacyclin agonist or
inducer of
endogenous prostacylin, and an amount of a second agent that lowers blood
pressure.
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In another embodiment, the oral therapeutic formulation further comprises an
amount of
a PDE inhibitor sufficient to stabilize an increase in cyclic nucleotide
levels within
glomerular cells induced by cicletanine.
[0022] In yet another embodiment of the oral therapeutic formulation, a second
agent
is selected from a group that includes diuretics, potassium-sparing diuretics,
beta
blockers, ACE or angiotensin II receptor antagonists, calcium antagonists, NO
inducers,
and aidosterone antagonists. In a specific exemplary embodiment, the second
agent is
a calcium antagonist selected from a group that includes amlodipine,
lacidipine,
lercanidipine, nitrendipine, mibefradil, isradipine, diltiazem, efonidipine,
nicardipine,
nifedipine, nimodipine, nisoldipine and verapamil. In another preferred
variation, the
second agent is an ACE inhibitor selected from a group that includes
lisinopril (Zestril ;
Prinivil ), enalapril maleate (Innovace ; Vasotec ), quinapril (Accupril ),
ramipril
(Tritace ; Altace ), benazepril (Lotensin ), captopril (Capoten@), cilazapril
(VascaceO), fosinopril (Staril ; Monopril ), imidapril hydrochloride (Tanatril
),
moexipril hydrochloride (Perdix@; Univasc@), trandolapril (Gopten ; Odrik ;
Mavik ),
and perindopril (Coversyl(D; Aceon ).
[0023] In accordance with another embodiment of the invention, a method is
disclosed
for treating and/or preventing complications in a hypertensive diabetic
mammal. The
method comprises administering an oral formulation comprising a
therapeutically
effective amount of cicletanine and a blood pressure lowering amount of a
second
agent. In one variation, the oral formulation may further comprise an amount
of a PDE
inhibitor sufficient to stabilize an increase in cyclic nucleotide levels
within glomerular
cells induced by the cicletanine.
[0024] In one preferred embodiment of the method, a second agent is selected
from a
group that includes diuretics, potassium-sparing diuretics, beta blockers, ACE
inhibitors
or angiotensin II receptor antagonists, calcium antagonists, NO inducers, and
aidosterone antagonists. In a specific exemplary embodiment, the second agent
is a
calcium antagonist selected from a group that includes amlodipine,
efonidipine,
lacidipine, lercanidipine, nitrendipine, mibefradil, isradipine, diltiazem,
nicardipine,
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nifedipine, nimodipine, nisoldipine and verapamil. In another variation the
second agent
is an ACE inhibitor selected from a group including lisinopril (Zestril ;
Prinivil ),
enalapril maleate (Innovace@; VasotecO), quinapril (Accupril(D), ramipril
(Tritace ;
Altace ), benazepril (Lotensin ), captopril (Capoten@), cilazapril (Vascace ),
fosinopril
(Staril ; Monopril0), imidapril hydrochloride (Tanatril ), moexipril
hydrochloride
(Perdix ; Univasc ), trandolapril (Gopten ; Odrik ; MavikO), and perindopril
(Coversyl. ; Aceon ).
[0025] In another embodiment of the method for treating and/or preventing
complications in a hypertensive diabetic mammal,, the method further comprises
a step
of monitoring a thromboxane/PGI2.ratio, wherein the amount of cicletanine
and/or
second agents may be adjusted to yield a thromboxane/PGI2 ratio of about 20.
Such
hypertensive/diabetic complications may include retinopathy, neuropathy,
nephropathy,
microalbuminuria, claudication, macular degeneration, and erectile
dysfunction.
[0026] In yet another embodiment, an oral therapeutic formulation is
disclosed,
wherein the formulation comprises a nephroprotective amount of cicletanine and
a
blood pressure lowering amount of a calcium channel blocker (also referred to
as a
calcium antagonist). As another exemplary embodiment, an oral therapeutic
formulation
disclosed, comprising a nephroprotective amount of cicletanine and a, blood
pressure
lowering amount of an ACE inhibitor or an angiotensin II receptor antagonist.
[0027] One embodiment of the present inventive method for treating and/or
preventing
nephropathies in a hypertensive diabetic patient is also disclosed. The
method, by
example comprises administering to the patient a nephroprotective amount of
cicietanine and a blood pressure lowering amount of a calcium antagonist or an
ACE
inhibitor. The nephroprotective amount of cicietanine is selected, for
example, such that
nephroprotection occurs without a significant adverse change in blood glucose
and/or
systolic blood pressure.
[0028] In another embodiment of the present invention, a method is disclosed
for
treating and/or preventing hypertension in patients. In one embodiment, the
method
comprises administering cicletanine via aerosol delivery to the lungs and
administering
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a second antihypertensive agent selected from the group consisting of
diuretics,
potassium-sparing diuretics, beta blockers, ACE inhibitors or angiotensin II
receptor
antagonists, calcium antagonists, NO inducers, and aldosterone antagonists.
[0029] In various embodiments of the inventive method, the therapeutically
effective
amount of the cicletanine is sufficient to mitigate a side effect of the
second agent. In
another aspect of the method, the amounts of the cicletanine and second agents
are
sufficient to produce a synergistic antihypertensive effect. In yet another
aspect the
addition of cicletanine enhances the duration of action of the second agent or
reduces
the development of tolerance to the second agent.
DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION
Combination Therapies and Formulations, General Considerations
[0030] In embodiments of the present invention, a combination therapy is
disclosed for
treating diabetes, metabolic syndrome, hypertension and from complications
that ensue
during the course of the disease. In some embodiments or applications of
therapeutic
embodiments of the present invention, the therapeutic benefit may be one of
preventing
disease, or slowing its progression. A hallmark of diabetes and metabolic
syndrome is
hyperglycemia, or high levels of blood glucose. The high glucose levels may
manifest
as a high basal level in a fasting state, compared to normal values, or they
may
manifest as higher and more sustained levels after a glucose load. Inasmuch as
the
symptom of the disease can be addressed by the administration of agents that
lower
blood glucose, agents used to treat patients with diabetes of metabolic
syndrome may
be referred to as agents that lower blood glucose. Inasmuch as these agents
address
diabetes and are taken orally, they may also be referred to as oral
antidiabetic drugs or
agents.
[0031] Prostacyclins, their mechanisms of action, and the therapeutic benefits
of such
action are described further below. Embodiments of the present invention make
use of
cicietanine as an inducer of prostacyclin, although cicietanine may operate
through
other mechanisms as well. Cicletanine naturally occurs as a racemic mixture of
equal
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proportions of a positive (+) and a negative (-) enantiomer, however
embodiments of
the present invention include formulations that consist purely of either the
positive (+) or
negative (-) enantiomer, as well as formulations with non-racemic mixtures
that may
vary in relative proportions, ranging from, for example a formulation with a
proportion of
about 99% (+) enantiomer: about 1%(-) enantiomer to a formulation with a
proportion
of about 1%(+) enantiomer: about 99% (-) enantiomer.
[0032] In embodiments of the invention, the combination therapies comprise
fixed
doses (of each component), in single tablet form. In one example, combination
therapies unified within a single tablet is to simplify treatment regimens,
and thereby
support patient compliance. Further, by way of example, doses of the combined
agents
relative to each other are fixed, based on supporting an appropriate level of
simplicity
for treatment regimens. The establishment of doses appropriately fixed
relative to each
other, still allows for variation in total dosage. Combination therapy, in
general, supports
appropriate level dosing in that it allows the application of doses of
individual agents
lower than those that elicit the unwanted side effects that may occur at
higher dose
levels. Further, in the case of combining agents that work toward a broadly
defined
common benefit but which operate through different mechanisms of action,
synergistic
therapeutic effects may occur. Synergistic effects, by their nature, are not
commonly
predictable, based solely on an understanding of the mechanisms of the
combined
individual agents, respectively.
[0033] A therapeutic embodiment of the present invention comprises a
prostacyclin, or
more particularly, an agonist or an inducer thereof such as a composition of
cicietanine,
in combination with an oral antidiabetic drug selected from sulfonureas,
biguanines,
alpha-glucosidase inhibitors, triazolidinediones and meglitinides are listed
in Table 1.
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TABLE 1. Oral antidiabetic drugs
Compound (medication) Mechanism of action Preferred patient type
Sulfonylureas increase Insulin insulinopenic, lean
(Daonil , Glimel, secretion chronically
Euglocon =glibenclamide or
Glyburide@;
Diabinese=Chlorpropamide;
Rastinon@=Tolbutamide;
Melizide, Glucotrol ,
Minidiab =glipizide;
Diamicron@= liclazide
Meglitinides increase Insulin hyperglycemic postprandially
(Repaglinide =Prandin , secretion acutely
Nate Iinide=StarlixT"')
oc - glucosidase inhibitors decrease postprandial hyperglycemic postprandially
(Voglibose; Acarbose = carbohydrate
Glucoba ; mi litol absorption
Biquanidines decrease hepatic overweight, with fasting
(Metformin=Glucophage ; glucose production hyperglycemia
Diabex ; Diaformin) decrease insulin
resistance
Thiazolidinediones, decrease insulin insulin-resistant, overweight,
glitazones resistance dyslipidemic and renally
(ActosO=pioglitazone; decrease hepatic impaired
Avandia =rosiglitazone, glucose production
Rezulin =tro litazone
Insulin decrease hepatic patients with a diabetic
glucose production emergency newly diagnosed
increase cellular with significant
uptake of glucose hyperglycemia, or those with
hyperglycemia despite
maximal doses of oral agents
[0034] Existing oral antidiabetic medicaments to be used in such treatment
include the
classic insulinotropic agents sulphonylureas (Lebovitz H. E. 1997 "The oral
hypoglycemic agents". In: Ellenberg and Rifkin's Diabetes Mellitus. D. J.
Porte and R. S.
Sherwin, Editors: Appleton and Lange, p. 761-788). They act primarily by
stimulating the
sulphonylurea-receptor on the insulin producing beta-cells via closure of the
K+
ATP-sensitive channels.
[0035] Alpha-glucosidase inhibitors, such as a carboys, have also been shown
to be
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effective in reducing the postprandial rise in blood glucose (Lefevre, et al.
1992 Drugs
44:29-38). Another treatment used primarily in obese diabetics is metformin, a
biguanide.
[0036] Compounds included in embodiments and useful in the combination
therapies
discussed above, and methods of making the compounds, are known and some of
these are disclosed in U.S. Pat. No. 5,223,522 issued Jun. 29, 1993; U.S. Pat.
No.
5,132,317 issued Jul. 12, 1992; U.S. Pat. No. 5,120,754 issued Jun. 9, 1992;
U.S. Pat.
No. 5,061,717 issued Oct. 29, 1991; U.S. Pat. No. 4,897,405 issued Jan. 30,
1990; U.S.
Pat. No. 4,873,255 issued Oct. 10, 1989; U.S. Pat. No. 4,687,777 issued Aug.
18, 1987;
U.S. Pat. No. 4,572,912 issued Feb. 25, 1986; U.S. Pat. No. 4,287,200 issued
Sep. 1,
1981; U.S. Pat. No. 5,002,953, issued Mar. 26, 1991; U.S. Pat. Nos. 4,340,605;
4,438,141; 4,444,779; 4,461,902; 4,703,052; 4,725,610; 4,897,393; 4,918,091;
4,948,900; 5,194,443; 5,232,925; and 5,260,445; WO 91/07107; WO 92/02520; WO
94/01433; WO 89/08651; and JP Kokai 69383/92. Each of the foregoing patent
publications are hereby incorporated by reference, in their entirety. In other
embodiments, compounds disclosed in these issued patents and applications are
useful
as therapeutic agents for the treatment of diabetes, hyperglycemia,
hypercholesterolemia, and hyperlipidemia. The teachings of these issued
patents are
incorporated herein by reference in their entireties.
[0037] In other embodiments of the present invention, a combination therapy is
disclosed for treating diabetes and metabolic syndrome comprising combining a
prostacyclin, an agonist thereof, or an inducer thereof, most particularly
cicletanine, in
combination with a Blood Lipid-Lowering Agent. Generally, the lipid profile of
patients
with diabetes and metabolic syndrome have elevated levels of lipid, for
example, total
cholesterol, low density lipoprotein (LDL), and triglycerides in blood, and
lowering these
levels is a therapeutic goal. For some classes of blood lipid, however, as for
example,
with high density lipoprotein (HDL), a higher level may be more desirable than
a lower
level. In some types of diagnostic analysis, it is the ratio of low density
lipoprotein (LDL)
to HDL that is monitored. Thus a low level of HDL may be considered in
relative terms,
where HDL, regardless of its level in absolute terms, is low relative to the
level of LDL.
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As such, improving the profile of lipids and lipoproteins in blood takes the
relative
proportions of lipid molecules to each other. Table 2 lists a number of agents
that are
therapeutically useful in lowering blood lipids, and more generally useful.in
improving
the blood lipid profile.
TABLE 2. Blood Lipid-Lowering Agents
Type Compound/name
Bile Acid Binding Resins Cholestyramine (Cholybar , Questran ); colestipol
(Colestid@)
HMG CoA Reductase lovastatin (Mevacor@); pravastatin (Pravochol );
Inhibitors simvastatin (Zocor )
Fibric Acid Derivatives gemfibrozil (Lobid); clofibrate (Atromid-S )
Miscellaneous nicotinic acid (Niacin); probucol (Lorelco)
[0038] In embodiments of the present invention, a combination therapy is
disclosed for
treating hypertension, and more particularly, for treating and/or preventing
the clinical
consequences of hypertension, such as nephropathies in hypertensive diabetic
patients.
Such embodiments comprise a prostacyclin, or an agonist or an inducer thereof,
particularly a composition of cicletanine, in combination with a second
antihypertensive
agent, selected from the group consisting of diuretics, potassium-sparing
diuretics, beta
blockers, ACE inhibitors or angiotensin II receptor antagonists, calcium
antagonists
(more particularly second generation, long-acting calcium channel blockers,
such as
.amlodipine), nitric oxide (NO) inducers, and aidosterone antagonists (see
Table 3).
TABLE 3. Antihypertensive drugs Diuretic combinations
Diuretic combinations
Amiloride and hydrochlorothiazide (5 mg/50 mg) Moduretic
Spironolactone and hydrochlorothiazide (25 mg/50 mg, 50 Aldactazide
m/50m =
Triamterene and hydrochlorothiazide (37.5 mg/25 mg, 50 mg/25 Dyazide
m )=
Triamterene and hydrochlorothiazide (37.5 mg/25 mg, 75 mg/50 Maxzide-25 mg,
mg) = Maxzide
Beta blockers and diuretics
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Atenolol and chlorthalidone (50 m/25 mg, 100 m/25 mg) Tenoretic0
Bisoprolol and hydrochlorothiazide (2.5 mg/6.25 mg, 5 mg/6.25 ZiacO
mg, 10 m/6.5m =
Metoprolol and hydrochlorothiazide (50 mg/25 mg, 100 mg/25 Lopressor HCTO
mg, 100 mg/50 mg) =
Nadolol and bendroflumethazide (40 m/5 m, 80 m/5 m= Corzide0
Propranolol and hydrochlorothiazide (40 mg/25 mg, 80 mg/25 Inderide0
m )=
Propranolol ER and hydrochlorothiazide (80 mg/50 mg, 120 Inderide LAO
m /50m , 160 m/50m =
Timolol and hydrochlorothiazide (10 mg/25 m) Timolide0
ACE inhibitors and diuretics
Benazepril and hydrochlorothiazide (5 mg/6.25 mg, 10 mg/12.5 Lotensin HCTO
m ,20m mg/12.mg, 2mg/2=
Captopril and hydrochlorothiazide (25 mg/15 mg, 25 mg/25 mg, Capozide0
50 mg/15 mg, 50 mg/25 mg) =
Enalapril and hydrochlorothiazide (5 mg/12.5 mg, 10 mg/25 mg) Vaseretic0
Lisinopril and hydrochlorothiazide (10 mg/12.5 mg, 20 mg/12.5 Prinzide0
m ,20m mg/2mg
Lisinopril and hydrochlorothiazide (10 mg/12.5 mg, 20 mg/12.5 Zestoretic0
m ,20m mg/2=
Moexipril and hydrochlorothiazide (7.5 mg/12.5 mg, 15 mg/25 Uniretic0
mg) =
Angiotensin-II receptor antagonists and diuretics
Losartan and hydrochlorothiazide (50 mg/12.5 mg, 100 mg/25 Hyzaar0
mg) =
Valsartan-and hydrochlorothiazide (80 mg/12.5 mg, 160 Diovan HCTO
mg/12.5 mg) =
Calcium channel blockers and ACE inhibitors
Amlodipine and benazepril (2.5 mg/10 mg, 5 mg/10 mg, 5 Lotrel0
m /20m mg
Diltiazem and enalapril (180 mg/5 m)= Teczem0
Efoni idine
Felodipine and enalapril 5 mg/5 mg) Lexxel0
Verapamil and trandolapril (180 mg/2 mg, 240 mg/l mg, 240 TarkaO
m/2m,240m/4m)=
Miscellaneous combinations
Clonidine and chlorthalidone (0.1 mg/15 mg, 0.2 mg/15 mg, 0.3 Combipres0
m /15m mg
Hydralazine and hydrochlorothiazide (25 mg/25 mg, 50 mg/50 Apresazide0
m ,100m /50m =
Methyldopa and hydrochlorothiazide (250 m/15 mg, 250 mg/25 Aldoril0
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m ,500m mg/3mg, 50mg/5=
Prazosin and polythiazide (1 mg/0.5 mg, 2 mg/0.5 mg, 5 mg/0.5 Minizide
mg) =
[0039] The combination may be formulated in accordance with the teachings
herein to
provide a clinical benefit that goes beyond the beneficial effects produced by
either drug
alone. Such an enhanced clinical benefit may be related to distinct mechanisms
of
action and/or a synergistic interaction of the drugs.
[0040] In one embodiment, the combination therapy includes in addition to the
prostacyclin, a phosphodiesterase (PDE) inhibitor, which stabilizes cAMP
(second
messenger for prostacyclins), and may amplify the vasodilatory and/or
nephroprotective
actions of the prostacyclin agonist or inducer. In another preferred
embodiment, the
combination therapy comprises cicletanine and amlodipine. In another
embodiment, the
combination therapy comprises cicietanine and an ACE inhibitor or angiotensin
II
receptor antagonist. In another embodiment, the combination therapy comprises
cicietanine and a thiazolidinedione (e.g., rosiglitazone, pioglitazone), which
is known to
be a ligand of the peroxisome proliferator-activated receptor gamma
(PPARgamma). In
another embodiment, the combination therapy comprises cicletanine and a
peroxisome
proliferator-activated receptor (PPAR) agonist, including but,not limited to
agonists of
one or more of the following types: alpha, gamma and delta). In another
embodiment,
the combination therapy comprises cicletanine and a sulfonurea (e.g.,
glibenclamide,
tolbutamide, melizide, glipiziede, gliclazide). In another preferred
embodiment, the
combination therapy comprises cicletanine and a meglitinide (e.g.,
repaglinide,
nateglinide). In another embodiment, the combination therapy comprises
cicletanine
and a biguanide (e.g., metformin, diaformin). In another preferred embodiment,
the
combination therapy comprises cicletanine and a lipid-lowering agent.
[0041] In another embodiment, the combination therapy comprises a fixed dose
(of
each component), oral dosage formulation (e.g., single tablet, capsule, etc.),
which
provides a systemic action (e.g., blood pressure-lowering, organ-protective,
glucose-
lowering, lipid-lowering, etc.), with minimal side effects. The rationale for
using a fixed-
dose combination therapy in accordance with a preferred embodiment of the
present
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invention is to obtain sufficient blood pressure control by employing an
antihypertensive
agent, e.g., cicletanine, which also lowers blood glucose and LDLs, while
enhancing
compliance by using a single tablet that is taken once or twice daily. Using
low doses of
different agents can also minimize the clinical and metabolic effects that
occur with
maximal dosages of the individual components of the combined tablet.
[0042] In addition to the advantages resulting from two distinct mechanisms of
action,
some drug combinations produce potentially synergistic effects. For example,
Vaali K.
et al. 1998 (Eur J Pharmacol 363:169-174) reported that the .beta.2 agonist,
salbutamol, in combination with micromolar concentrations of NO donors, SNP
and SIN-
1, caused a synergistic relaxation in metacholine-induced contraction of
guinea pig
tracheal smooth muscle.
[00431 In another embodiment, the combination may be formulated to generate an
enhanced clinical benefit which is related to the diminished side-effect(s) of
one or both
of the drugs. For example, one significant side-effect of calcium antagonists,
such as
amiodipine (Norvasc RO), the most commonly prescribed calcium channel blocker,
is
edema in the legs and ankles. In contrast, cicletanine has been shown to cause
significant and major improvement in edema of the lower limbs (Tarrade et al.
1989
Arch Mal Couer Vaiss 82 Spec No. 4:91-7). Thus, in addition to their distinct
antihypertensive actions the combination of cicletanine and amlodipine may be
particularly beneficial as a result of diminished edema in the lower limbs. In
another
example, aldosterone antagonists may cause hyperkalemia and cicletanine in
high
doses causes potassium excretion. Thus, the combination of cicletanine and an
aidosterone antagonist may relieve hyperkalemia, a potential side effect of
the
aldosterone inhibitor alone. In yet another example, thiazolidinediones (aka
glitazones),
of which there are two marketed in the US: Rosiglitazone (Avandia0) and
Pioglitazone
(ActosO), are effective in lowering blood glucose), but they have diverging
effects on
LDL. ActosO tends to reduce LDL, while Avandia0 tends to increase LDL (Viberti
G. C.
2003 Int J Clin Pract 57:128-34; Ko S. H. et al. 2003 Metabolism 52:731-4;
Raji A. et al.
2003 Diabetes Care 26:172-8). Thiazolidinediones also known to cause weight
gain and
fluid retention. The combination of cicletanine with thiazolidinediones is
envisioned to
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control the lipid metabolism and the fluid retention, due to the differences
in the
mechanism of action of the named compounds. Moreover, the thiazolidinediones
tend
to be hepatotoxic. The composition of the present invention will allow to
lower the
thiazolidinediones dose necessary to achieve a comparable level of insulin
sensitization
and glucose control, thereby reducing the risk of hepatotoxicity.
Prostacyclins
[0044] In a broad sense, the prostacyclin species induced by cicletanine
compositions
of embodiments of the invention include any eicosanoid that exhibits
vasodilatory
effects. Some eicosanoids, however, such as the thromboxanes have opposing
vasoconstrictive effects, and would therefore not be particularly for use in
the inventive
formulations. The eicosanoids are defined herein as a class of oxygenated,
endogenous, unsaturated fatty acids derived from arachidonic acid. The
eicosanoids
include prostanoids (which refers collectively to a group of compounds
including the
prostaglandins, prostacyclins and thromboxanes), leukotrienes and
hydroxyeicosatetraenoic acid compounds. They are hormone-like substances that
act
near the site of synthesis without altering functions throughout the body.
[0045] The prostanoids (prostaglandins, prostacyclins and thromboxanes) are
any of a
group of components derived from unsaturated 20-carbon fatty acids, primarily
arachidonic acid, via the cyclooxygenase (COX) pathway that are extremely
potent
mediators of a diverse group of physiologic processes. The prostagiandins
(PGs) are
designated by adding one of the letters A through I to indicate the type of
substituents
found on the hydrocarbon skeleton and a subscript (1, 2 or 3) to indicate the
number of
double bonds in the hydrocarbon skeleton for example, PGE2. The
predominant
naturally occurring prostaglandins all have two double bonds and are
synthesized from
arachidonic acid (5, 8, 11, 14 eicosatetraenoic acid). The 1 series and 3
series are
produced by the same pathway with fatty acids having one fewer double bond (8,
11, 14
eicosatrienoic acid or one more double bond (5, 8, 11, 14, 17 eicosapentaenoic
acid)
than arachidonic acid. The prostagiandins act by binding to specific cell
surface
receptors causing an increase in the level of the intracellular second
messenger cyclic
AMP (and in some cases cyclic GMP). The effect produced by the cyclic AMP
increase
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depends on the specific cell type. In some cases there is also a positive
feedback effect.
Increased cyclic AMP increases prostaglandin synthesis leading to further
increases in
cyclic AMP.
[0046] Prostaglandins have a variety of roles in regulating cellular
activities, especially
in the inflammatory response where they may act as vasodilators in the
vascular
system, cause vasoconstriction or vasodilatation together with bronchodilation
in the
lung and act as hyperalgesics. Prostaglandins are rapidly degraded in the
lungs and will
not therefore persist in the circulation.
[0047] Prostacyclin, also known as PGI2, is an unstable vinyl ether
formed from
the prostaglandin endoperoxide, PGH2. The conversion of PGH2 to
prostacyclin is catalyzed by prostacyclin synthetase. The two primary sites of
synthesis
are the veins and arteries. Prostacyclin is primarily produced in vascular
endothelium
and plays an important inhibitory role in the local control of vascular tone
and platelet
aggregation. Prostacyclin has biological properties opposing the effect of
thromboxane
A2. Prostacyclin is a vasodilator and a potent inhibitor of platelet
aggregation
whereas thromboxane A2 is a vasoconstrictor and a promoter of platelet
aggregation. A physiological balance between the activities of these two
effectors is
probably important in maintaining a healthy blood supply.
[0048] In one aspect of the present combination therapy, the relative dosages
and
administration frequency of the prostacyclin agent and the second therapeutic
agent
may be optimized by monitoring the thromboxane/PGI2 ratio. Indeed, it has
been
observed that this ratio is significantly increased in diabetics compared to
normal
individuals, and even higher in diabetics with retinopathy (Hishinuma et al.
2001
Prostaglandins, Leukotrienes and Essential Fatty Acids 65(4): 191-196). The
thromboxane/PGI2 ratio may be determined as detailed by Hishinuma et al.,
(2001)
by measuring the levels (pg/mg) in urine of 11-dehydro-thromboxane B2 and
2,3-
dinor-6-keto-prostaglandin Fl.alpha., the urinary metabolites of
thromboxane
A2 and prostacyclin, respectively. Hishinuma et al. found that the
thromboxane/PGI2 ratio in healthy individuals was 18.4±14.3. In
contrast, the
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thromboxane/PGI2 ratio in diabetics was 52.2±44.7. Further, the
thromboxane/PGI2 ratio was even higher in diabetics exhibiting
microvascular
complications, such as retinopathy (75.0±67.8). Accordingly, optimization
of relative
dosages and administration frequencies would target thromboxane/PGI2
ratios of
less than about 50, and more particularly between about 20 and 50, and most
particularly, about 20. The treating physician may also monitor a variety of
indices,
including blood glucose, blood pressure, lipid profiles, impaired clotting
and/or excess
bleeding, as well known by those of skill in the art.
[0049] Prostacyclin Agonists--Prostacyclin is unstable and undergoes a
spontaneous hydrolysis to 6-keto-prostagiandin F1.alpha. (6-keto-PGF1.alpha.).
Study
of this reaction in vitro established that prostacyclin has a half-life of
about 3 min.
Because of its low stability, several prostacyclin analogues have been
synthesized and
studied as potential therapeutic compounds. One of the most potent
prostacyclin
agonists is iloprost, a structurally related synthetic analogue of PGI2.
Cicaprost is
closely related to iloprost and possess a higher degree of tissue selectivity.
Both iloprost
and cicaprost are amenable to oral delivery and provide extended half-life.
Other
prostacyclin analogs include beraprost, epoprostenol (Flolan ) and
treprostinil
(Remodulin ).
[0050] Prostacyclin plays an important role in inflammatory glomerular
disorders by
regulating the metabolism of glomerular extracellular matrix (Kitahara M. et
al. 2001
Kidney Blood Press Res 24:18-26). Cicaprost attenuated the progression of
diabetic
renal injury, as estimated by lower urinary albumin excretion, renal and
glomerular
hypertrophies, and a better renal architectural preservation. Cicaprost also
induced a
significant elevation in renal plasma flow and a significant decrease in
filtration fraction.
These findings suggest that oral stable prostacyclin analogs could have a
protective
renal effect, at least in this experimental model (Villa E. et al. 1993 Am J
Hypertens
6:253-7).
[0051] In a follow-up study, Villa et al. (Am J Hypertens 1997 10:202-8),
found that
chronic therapy with cicaprost, fosinopril (an ACE inhibitor), and the
combination of both
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drugs, stopped the progression of diabetic renal injury in an experimental rat
model of
diabetic nephropathy (uninephrectomized streptozotocin-induced diabetic rats).
Control
rats exhibited characteristic features of this model, such as high blood
pressure and
plasma creatinine and urinary albumin excretion, together with prominent
alterations in
the kidney (renal and glomerular hypertrophies, mesangial matrix expansion,
and
tubular alterations). The three therapies attenuated equivalently the
progression of
diabetic renal injury, as estimated by lower urinary albumin excretion, renal
and
glomerular hypertrophies, and a better renal architectural preservation. No
synergistic
action was observed with the combined therapy. However, renal preservation
achieved
with cicaprost was not linked to reductions in systemic blood pressure,
whereas in the
groups treated with fosinopril the hypotensive effect of this drug could have
contributed
to the positive outcome of the therapy. The authors speculated that impaired
prostacyclin synthesis or bioavailability may have been involved in the
pathogenesis of
the diabetic nephropathy in this model.
[0052] Cicletanine--Cicletanine is a drug that increases endogenous
prostacyclin
levels. It was originally developed as an antihypertensive agent that has
diuretic
properties at high doses. Cicletanine occurs naturally as a racemic (1:1)
composition of
the two enantiomers [(-)- and (+)-cicletanine] which, according to the
observations of
the inventors, independently contribute to the vasorelaxant and natriuretic
mechanisms
of this drug. The observations and theoretical considerations of the inventors
have led
them to several conclusions regarding the activity of cicletanine compositions
(particularly enantiomer-specific aspects therof, and comparisons of racemic
and non-
racemic mixtures thereof) which they have reduced to practice by this
invention. The
inventors believe that the renal component of the antihypertensive action of
cicletanine
may be mediated by (+)-cicletanine sulfate, while the (-)enantiomer is
primarily
responsible for vasorelaxant activity and has more potent cardioprotective
activity. They
further conclude that (1) the (-) enantiomer contributes to antihypertensive
activity by
reducing the vascular reactivity to endogenous pressor substances such as
angiotensin
II and vasopressin; (2) the (-)-enantiomer reduces the Et-1 (endothelin-1)
dependent
vasoconstriction more potently than (+)-cicietanine, and (3) both enantiomers
have
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cardioprotective effects. They further note that the (-) enantiomer has a
greater
protective effect (anti-ischemic and antiarrythmic), and the antiarrythmic
action of (-)
cicletanine may be of particular significance in combination therapies
involving
sulfonylureas, some of which have been associated with an increased incidence
of
cardiac arrhythmias.
[0053] The inventors conclude that cicletanine, a furopyridine
antihypertensive drug,
exhibits three major effects, vasorelaxation, natriuretic and diuretic, and
organ
protection, and they further observe that it has an excellent record of safety
and
absence of serious side effects. Cicletanine has several mechanisms of action.
Its
natriuretic activity is attributed to inhibition of apical Na+-dependent
Cl-
/HCO3- anion exchanger in the distal convoluted tubule. The nature
of
vasorelaxant activity of cicietanine is more complex and involves inhibition
of low
Km cGMP phosphodiesterases; stimulation of vascular NO synthesis,
inhibition of
Protein Kinase C, and antioxidant activity. Combination of the above effects
explains the
results of numerous clinical and experimental reports regarding the most
promising
feature of cicletanine, i.e., organ protection, including, merely by way of
example,
protection of the kidney, vascular structures, and the eye.
[0054] Natriuretic and diuretic activity-- In healthy subjects and
nonhypertensive
experimental animals racemic cicletanine exhibits moderate diuretic and
natriuretic
effects. In the hypertensives, however, cicletanine does induce natriuresis
without
affecting plasma potassium levels, although its effect is milder than that of
thiazide
diuretics. However, to it is unclear to what extent natriuretic properties of
cicietanine in
the hypertensives are related to its renoprotective (vs. direct renotubular)
effect.
[0055] In the late 1980's clinical studies were aimed towards assessment of
antihypertensive efficacy of cicletanine. In a multicenter trial -1050
hypertensives were
administered 50 mg/kg cicietanine for three months (Tarrade T. & Guinot P.
1988 Drugs
Exp Clin Res 14:205-14). In one third of patients the dose was doubled. The
blood
pressure decreased from 176/104 to 151/86 (Tarrade T. & Guinot P. 1988 Drugs
Exp
Clin Res 14:205-14). In another study, in a group of patients whose blood
pressure had
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not been normalized by calcium channel blockers, beta blockers and ACE
inhibitors,
cicletanine (50 and 100 mg per day) has been tested in combination with the
above
drugs (Tarrade T. et al. 1989 Arch Mal Coeur Vaiss 82 Spec No 4:103-8). The
addition
of cicletanine normalized the blood pressure in 50% of patients from all three
groups
without major adverse effects. Accordingly, the inventors propose that
cicletanine may
be effective respect to lowering the blood pressure, particularly in cases of
NaCl
sensitive hypertension.
[0056] It is believed that excessive NaCI intake is a risk factor for insulin
resistance,
and insulin resistance, vice versa, is frequently associated with the
development of
NaCI sensitive hypertension (Galletti F. et al. 1997 J Hypertens 15:1485-1492;
Ogihara
T. et al. 2003 Life Sci 73: 509-523). The exaggerated efficacy of cicletanine
in sodium
dependent hypertension, as well as the ability of cicletanine to improve
kidney function
in experimental diabetes mellitus, make this drug potentially very attractive
for treatment
of hypertension in diabetics, patients with metabolic and cardiac syndrome X,
and
hypertensives with impaired glucose tolerance.
[0057] Many molecular mechanisms underlie hypertrophic signaling in the
cardiovascular system in diabetics, including PKC signaling (Nakamura J. et
a/. 1999
Diabetes 48:2090-5; Meier M. & King G. L. 2000 Vasc Med 5:173-85) and
dysregulation
of the Na/K-ATPase (Ottlecz A. et al. 1996 Invest Ophthalmol Vis Sci 37:2157-
64; Chan
J. C. et al. 1998 Lancet 351:266), which, in turn, initiates several cascades
of growth
promoting signaling (Kometiani P. et al. 1998 J Biol Chem 273:15249-15267).
Moreover, inhibition of beta-2 isoform of the PKC is thought to be a promising
direction
in the treatment of diabetic complications (Meier M. & King G. L. 2000 Vasc
Med 5:173-
85). According to the inventors' understanding of the actions of PKC and
cicietanine, the
inventors propose that cicletanine may inhibit the activity of PKC. Further,
based on the
inventors' understanding of the mechanisms of cicletanine action, they propose
that
cicletanine may be able to improve the insulin sensitivity, in a manner
consistent with
the ability of cicletanine to inhibit PKC, which is involved in the mechanisms
of tissue
insulin resistance.
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[0058] It is proposed that cicletanine, due to a unique combination of several
properties: vasorelaxation, natriuresis, renal protection, improvement of
endothelial
function, inhibition of PKC, improvement of glucose/insulin metabolism, may be
especially effective as a monotherapy and in combination with the other drugs
in the
hypertensive patients with diabetes mellitus and metabolic syndrome.
[0059] In accordance with this understanding, inventors propose, by way of
example,
that the efficacy of a combination of cicletanine (100 mg per day) with a
second agent
such as an antihypertensive agent (an ACE inhibitor, angiotensin II receptor
antagonist,
beta blocker, calcium channel blocker, etc.), or an oral antidiabetic (a
sulfonurea,
biguanines, an alpha-glucosidase inhibitor, a triazolidinedione or a
meglitinide), or a
lipid-lowering agent (a resin, an HMG CoA Reductase Inhibitor, a fibric acid
derivative
(or fibrin), or nicotinic acid, or probucol) be assessed in a study in the
hypertensives
with and without type 1 or 2 diabetes mellitus or metabolic syndrome. The
major
endpoints of such a study would be effects of blood pressure, left ventricular
function,
insulin sensitivity, blood glucose, HDL levels, LDL levels, and renal
functions.
[0060] Inventors further propose that cicletanine would ameliorate the
development of
hypertension in Dahl-S rats and protects the cardiovascular and renal systems
against
the injuries seen in the hypertension. Inventors further propose that PKC-
induced
phosphorylation of cardiac alpha-1 Na/K-ATPase is a likely target for
cicletanine action.
Still further, the inventors propose that cicietanine may have a renal-
protective action,
which is not related to improvement of diabetes or improvement of high blood
pressure
in diabetic rats with hypertension.
Nephroprotective Mechanisms of Action of Prostacyclins
[0061] Although the renal protective mechanism of action of prostacyclins and
prostacyclin inducers is largely unknown, there are at present numerous
theories. For
example, Kikkawa et al. (Am J Kidney Dis 2003 41(3 Suppl 2):S19-21), have
postulated
that the PKC-MAPK pathway may play an important role in prostacyclin-mediated
nephroprotection. They examined whether inhibition of the PKC-MAPK pathway
could
inhibit functional and pathological abnormalities in glomeruli from diabetic
animal
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models and cultured mesangial cells exposed to high glucose condition and/or
mechanical stretch. The authors reported that direct inhibition of PKC by PKC
beta
inhibitor prevented albuminuria and mesangial expansion in db/db mice, a model
of type
2 diabetes. They also found that inhibition of MAPK by PD98059, an inhibitor
of MAPK,
or mitogen-activated extracellular regulated protein kinase prevented
enhancement of
activated protein-1 (AP-1) DNA binding activity and fibronectin expression in
cultured
mesangial cells exposed to mechanical stretch in an in vivo model of
glomerular
hypertension. These findings highlight the potential role of PKC-MAPK pathway
activation in mediating the development and progression of diabetic
nephropathy.
[0062] There is evidence for endothelial dysfunction in both type 1 and type 2
diabetics. This dysfunction is manifest as blunting of the biologic effect of
a potent
endothelium-derived vasodilator, nitric oxide (NO), and increased production
of
vasoconstrictors such as angiotensin II, ET-1, and cyclooxygenase and
lipoxygenase
products of arachidonic acid metabolism. These agents and other cytokines and
growth
factors whose production they stimulate cause acute increases in vascular
tone,
resulting in increases in blood pressure, and vascular and cardiac remodeling
that
contributes to the microvascular, macrovascular, and renal complications in
diabetes.
Reactive oxygen species, overproduced in diabetics, may serve as signaling
molecules
that mediate many of the cellular biochemical reactions that result in these
deleterious
effects. Adverse vascular consequences associated with endothelial dysfunction
in
diabetes mellitus include: decreased NO formation, release, and action;
increased
formation of reactive oxygen species; decreased prostacyclin formation and
release;
increased formation of vasoconstrictor prostanoids; increased formation and
release of
ET-1; increased lipid oxidation; increased cytokine and growth factor
production;
increased adhesion molecule expression; hypertension; changes in heart and
vessel
wall structure; and acceleration of the atherosclerotic process. It is
proposed that
treatment with antioxidants and ACE inhibitors may reverse some of the
pathologic
vascular changes associated with endothelial dysfunction. Further, since
prostacyclins
enhance NO release and exert direct vasodilatory effects, treatment with
prostacyclin
agonists or inducers should be effective in protecting against and possibly
reversing
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vascular changes associated with diabetic glomerulosclerosis.
[0063] Applicants propose= that cicletanine plus an ACE inhibitor could
provide a
preferred combination therapy in treating diabetes patients with hypertension.
It is
anticipated that cicietanine would produce positive results in diabetic animal
models
alone and in combination with the ACE inhibitor, fosinopril, and to reduce
microalbuminuria in diabetic humans. Cicletanine is also suggested as a drug
of choice
in diabetics because it inhibits the beta isoform of PKC, and such inhibition
has been
demonstrated effective against diabetic complications in animal models, and
increasingly, in human clinical trials. Another reason for using cicletanine
in combination
with an ACE inhibitor is the predicted balance between cicletanine's
enhancement of
potassium excretion and the mild retention of potassium typically seen with
ACE
inhibitors.
[0064] Another therapeutic approach is the use of PKC inhibitors such as
LY333531.
Cicletanine is particularly interesting in this regard because of evidence
that it has, at
least in some populations, a three-fold action of glycemic control, blood-
pressure
reduction and PKC inhibition. The combination of cicietanine with a commonly-
used
antihypertensive medication is therefore a promising approach to treating
hypertension,
particularly in patients with diabetes or metabolic syndrome.
Prostacyclin Delivery and Side Effects-
[0065] Clinical experiences with prostacyclin agonists have been significantly
documented in treatment of primary pulmonary hypertension (PPH). The lessons
learned in treating PPH may be valuable in developing prostacyclin-mediated
therapies
for treatment and/or prevention of diabetic complications (e.g., nephropathy,
retinopathy, neuropathy, etc.). Prostacyclin agonists, such as epoprostenol
(Flolan ),
have been delivered by injection through a catheter into the patient, usually
near the
gut. The drug is slowly absorbed after being injected into fat cells. These
agonists have
been shown to exert direct effects the blood vessels of the lung, relaxing
them enabling
the patient to breathe easier. This treatment regimen is used for primary
pulmonary
hypertension. Some researchers believe it may also slow the PPH scarring
process.
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The intravenous prostacyclin agonist, epoprostenol, has been shown to improve
survival, exercise capacity, and hemodynamics in patients with severe PPH.
[0066] Side effects typically seen in patients receiving prostacyclins
(agonists or
inducers) include headache, jaw pain, leg pain, and diarrhea, and there may be
complications with the injection delivery system. These findings are
documented for
continuous intravenous epoprostenol therapy and have also been reported with
the
subcutaneous delivery of the prostacyclin preparation treprostinil. Oral
application of the
prostacyclin agonist, beraprost, may decrease delivery-associated risks, but
this
delivery route has not yet been shown to be effective in severe disease,
although in
moderately ill PPH patients, there was a significant benefit in a controlled
study.
[0067] Aerosolization of prostacyclin and its stable analogues caused
selective
pulmonary vasodilation, increased cardiac output and improved venous and
arterial
oxygenation in patients with severe pulmonary hypertension. However, the
severe
vasodilator action of prostacyclin and its analogs also produced severe
headache and
blood pressure depression. Inventors thus propose that Inhaled prostacyclin
therapy for
pulmonary hypertension may offer selectivity of hemodynamic effects for the
lung
vasculature, thus avoiding systemic side effects.
Phosphodiesterase Involvement
[0068] PDE's Potentiate Prostacyclin Activity--Although aerosolized
prostacyclin
(PGI2) has been suggested for selective pulmonary vasodilation as
discussed
above, its effect rapidly levels off after termination of nebulization.
Stabilization of the
second-messenger cAMP by phosphodiesterase (PDE) inhibition has been suggested
as a strategy for amplification of the vasodilative response to nebulized
PGI2. Lung
PDE3/4 inhibition, achieved by intravascular or transbronchial administration
of
subthreshold doses of specific PDE inhibitors, syne,rgistically amplified the
pulmonary
vasodilatory response to inhaled PGI2, concomitant with an improvement in
ventilation-perfusion matching and a reduction in lung edema formation. The
combination of nebulized PGI2 and PDE3/4 inhibition may thus offer a new
concept for selective pulmonary vasodilation, with maintenance of gas exchange
in
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respiratory failure and pulmonary hypertension (Schermuly R. T. et al. 2000 J
Pharmacol Exp Ther 292:512-20).
[0069] A phosphodiesterase (PDE) inhibitor is any drug used in the treatment
of
congestive cardiac failure (CCF) that works by blocking the inactivation of
cyclic AMP
and acts like sympathetic simulation, increasing cardiac output. There are
five major
subtypes of phosphodiesterase (PDE); the drugs enoximone (inhibits PDE IV) and
milrinone (Primacor ) (inhibits PDE Illc) are most commonly used medically.
Other
phosphodiesterase inhibitors include sildenafil (Viagra(D); a PDE V inhibitor
used to treat
neonatal pulmonary hypertension) and Amrinone (InocorO) used to improve
myocardial
function, pulmonary and systemic vasodilation.
[0070] Isozymes of cyclic-3',5'-nucleotide phosphodiesterase (PDE) are
important
component of the cyclic-3',5'-adenosine monophosphate (cAMP) protein kinase A
(PKA)
signaling pathway. The superfamily of PDE isozymes consists of at least nine
gene
families (types): PDE1 to PDE9. Some PDE families are very diverse and consist
of
several subtypes and numerous PDE isoform-splice variants. PDE isozymes differ
in
molecular structure, catalytic properties, intracellular regulation and
location, and
sensitivity to selective inhibitors, as well as differential expression in
various cell types.
Type 3 phosphodiesterases are responsible for cardiac function.
[0071] A number of type-specific PDE inhibitors have been developed. Current
evidence indicates that PDE isozymes play a role in several pathobiologic
processes in
kidney cells. Administration of selective PDE isozyme inhibitors in vivo
suppresses
proteinuria and,pathologic changes in experimental anti-Thy-1.1 mesangial
proliferative
glomerulonephritis in rats. Increased activity of PDE5 (and perhaps also PDE9)
in
glomeruli and in cells of collecting ducts in sodium-retaining states, such as
nephrotic
syndrome, accounts for renal resistance to atriopeptin; diminished ability to
excrete
sodium can be corrected by administration of the selective PDE5 inhibitor
zaprinast.
Anomalously high PDE4 activity in collecting ducts is a basis of
unresponsiveness to
vasopressin in mice with hereditary nephrogenic diabetes insipidus. PDE
isozymes are
a target for action of numerous novel selective PDE inhibitors, which are key
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components in the design of novel "signal transduction" pharmacotherapies of
kidney
diseases (Dousa T. P. 1999 Kidney Int 55:29-62).
Nitric oxide (NO) donors/inducers
[0072] NO is an important signaling molecule that acts in many tissues to
regulate a
diverse range of physiological processes. One role is in blood vessel
relaxation and
regulating vascular tone. Nitric oxide is a short-lived molecule (with a half-
life of a few
seconds) produced from enzymes known as nitric oxide synthetases (NOS). Since
it is
such a small molecule, NO is able to diffuse rapidly across cell membranes
and,
depending on the conditions, is able to diffuse distances of more than several
hundred
microns. The biological effects of NO are mediated through the reaction of NO
with a
number of targets such as heme groups, sulfhydryl groups and iron and zinc
clusters.
Such a diverse range of potential targets for NO explains the large number of
systems
that utilize it as a regulatory molecule.
[0073] The earliest medical applications of NO relate to the function of NOS
in the
cardiovascular system. Nitroglycerin was first synthesized by Alfred Nobel in
the 1860s,
and this compound was eventually used medicinally to treat chest pain. The
mechanism
by which nitrovasodilators relax blood vessels was not well defined but is now
known to
involve the NO signaling pathway. Cells that express NOS include vascular
endothelial
cells, cardiomyocytes and others. In blood vessels, NO produced by the NOS of
endothelial cells functions as a vasodilator thereby regulating blood flow and
pressure.
Mutant NOS knockout mice have blood pressure that is 30% higher than wild-type
littermates. Within cardiomyocytes, NOS affects Ca2+ currents and
contractility.
Expression of NOS is usually reported to be constitutive though modest degrees
of
regulation occur in response to factors such as shear stress, exercise
training, chronic
hypoxia, and heart failure.
[0074] The unique N-terminal sequence of NOS is about 70 residues long and
functions to localize the enzyme to membranes. Upon myristoylation at one site
and
palmitoylation at two other sites within this segment, the enzyme is
exclusively
membrane-bound. Palmitoylation is a reversible process that is influenced by
some
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agonists and is essential for membrane localization. Within the membrane, NOS
is
targeted to the caveolae, small invaginations characterized by the presence of
proteins
called caveolins. These regions serve as sites for the sequestration of
signaling
molecules such as receptors, G proteins and protein kinases. The oxygenase
domain of
NOS contains a motif that binds to caveolin-1, and calmodulin is believed to
competitively displace caveolin resulting in NOS activation. Bound calmodulin
is
required for activity of NOS, and this binding occurs in response to transient
increases
in intracellular Ca2+. Thus, NOS occurs at sites of signal transduction
and
produces short pulses of NO in response to agonists that elicit Ca2+
transients.
Physiological concentrations of NOS-derived NO are in the picomolar range.
[0075] Within the cardiovascular system, NOS generally has protective effects.
Studies with NOS knockout mice clearly indicate that NOS plays a protective
role in
cerebral ischemia by preserving cerebral blood flow. During inflammation and
atherosclerosis, low concentrations of NO prevent apoptotic death of
endothelial cells
and preserve the integrity of the endothelial cell monolayer. Likewise, NO
also acts as
an inhibitor of platelet aggregation, adhesion molecule expression, and
vascular smooth
muscle cell proliferation. Therefore, NOS-related pathologies usually result
from
impaired NO production or signaling. Altered NO production and/or
bioavailability have
been linked to such diverse disorders as hypertension, hypercholesterolemia,
diabetes,
and heart failure.
[0076] Cicletanine's vasorelaxant and vasoprotective properties may be
mediated by
its effects on nitric oxide and superoxide. It was been shown in situ that
cicletanine
stimulates NO release in endothelial cells at therapeutic concentrations.
(Kalinowski, et
al. 2001 J Vascular Pharmacol 37:713-724). NO release was observed at
concentrations similar to the plasma concentrations obtained following dosing
with 75-
200 mg of cicietanine. While cicletanine stimulates both NO release and
release of
O2-, cicletanine scavenges superoxide at nanomolar levels. Thus,
cicletanine
is able to increase the net production of diffusible NO. These effects may
contribute to
the potent vasorelaxation properties of cicletanine.
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[0077] Superoxide consumes NO to produce peroxynitrite (OONO-) which in
turn
may undergo cleavage to produce OH, NO2 radicals and NO2+,
which
are among the most reactive and damaging species in biological systems.
Cicletanine
prevents production of these damaging species both by its stimulation of NO
and by
scavenging superoxide and may account for cicletanine's protective effects on
the
cardiovascular and renal systems. Inventors thus propose that cicletanine
increases
vascular NO and decreases superoxide and peroxynitrite production.
[0078] Oxatriazoles--The novel sulfonamide NO donors GEA 3268, (1,2,3,4-
oxatriazolium, 3-(3-chloro-2-methylphenyl)-5-[[(4-methoxyphenyl)-
sulfonyl]amino]-,
hydroxide inner salt) and GEA5145, (1,2,3,4-oxatriazolium, 3-(3-chloro-2-
methylphenyl)-
5-[(methylsulfonyl)am- ino]-, hydroxide inner salt) are both derivatives of an
imine, GEA
3162, that is an NO donor; and sulfonamide GEA 3175, which most probably is an
NO
donor. It has been suggested that the enzymatic degradation of the sulfonamide
moiety
has to take place before NO is released.
[0079] Inorganic NO donors --SNP (sodium nitroprusside, sodium
pentacyanonitrosyl
ferrate) compounds, together with other commonly used anti-ischemic drugs like
glyceryl trinitrate, amyl nitrite and isosorbide dinitrate, have the
disadvantage of
consuming organic reduced thiols. The lack of reduced thiols has been
implicated in
tolerance. SNP is an inorganic complex, in which Fe2+ atom is surrounded
by 4
cyanides, has a covalent binding to NO, and forms an ion bond to one Na+.
When
the compound becomes decomposed, cyanides are released and this may induce
toxicity in long term clinical use. SNP releases NO intracellularly which can
lead to
problems in the estimation of NO delivery. Though many possible forms of
reactive NO
derivatives have been discussed, it is somewhat surprising that in vitro SNP-
induced
relaxation in guinea pig tracheal preparation has been reported to be induced
completely via cyclic GMP production.
[0080] S-nitrosothiols (thionitrates, RSNO)--S-nitroso-N-acetylpenicillamine
(SNAP)
is one of the most commonly used NO donors in experimental research since the
mid-
1990's. In physiological solutions many nitrosothiols rapidly decompose to
yield NO.
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The disadvantage of nitrosothiols is that their half-life can vary from
seconds to hours
even at a pH of 7.4, and this is dependent on the buffer used. In
physiological buffers,
many of the RSNOs become decomposed rapidly to yield disulfide and NO.
[0081] Sydnonimines --SIN-1 is the active metabolite of the antianginal
prodrug
molsidomine (N-ethoxycarbonyl-3-morpholinosydnonimine), these two compounds
are
sydnonimines that are also mesoionic heterocycles. Liver metabolism needs to
convert
molsidomine it into its active form. SIN-1 is a potent vasorelaxant and an
antiplatelet
agent causing spontaneous, extracellular release of NO. SIN-1 can activate sGC
independently of thiol groups. SIN-1 can rapidly and non-enzymatically
hydrolyze into
SIN-1A when there are traces of oxygen present, it donates NO and
spontaneously
turns into NO-deficient SIN-1C. SIN-1C prevents human neutrophil degranulation
in a
concentration-dependent manner and can reduce Ca2+ increase, a property
which
is common to SIN-1. SIN-1 has been shown to release NO, ONOO-- and O2-.
[0082] NO inducers--Various drugs and compositions have been shown to up-
regulate endogenous NO release by inducing NOS expression. For example, Hauser
et
a/. 1996 Am J Physiol 271:H2529-35), reported that endotoxin
(Iipopolysaccharide,
LPS)-induced hypotension is, in part, mediated via induction of NOS, release
of nitric
oxide, and suppression of vascular reactivity (vasoplegia).
Calcium Channel Blockers
[0083] Calcium channel blockers act by blocking the entry of calcium into
muscle cells
of heart and arteries so that the contraction of the heart decreases and the
arteries
dilate. With the dilation of the arteries, arterial pressure is reduced so
that it is easier for
the heart to pump blood. This also reduces the heart's oxygen requirement.
Calcium
channel blockers are useful for treating angina. Due to blood pressure
lowering effects,
calcium channel blockers are also useful to treat high blood pressure. Because
they
slow the heart rate, calcium channel blockers may be used to treat rapid heart
rhythms
such as atrial fibrillation. Calcium channel blockers are also administered to
patients
after a heart attack and may be helpful in treatment of arteriosclerosis.
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[0084] Examples of calcium channel blockers include, but are not limited to
diltiazem
malate, amlodipine bensylate, verapamil hydrochloride, diltiazem
hydrochloride,
efonidipine, nifedipine, felodipine, lacidipine, nisoldipine, isradipine,
nimodipine,
nicardipine hydrochloride, bepridil hydrochloride, and mibefradil di-
hydrochloride.
Preferred calcium channel blockers comprise amiodipine, diltiazem, isradipine,
nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, and verapamil,
or, e.g.
dependent on the specific calcium channel blockers, a pharmaceutically
acceptable salt
thereof. The scope of the present invention includes all those calcium channel
blockers
now known and all those calcium channel blockers to be discovered in the
future.
[0085] The compounds to be combined can be present as pharmaceutically
acceptable salts. If these compounds have, for example, at least one basic
center, they
can form acid addition salts. Corresponding acid addition salts can also be
formed
having, if desired, an additionally present basic center. The compounds having
at least
one acid group (for example COOH) can also form salts with bases.
Corresponding
internal salts may furthermore be formed, if a compound of formula comprises
e.g., both
a carboxy and an amino group. Suitable salts of corresponding calcium channel
blockers include, but are not limited to amiodipine besylate, diltiazem
hydrochloride,
fendiline hydrochloride, flunarizine di-hydrochloride, gallopamil
hydrochloride, mibefradil
di-hydrochloride, nicardipine hydrochloride, lercanidipine and verapamil
hydrochloride.
[0086] In accordance with one embodiment of the present combination therapy,
cicletanine is administered together with the second generation calcium
antagonist,
amlodipine. The combination may administered in a sustained release dosage
form.
Because amlodipine is a long acting compound it may not warrant sustained
release;
however, where cicletanine is dosed two or more times daily, then in
accordance with
one embodiment, the cicietanine may be administered in sustained release form,
along
with immediate release amlodipine. In another embodiment, the combination
dosage
and release form is optimized for the treatment of hypertensive patients, more
particularly, the oral combination is administered once daily.
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ACE Inhibitors
[0087] Angiotensin converting enzyme (ACE) inhibitors are compounds that
inhibit the
action of angiotensin converting enzyme, which converts angiotensin I to
angiotensin II.
ACE inhibitors have individually been shown to be somewhat effective in the
treatment
of cardiac disease, such as congestive heart failure, hypertension,
asymptomatic left
ventricular dysfunction, or acute myocardial infarction.
[0088] A number of ACE inhibitors are known and available. These compounds
include inter alia lisinopril (Zestril@; Prinivil ), enalapril maleate
(Innovace ; Vasotec ),
quinapril (Accupril ), ramipril (Tritace ; Altaceft benazepril (Lotensin(D),
captopril
(Capoten ), cilazapril (Vascace ), fosinopril (StarilO; Monopril ), imidapril
hydrochloride (Tanatril ), moexipril hydrochloride (Perdix ; Univasc ),
trandolapril
(Gopten@; Qdrik ; Mavik ), and perindopril (Coversyl ; Aceon ). The scope of
the
present invention includes all those ACE inhibitors now known and all those
ACE
inhibitors to be discovered in the future.
[0089] In accordance with one preferred embodiment of the present combination
therapy, cicletanine is administered together with an ACE inhibitor. For
example, the
combination may be administered in a once-daily oral dosage form. More
particularly,
the combination is optimized for treatment of hypertension in patients with
and without
type 2 diabetes mellitus. Some of the major endpoints of such a study would be
effects
on blood pressure, left ventricular function, insulin sensitivity, and renal
functions.
Angiotensin II Receptor Antagonists
[0090] Angiotensin II receptor antagonists (blockers; ARB's), lower both
systolic and
diastolic blood pressure by blocking one of four receptors with which
angiotensin II can
interact to effect cellular change. Examples of angiotensin II receptor
antagonists
include losartan potassium, valsartan, irbesartan, candesartan cliexetil,
telmisartan,
eprosartan mesylate, and olmesartan medoxomil. Angiotensin II receptor
antagonists in
combination with a diuretic are also available and include losartan
potassium/hydrochlorothiazide, valsartan/hydrochlorothiazide,
irbesartan/hydrochlorothiazide, candesartan cilexetil/hydrochlorothiazide- ,
and
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telmisartan/hydrochlorothiazide. The scope of the present invention includes
all those
angiotensin receptor antagonists now known and all those angiotensin receptor
antagonists to be discovered in the future.
Diuretics
[0091] Individual diuretics increase urine volume. One mechanism is by
inhibiting
reabsorption of liquids in a specific segment of nephrons, e.g., proximal
tubule, loop of
Henle, or distal tubule. For example, a loop diuretic inhibits reabsorption in
the loop of
Henle. Examples of diuretics commonly used for treating hypertension include
hydrochlorothiazide, chlorthalidone, bendroflumethazide, benazepril,
enalapril, and
trandolapril. The scope of the present invention includes all those diuretics
now known
and all those diuretics to be discovered in the future.
Beta Blockers
[0092] Beta blockers, prevent the binding of adrenaline to the body's beta
receptors
which blocks the "fight or flight" response. Beta receptors are found
throughout the
body, including the heart, lung, arteries and brain. Beta blockers slow down
the nerve
impulses that travel through the heart. Consequently, the heart needs less
blood and
oxygen. Heart rate and force of heart contractions are decreased.
[0093] There are two types of beta receptors, beta 1 and beta 2 that are
commonly
targeted in hypertension therapy. Beta 1 receptors are associated with heart
rate and
strength of heart beat and some beta blockers selectively block beta 1 more
than beta
2. Beta blockers are used to treat a wide variety of conditions including high
blood
pressure, congestive heart failure, tachycardia, heart arrhythmias, angina,
migraines,
prevention of a second heart attack, tremor, alcohol withdrawal, anxiety, and
glaucoma.
[0094] Suitable beta blockers include, but are not limited to, atenolol,
metoprolol
succinate., metoprolol tartrate, propranolol hydrochloride, nadolol,
acebutolol
hydrochloride, bisoprolol fumarate, pindolol, betaxolol hydrochloride,
penbutolol sulfate,
timolol maleate, carteolol hydrochloride, esmolol hydrochloride. Beta
blockers,
generally, are compounds that block beta receptors found throughout the body.
The
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scope of the present invention includes all those beta blockers now known and
all those
beta blockers to be discovered in the future.
Aldosterone Antagonists
[0095] Aldosterone is a mineralocorticoid steroid hormone which acts on the
kidney
promoting the reabsorption of sodium ions (Na+) into the blood. Water
follows the
salt, helping maintain normal blood pressure. Aldosterone has the potential to
cause
edema through sodium and water retention. Aldosterone antagonists inhibit the
action of
aldosterone and have shown significant benefits for patients suffering from
congestive
heart failure, hypertension, and microalbuminuria.
[0096] A number of aldosterone antagonists are known including sprironolactone
and
eplerenone (Inspra(D). Aldosterone antagonists, generally, are compounds that
block
the action of aidosterone throughout the body. The scope of the present
invention
includes all those aldosterone antagonists now known and those aldosterone
antagonists to be discovered in the future. Suitable classes of
antihypertensive agents
that are envisioned in combination with cicietanine include endothelin
antagonists,
urotensin antagonists, vasopeptidase inhibitors, neutral endopeptidase
inhibitors,
hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors, vasopressin
antagonists,
and T-type calcium channel antagonists.
Endothelin Antagonists
[0097] Endothelin-1 (ET-1) is a potent vasoconstrictor, and thus its role in
the
development and/or maintenance of hypertension has been studied extensively.
ET-1,
the predominant isoform of the endothelin peptide family, regulates
vasoconstriction and
cell proliferation in tissues both within and outside the cardiovascular
system through
activation of protein-coupled ETA or ETB receptors. The endothelin system has
been
implicated in the pathogenesis of arterial hypertension and renal disorders.
Plasma
endothelin also appears to be greater in obese individuals, particularly obese
hypertensives. Blood vessel endothelin expression and cardiac levels of ET-1 -
like
immunoreactivity have been shown to be increased in various animal models of
hypertension. Renal prepro-ET-1 mRNA levels are also increased in DOCA-salt
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hypertensive animals and endothelin production from cultured endothelial cells
is
upregulated in hypertensive rats. Both ETA and ETB receptors have been shown
to be
reduced in mesenteric vessels of spontaneously hypertensive rats. There are a
number
of experimental studies demonstrating that direct and indirect endothelin-
antagonists
can have beneficial effects in hypertension.
[0098] Administration of the endothelin-converting enzyme inhibitor,
phosphoramidon,
or ET-receptor antagonists (e.g., bosentan) have been shown to reduce blood
pressure
in a number of different hypertensive rat models.
Neutral Endopeptidase Inhibitors
[0099] Since angiotensin 11 is an established target of pharmacologic
interventions,
there is an increasing interest in the biological effects and metabolism of
other
vasoactive peptides, such as atrial natriuretic peptide (ANP) and ET.
Exogenous
administration of the vasodilatory and natriuretic ANP and of its analogues
improved
hemodynamics and renal function in cardiovascular disease, including
congestive heart
failure. Promising results have been obtained in animal experiments and
initial human
clinical studies concerning hemodynamics and kidney function with inhibition
of ANP
metabolism by inhibitors of neutral endopeptidase (NEP). In further clinical
studies,
moderately relevant effects of acute intravenous or oral NEP inhibition were
observed,
but these effects were blunted with acute drug administratiori. There is
increasing
evidence the NEP inhibitors, such as candoxatril and ecadotril, expected to
exhibit
vasod'ilatory activity at least at certain doses in certain clinical
situations, even induce
vasoconstriction. An explanation for the ineffectiveness of NEPs in reducing
blood
pressure when used alone may lie in the effect of the role of NEP in the
metabolism of
other peptides besides ANP. In addition to ANP and other natriuretic peptides,
NEP also
metabolizes the vasoactive peptides ET-1, angiotensin II, and bradykinin.
Vasopeptidase Inhibitors =
[00100] Vasopeptidase inhibition is a novel efficacious strategy for treating
cardiovascular disorders, including hypertension and heart failure, that may
offer
advantages over currently available therapies. Vasopeptidase inhibitors are
single
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molecules that simultaneously inhibit two key enzymes involved in the
regulation of
cardiovascular function, NEP and ACE. Simultaneous inhibition of NEP and ACE
increases natriuretic and vasodilatory peptides (including ANP), brain
natriuretic peptide
of myocardial cell origin, and C-type natriuretic peptide of endothelial
origin. This
inhibition also increases the half-life of other vasodilator peptides,
including bradykinin
and adrenomedullin. By simultaneously inhibiting the renin-angiotensin-
aldosterone
system and potentiating the natriuretic peptide system, vasopeptidase
inhibitors reduce
vasoconstriction and enhance vasodilation, thereby decreasing vascular tone
and
lowering blood pressure. Omapatrilat, a heterocyclic dipeptide mimetic, is the
first
vasopeptidase inhibitor to reach advanced clinical trials in the United
States. Unlike
ACE inhibitors, omapatrilat demonstrates antihypertensive efficacy in low-,
normal-, and
high-renin animal models. Unlike NEP inhibitors, omapatrilat provides a potent
and
sustained antihypertensive effect in spontaneously hypertensive rats, a model
of human
essential hypertension. In animal models of heart failure, omapatrilat is more
effective
than ACE inhibition in improving cardiac performance and ventricular
remodeling and
prolonging survival. Omapatrilat effectively reduces blood pressure, provides
target
organ protection, and reduces morbidity and mortality from cardiovascular
events in
animal models. Human studies with omapatrilat (Vanlev, Bristol-Myers Squibb),
administered orally once daily, have demonstrated a dose-dependent reduction
of
systolic and diastolic blood pressure, regardless of age, race, or gender. Its
ability to
decrease systolic blood pressure is especially notable, since evidence
suggests that
systolic blood pressure is a better predictor than diastolic blood pressure of
stroke, heart
attack, and death. Omapatrilat appears to be a safe, well-tolerated, effective
hypertensive agent in humans, and it has the potential to be'an effective,
broad-
spectrum antihypertensive agent. Adverse effects are comparable to those of
currently
available antihypertensive agents. Another vasopeptidase inhibitor that is
currently
under clinical development is the agent sampatrilat (Chiron).
HMG-CoA Reductase Inhibitors
[00101] Hydroxymethylglutaryl Coenzyme A (HMG-CoA) reductase inhibitors (e.g.,
statins) are increasingly being used to treat high cholesterol levels and have
been
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shown to prevent heart attacks and strokes. Many individuals with high
cholesterol also
have high blood pressure, so the effect of the statins on blood pressure is of
great
interest. Certain HMG-CoA reductase inhibitors may cause vasodilation by
restoring
endothelial dysfunction, which frequently accompanies hypertension and
hypercholesterolemia. There have also been reports of a synergistic effect on-
vasodilation between ACE inhibitors and statins. Several studies have found
that a
blood pressure reduction is associated with the use of statins, but conclusive
evidence
from controlled trials is lacking. In a recent clinical study in individuals
with moderate
hypercholesterolemia and untreated hypertension, the HMG-CoA reductase
inhibitor
pravastatin (20 to 40 mg/day, 16 weeks) decreased total (6.29 to 5.28 mmol/L)
and low-
density lipoprotein (4.31 to 3.22 mmol/L) cholesterol, systolic and diastolic
blood
pressure (149/97 to 131/91), and pulse pressure. In this same study,
circulating ET-1
levels were decreased by pretreatment with pravastatin. In conclusion,
clinical studies
have demonstrated that a specific statin, pravastatin, decreases systolic,
diastolic, and
pulse pressures in persons with moderate hypercholesterolemia and
hypertension.
Vasopressin Antagonists
[00102] The hormone vasopressin plays a particular role in peripheral
vasoconstriction,
hypertension, and in several disease conditions with dilutional hyponatremia
in
edematous disorders, such as congestive heart failure, liver cirrhosis,
syndrome of
inappropriate secretion of antidiuretic hormone, and nephrotic syndrome. These
effects
of vasopressin are mediated through vascular (V1 a) and renal (V2) receptors.
A series
of orally active nonpeptide antagonists against the vasopressin receptor
subtypes have
recently been synthesized and are now under intensive examination. Nonpeptide
V1 a-
receptor antagonists, OPC21268 and SR49059, nonpeptide V2-receptor-specific
antagonists, SR121463A and VPA985, and combined V1aN2-receptor antagonists,
OPC31260 and YM087, are currently available.
T-Type Calcium Ion Channel Antagonists
[00103] Recent clinical trials have been conducted with a new class of calcium
channel
antagonists that selectively block T-type voltage-gated plasma membrane
calcium
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channels in vascular smooth muscle. The prototypical member of this group is
the agent
mibefradil (Roche), which is 10 to 50 times more selective for blocking T-type
than L-
type calcium channels. This drug is structurally and pharmacologically
different from
traditional calcium antagonists. It does not produce negative inotropic
effects at
therapeutic concentrations and is not associated with reflex activation of
neurohormonal
and sympathetic systems. In clinical studies of hypertension, mibefradil (50
and 100
mg/day) reduced trough sitting diastolic and systolic blood pressure in a dose-
related
manner. Dosages exceeding 100 mg/day generally did not result in significantly
greater
efficacy, but were associated with a higher frequency of adverse events. No
first- dose
hypotensive phenomenon was observed. Mibefradil has antiischemic properties
resulting from dilation of coronary and peripheral vascular smooth muscle, and
a slight
reduction in heart rate. Mibefradil (Posicor ) was approved by the FDA in June
1997 for
the treatment of hypertension and angina, but was withdrawn from the market in
1998
because of severe drug interactions. Since the effects of this type of calcium
channel
blocker were so profound on hypertension, studies with other selective T-type
calcium
channel antagonists have continued.
Urotensin-II Antagonists
[00104] Recent discoveries have identified Urotensin-II (U-II) as an important
regulator
of the cardiovascular system, working to constrict arteries and possibly to
increase
blood pressure in response to exercise and stress. It was found that U-II
constricts
arteries more mildly and for a longer period than other chemicals known for
similar
effects on blood pressure. The potency of vasoconstriction of U-II is an order
of
magnitude greater than that of ET-1, making human U-II the most potent
mammalian
vasoconstrictor identified to date. In vivo, human U-II markedly increases
total
peripheral resistance in anesthetized nonhuman primates, a.response associated
with
profound cardiac contractile dysfunction. These effects are mediated by U-II
binding to
receptors in the brainstem, heart, and in major blood vessels, including the
pulmonary
artery, which supplies blood to the lungs, and the aorta, the major vessel
leading from
the heart.
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PPAR Agonists
[00105] Peroxisome proliferator-activated receptors (PPARs) are a family of
ligand-
activated nuclear hormone receptors belonging to the steroid receptor super-
family that
regulate lipid and carbohydrate metabolism in response to extracellular fatty
acids and
their metabolites. They are involved in the regulation of fat storage, besides
having a
potential role in insulin resistance syndrome. They also may have relevance in
understanding the cause of common clinical conditions such as type 2 diabetes
mellitus,
cellular growth and neoplasia, and in the development of drugs for treating
such
conditions. Three types of receptors were identified: PPAR alpha, gamma and
delta.
Whereas PPAR alpha is a regulator of fatty acid catabolism in the liver PPAR
gamma
plays a key role in adipogenesis. The use of synthetic PPAR ligands has
demonstrated
the involvement of these receptors in the regulation of lipid and glucose
homeostasis
and today PPARs are established molecular targets for the treatment of type 2
diabetes
and cardiovascular disease. The fibrate family of lipid lowering agents binds
to the alpha
isoform and the glitazone family of insulin sensitizers binds to the gamma
isoform of
PPARs.
Oral Antidiabetics
Sulfonylureas
[00106] Sulfonureas--The sulfonylurea group has dominated oral antidiabetic
treatment for years. They primarily increase insulin secretion. Their action
is initiated by
binding to and closing a specific sulfonylurea receptor (an ATP-sensitive
K+
channel) on pancreatic .beta.-cells. This closure decreases K+ influx,
leading to
depolarization of the membrane and activation of a voltage-dependent Ca2+
channel. The resulting increased Ca2+ flux into the .beta.-cell,
activates a
cytoskeletal system that causes translocation of insulin to the cell surface
and its
extrusion by exocytosis.
[00107] The proximal step in this sulfonylurea signal transduction is the
binding to (and
closure) of high-affinity protein receptors in the .beta.-cell membrane. There
are both
high and low-affinity sulfonylurea receptor populations. Sulfonylurea binding
to the high-
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affinity sites affects primarily K+ (ATP) channel activity, while
interaction with the
low-affinity sites inhibits both Na+/K+-ATPase and K(ATP) channel
activities.
The potent second-generation sulfonylureas, glyburide and glipizide, are able
to
saturate receptors in low nanomolar concentration ranges, whereas older, first-
generation drugs bind to and saturate receptors in micromolar ranges.
[00108] There is a synergy between the action of glucose and that of the
sulfonylureas:
sulfonylureas are better effectors of insulin secretion in the presence of
glucose. For
that reason, the higher the level of plasma glucose at the time of initiation
of
sulfonylurea treatment, the greater the reduction of hyperglycemia.
[00109] Exposure of perfused rat hearts to the second-generation sulfonylurea
glyburide leads to a dramatic increase in glycolytic flux and lactate
production. When
insulin is included in the buffer, the response to glyburide is significantly
increased.
(Similarly, glyburide potentiates the metabolic effects of insulin.) Because
glyburide
does not promote glycogenolysis, this increase in glycolytic flux is caused
solely by a
rise in glucose utilization. Since the drug does not alter oxygen consumption,
the
contribution of glucose to overall ATP production rises while that of fatty
acids falls.
These metabolic changes aid the heart in resisting ischemic,insults.
[00110] Insulin, on the other hand, is released by the pancreas into the
portal vein,
where the resultant hyperinsulinemia suppresses hepatic glucose production and
the
elevated level of arterial insulin enhances muscle glucose uptake, leading to
a reduction
in postprandial plasma glucose levels.
[00111] The initial hypoglycemic effect of suifonylureas results from
increased
circulating insulin levels secondary to the stimulation of insulin release
from pancreatic
.beta.-cells and, perhaps to a lesser extent, from a reduction in its hepatic
clearance.
Unfortunately, these initial increases in plasma insulin levels and .beta.-
cell responses
to oral glucose are not sustained during chronic sulfonylurea, therapy. After
a few
months, plasma insulin levels decline to those that existed before treatment,
even
though reduced glucose levels are maintained. Because of downregulation of
.beta.-cell
membrane receptors for sulfonylurea, its chronic use results in a reduction in
the insulin
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stimulation usually recorded following acute administration of these drugs.
More
globally, impairment of even proinsulin biosynthesis and, in some instances,
inhibition of
nutrient-stimulated insulin secretion may follow chronic (greater than several
months)
administration of any of the sulfonylureas. (However, the initial view that
the
proinsulin/insulin ratio is reduced by sulfonylurea treatment seems unlikely
in light of
recent research.). If chronic sulfonylurea therapy is discontinued, a more
sensitive
pancreatic .beta.-cell responsiveness to acute administration of the drug is
restored.
[00112] It is probable that this long-term sulfonylurea failure results from
chronically
lowered plasma glucose levels (and a resulting feedback reduction of
sulfonylurea
stimulation); it does, however, lead to a diminishment of the vicious
hyperglycemia-
hyperinsulinemia cycle of glucose toxicity. As a result, the sulfonylureas
reduce
nonenzymatic glycation of cellular proteins and the association of the latter
with an
increased generation of advanced glycation end products (AGEs), and improve
insulin
sensitivity at the target tissues. But, it should be kept in mind that one of
these cellular
proteins is insulin, which is readily glycated within pancreatic .beta.-cells
and under
these conditions, when it is secreted it presumably is now ineffective as a
ligand.
[00113] Sulfonylureas may have a direct effect in reducing insulin resistance
on
peripheral tissues. However, most investigators believe that whatever small
improvement in insulin action is observed during sulfonylurea treatment is
indirect,
possibly explained (as above) by the lessening of glucose toxicity and/or by
decreasing
the amount of ineffective, glycated insulin.
[00114] When sulfonylurea treatment is compared with, insulin treatment it is
found that:
(1) treatment with suifonylurea or insulin results in equal improvement in
glycemia and
insulin sensitivity, (2) the levels of proinsulin and plasminogen activator
inhibitor-1 (PAI-
1) antigen and its activity are higher with sulfonylurea, and (3) there are no
differences
in lipid concentrations between therapies.
[00115] Type 2 diabetes mellitus is part of a complicated metabolic-
cardiovascular
pathophysiologic cluster alternately referred to as the insulin resistance
syndrome,
Reaven's syndrome, the metabolic syndrome or syndrome X. Since the
macrovascular
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coronary artery disease associated with insulin resistance and type 2 diabetes
is the
major cause of death in the latter, it is desirable that any hypoglycemic
agent favorably
influences known cardiovascular risk factors. But the results in this area
have been only
mildly encouraging. This invention will add a cardiovascular risk reduction
dimension to
sulfonylurea therapy.
[00116] Sulfonylureas may have a neutral or just slightly beneficial effect on
plasma
lipid levels: plasma triglyceride levels decrease modestly in some studies.
This
hypolipidemic effect probably results from both a direct effect of
sulfonylurea on the
metabolism of very-low-density lipoprotein (VLDL) and an indirect effect of
sulfonylurea
secondary to its reduction of plasma glucose levels. The formulations of this
invention
provide appropriate therapeutic levels of a sulfonylurea and will enhance
and/or extend
the beneficial effect of the sulfonylureas upon plasma lipids, coagulopathy
and
microvascular permeability by additionally lowering the blood pressure.
[00117] Sulfonylureas, under some conditions, have various unwanted side
effect; a
frequent adverse effect is weight gain, which is also implicated as a cause of
secondary
drug failure. The side effects of the various sulfonylureas may vary among the
members
of the family. Sulfonylureas frequently: (1) stimulate renal renin release;
(2) inhibit renal
carnitine resorption; (3) increase PAI-1; and (4) increase insulin resistance.
Renal
effects from treatment with the sulfonylureas can be detrimental. Because the
sulfonylureas are KATP blockers they are diuretics although, fortunately,
they do
not produce kaliuresis. They may stimulate renin secretion from the kidney,
initiating a
cascade to angiotensin II in the vascular endothelium that results in
vasoconstriction
and elevated blood pressure. Therefore, the therapeutic combination of the
present
invention will be beneficial to controlling the renal side effects of
sulfonureas.
[00118] A particularly adverse effect of chronic sulfonylureas use is long
lasting,
significant hypoglycemia. The latter may lead to permanent neurological damage
or
even death, and is most'commonly seen in elderly subjects who are exposed to
some
intercurrent event (e.g., acute energy deprivation) or to drug interactions
(e.g., aspirin,
alcohol). Long-lasting hypoglycemia is more common with the longer-acting
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sulfonylureas glyburide and chlorpropamide. For this reason sulfonylurea
therapy
should be maintained at the lowest possible dose. By complementing and
efficiently
optimizing the therapeutic action of sulfonylurea, the formulations of this
invention
permit the use of minimal doses of sulfonylureas, thereby lowering the risks
of
sulfonylurea therapy, including hypoglycemia. As the population ages and as
the
prevalence of a sedentary life style increases, the danger of sulfonylurea-
induced
hypoglycemia also increases; and thus increases as well the desirability of
therapeutic
approaches that allow reductions in sulfonylurea dose levels.
[00119] Sulfonylureas are divided into first-generation and second-generation
drugs.
First-generation sulfonylureas have a lower binding affinity to the
sulfonylurea receptor
and require higher doses than second-generation sulfonylureas. Generally,
therapy is
initiated at the lowest effective dose and titrated upward every 1 to 4 weeks
until a
fasting plasma glucose levei of 110 to 140 mg/dL is achieved. Most (75%) of
the
hypoglycemic action of the sulfonylurea occurs with a daily dose that is half
of the
maximally effective dose. If no hypoglycemic effect is observed with half of
the
maximally effective dose, it is unlikely that further dose increases will have
a clinically
significant effect on blood glucose level.
[00120] In summary, sulfonylureas are effective glucose-lowering drugs that
work by
stimulating insulin secretion. They have a beneficial effect on diabetic
microangiopathy,
but no appreciable beneficial effect on diabetic macroangiopathy. Weight gain
is
common with their use. Sulfonylureas may cause hypoglycemia, which can be
severe,
even fatal. They may reduce platelet aggregation and slightly increase
fibrinolysis,
perhaps indirectly. They have no direct effect on plasma lipids. They inhibit
renal
resorption of carnitine and may stimulate renal renin secretion. The
sulfonylureas,
especially generics, are inexpensive. Sulfonylurea dosage can be minimized,
therapeutic effect maximized, safety improved and the scope of beneficial
effects
broadened in progressive insulin resistance, insulin resistance syndrome and
type 2
diabetes when delivered in the formulations of this invention.
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Biguanides
[00121] Biguanides (Metformin)--Metformin (Glucophage ) has a unique mechanism
of action and controls glycemia in both obese and normal-weight, type 2
diabetes
patients without inducing hypoglycemia, insulin stimulation or
hyperinsulinemia. It
prevents the desensitization of human pancreatic islets usually induced by
hyperglycemia and has no significant effect on the secretion of glucagon or
somatostatin. As a result it lowers both fasting and postprandial glucose and
HbAlc
levels. It also improves the lipid profile. Glucose levels are reduced during
metformin
therapy secondary to reduced hepatic glucose output from inhibition of
gluconeogenesis
and glycogenolysis. To a lesser degree it increases insulin action in
peripheral tissues.
[00122] Metformin enhances the sensitivity of both hepatic and peripheral
tissues
(primarily muscle) to insulin as well as inhibiting hepatic gluconeogenesis
and hepatic
glycogenolysis. This decline in basal hepatic glucose production is correlated
with a
reduction in fasting plasma glucose levels. Its enhancement of muscle insulin
sensitivity
is both direct and indirect. Improved insulin sensitivity in muscle from
metformin is
derived from multiple events, including increased insulin receptor tyrosine
kinase
activity, augmented numbers and activity of GLUT4 transporters, and enhanced
glycogen synthesis. However, the primary receptor through which metformin
exerts its
effects in muscle and in the liver is as yet unknown. In metformin-treated
patients both
fasting and postprandial insulin levels consistently decrease, reflecting a
normal
response of the pancreas to enhanced insulin sensitivity.
[00123] Metformin has a mean bioavailability of 50-60%. It is eliminated
primarily by
renal filtration and secretion and has a half-life of approximately 6 hours in
patients with
type 2 diabetes; its half-life is prolonged in patients with renal impairment.
It has no
effect in the absence of insulin. Metformin is as effective as the
sulfonylureas in treating
patients with type 2 diabetes, but has a more prominent postprandial effect
than either
the sulfonylureas or insulin. It is therefore most useful in managing patients
with poorly
controlled postprandial hyperglycemia and in obese or dyslipidemic patients;
in contrast,
the sulfonylureas or insulin are more effective in managing patients with
poorly
controlled fasting hyperglycemia.
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[00124] Metformin is absorbed mainly from the small intestine. It is stable,
does not bind
to plasma proteins, and is excreted unchanged in the urine. It has a half-life
of 1.3 to 4.5
hours. The maximum recommended daily dose of metformin is 3 g, taken in three
doses
with meals.
[00125] When used as monotherapy, metformin clinically decreases plasma
triglyceride
and low-density lipoprotein (LDL) cholesterol levels by 10% to 15%, reduces
postprandial hyperlipidemia, decreases plasma free fatty acid levels, and free
fatty acid
oxidation. Metformin reduces triglyceride levels in non-diabetic patients with
hypertriglyceriderriia. HDL cholesterol levels either do not change or
increase slightly
after metformin therapy. By reducing hyperinsulinemia, metformin improves
levels of
plasminogen activator inhibitor (PAI-1) and thus improves fibrinolysis in
insulin
resistance patients with or without diabetes. Weight gain does not occur in
patients with
type 2 diabetes who receive metformin; in fact, most studies show modest
weight loss
(2 to 3 kg) during the first 6 months of treatment. In one 1-year randomized,
double
blind trial, 457 non-diabetic patients with android (abdominal) obesity,
metformin caused
significant weight loss.
[00126] Metformin reduces blood pressure, improves blood flow rheology and
inhibits
platelet aggregation. The latter is also an effect of prostacyclins, and
cicietanine which
increases endogenous prostacyclin. See e.g., Arch Mal Coeur Vaiss,. 1989
November;82 Spec No 4:11-4.
[00127] These beneficial effects of metformin on various elements of the
insulin
resistance syndrome help define its usefulness in the treatment of insulin
resistance and,
type 2 diabetes. These useful effects are enhanced when metformin is combined
with
components of this invention (e.g. cicietanine). The latter is envisioned to
increase its
effectiveness and efficiency, improve its safety and expand the arena of its
medical
benefit. On the other hand, metformin in combination with cicletanine is
envisioned to
allow reduction in the dose of the latter to achieve the same antihypertensive
effect.
[00128] Metformin also reduces measurable levels of plasma triglycerides and
LDL
cholesterol and is the only oral, monotherapy, antidiabetic agent that has the
potential to
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reduce macrovascular complications, although this favorable effect is
attenuated by its
tendency to increase homocysteine levels. Likewise, it is the only oral
hypoglycemic
drug wherein most patients treated lose weight or fail to gain weight.
[00129] This invention introduces a strategy to increase the safety and
efficiency of
metformin in suppressing recognized risk factors, thus slowing the progression
of
disease by extending both the duration and the breadth of metformin's
therapeutic
value. The strategy of this invention will increase the number of patients by
whom
metformin can be used at reduced dose levels, thereby avoiding, delaying and
lessening metformin's adverse effects.
[00130] Gastrointestinal side effects (diarrhea, nausea, abdominal pain, and
metallic
taste--in decreasing order) are the most common adverse events, occurring in
20% to
30% of patients., These side effects usually are mild and transient and can be
minimized
by slow titration. If side effects occur during titration, they can be
eliminated by reducing
the dose by administering metformin in the combination of the present
invention.
Meglitinides and phenylalanine derivatives
[00131] --Meglitinides, such as repaglinide, are derived from the non-
sulfonylurea part
of the glyburide molecule and nateglinide is derived from D-phenylalanine.
Both
repaglinide and nateglinide bind competitively to the sulfonylurea receptor of
the
pancreatic .beta.-cell and stimulate insulin release by inhibiting KATP
channels in
the .beta.-cells. The relative potency of inhibition of KATP channels is
repaglinide>glyburide>nateglinide. Nateglinide exhibits rapid inhibition and
reversal of
inhibition of the KATP channel.
[00132] The plasma half-life of these drugs (50-60 min) is much shorter than
that of
glyburide (4-11 h). Repaglinide and nateglinide are absorbed rapidly,
stimulate insulin
release within a few minutes, and are quickly metabolized. Repaglinide is
excreted by
the liver and nateglinide is excreted by the kidneys.
[00133] Insulin secretion is more rapid in response to nateglinide than in
response to
repaglinide. If nateglinide is taken before a meal, insulin becomes available
during and
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after the meal, significantly reducing postprandial hyperglycemia without the
danger of
hypoglycemia between meals. Nateglinide, therefore, may potentially replace
the absent
Phase 1 insulin secretion in patients with type 2 diabetes.
[00134] The meglitinides and D-phenylalanine derivatives, classified as
"prandial
glucose regulators," must be taken before each meal. The dosage can be
adjusted
according to the amount of carbohydrate consumed. These drugs are especially
useful
when metformin is contraindicated (e.g., in patients with creatinine clearance
<50
mI/min). Treatment can be combined with other OADs as well as with
cicletanine. As a
result of the rapidity of their insulin-releasing action, repaglinide and
nateglinide may be
more effective in reducing postprandial hyperglycemia and pose a lower
hypoglycemia
risk than sulfonylureas such as glyburide.
alpha.-Glucosidase inhibitors
[00135] The .alpha.-glucosidase inhibitors (e.g., acarbose, miglitol, and
voglibose)
reduce the small intestinal absorption of starch, dextrin, and disaccharides
by
competitively inhibiting the action of the intestinal brush border enzyme,
.alpha.-
glucosidase. .alpha.-Glucosidase is responsible for the generation of
monosaccharides,
so that inhibition of .alpha.-glucosidase, which is the final step in
carbohydrate transfer
across the small intestinal mucosa, slows down the absorption of
carbohydrates.
[00136] These drugs are used for the treatment of patients with type 2
diabetes who are
inadequately controlled by diet or other oral antidiabetic drugs. Clinical
trials of .alpha.-
glucosidase inhibitors show decreases in postprandial glucose levels,
especially when
taken at the start of a meal, as well as decreases in glycosylated hemoglobin
(HbA1 c)
of 0.5-1 %. It has been reported that miglitol reduces HbA1 c less effectively
than
glyburide (glibenclamide) and also causes more alimentary side effects.
Miglitol, which
must be taken with each meal, has little effect on fasting blood glucose
concentrations
but blunts postprandial glucose increases at lower postprandial insulin
concentrations
than those observed with sulfonylureas. Unlike glyburide, miglitol is not
associated with
hypoglycemia, hyperinsulinism, or weight gain.
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[00137] The combination of acarbose or miglitol with, for example, cicletanine
is
envisioned to achieve the therapeutic effects of the individual agents in the
composition
of the present invention at lower doses that when administered individually,
therefore
reducing the incidence of side effects.
Formulations and Treatment Regimens
[00138] For oral and buccal administration, a pharmaceutical composition can
take the
form of solutions, suspensions, tablets, pills, capsules, powders, and the
like. Tablets
containing various excipients such as sodium citrate, calcium carbonate and
calcium
phosphate are employed along with various disintegrants such as starch and
particularly potato or tapioca starch and certain complex silicates, together
with binding
agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
Additionally,
lubricating agents such as magnesium stearate, stearic acid and talc are often
very
useful for tabletting purposes. Solid compositions of a similar type are also
employed as
fillers in soft and hard-filled gelatin capsules; preferred materials in this
connection also
include lactose or milk sugar as well as high molecular weight polyethylene
glycols.
When aqueous suspensions and/or elixirs are desired for oral administration,
the
compounds of this invention can be combined with various sweetening agents,
flavoring
agents coloring agents, emulsifying agents and/or suspending agents, as well
as such
diluents such as water, ethanol, propylene glycol, glycerin and various like
combinations
thereof.
[00139] For purposes of parenteral administration, solutions, in aqueous
propylene
glycol can be employed, as well as sterile aqueous solutions of the
corresponding
water-soluble salts. Such aqueous solutions may be suitably buffered, if
necessary, and
the liquid diluent first rendered isotonic with sufficient saline or glucose.
These aqueous
solutions are especially suitable for intravenous, intramuscular, subcutaneous
and
intraperitoneal injection purposes. In this connection, the sterile aqueous
media
employed are all readily obtainable by standard techniques well-known to those
skilled
in the art.
[00140] For purposes of transdermal (e.g., topical) administration, dilute
sterile,
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aqueous or partially aqueous solutions (usually in about 0.1 % to 5%
concentration),
otherwise similar to the above parenteral solutions, are prepared.
[00141] Methods of preparing various pharmaceutical compositions with a
certain
amount of active ingredient are known, or will be apparent in light of this
disclosure, to
those skilled in this art. For examples of methods of preparing pharmaceutical
compositions, see Remington's Pharmaceutical Sciences, Mack Publishing
Company,
Easter, Pa., 15th Edition (1975).
[00142] In one embodiment of the present invention, a therapeutically
effective amount
of each component may be administered simultaneously or sequentially and in
any
order. The corresponding active ingredient or a pharmaceutically acceptable
salt thereof
may also be used in form of a hydrate or include other solvents used for
crystallization.
The pharmaceutical compositions according to the invention can be prepared in
a
manner known per se and are those suitable for enteral, such as oral or
rectal, and
parenteral administration to mammals (warm-blooded animals), including man,
comprising a therapeutically effective amount of the pharmacologically active
compound, alone or in combination with one or more pharmaceutically acceptable
carriers, especially suitable for enteral or parenteral application.
[00143] The novel pharmaceutical preparations contain, for example, from about
10%
to about 80%, more particularly from about 20% to about 60%, of the active
ingredient.
In one aspect, pharmaceutical preparations according to the invention for
enteral
administration are, for example, those in unit dose forms, such as film-coated
tablets,
tablets, or capsules. These are prepared in a manner known per se, for example
by
means of conventional mixing, granulating, or film-coating. Thus,
pharmaceutical
preparations for oral use can be obtained by combining the active ingredient
with solid
carriers, if desired granulating a mixture obtained, and processing the
mixture or
granules, if desired or necessary, after addition of suitable excipients to
give tablets or
film-coated tablet cores.
[00144] In another aspect, novel pharmaceutical preparations for parenteral
administration contain, for example, from about 10% to about 80%, more
particularly
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from about 20% to about 60%, of the active ingredient. These novel
pharmaceutical
preparations include liquid formulations for injection, suppositories or
ampoules. These
are prepared in manners known in the art, for example by means of conventional
mixing, dissolving, or lyophilizing processes.
[00145] Table 4 provides guidance regarding daily dosage levels of cicletanine
compositions as well as exemplary second agents that are included in various
combination-therapy embodiments of the present invention.
Table 4: Daily Dosage Ranges for Cicletanine Compositions and Second Agents
included in the embodiments of combination therapies
Therapeutic Agent Daily Dosage
Cicletanine, enantiomers and non- 5 mg - 1600 mg
racemic mixtures for mono- and particularly: 12.5 mg - 1250 mg.
combination therapy more particularly: 25 mg - 800 mg.
Antihypertensives
ACE inhibitors 1 - 150 mg,
particularly: 2.5 mg - 100 mg
more particularly: 5 mg - 80 mg
exceptions:
Captopril as high as 450 mg,
Trandolapril as low as 1 mg
Aldosterone Antagonists 5 mg to 300 mg
particularly: 10 mg. - 250 mg
more particularly: 20 mg - 200 mg
Anti adrenergic agents (except 0.05 mg - 125 mg
Methyldopa, see below) particularly: 0.1 mg - 100 mg
more particularly: 0.5 mg - 75 mg
exception: methyldopa: up to 3000 mg
Angiotensin Receptor Blockers 2.5 mg to 500 mg
particularly: 5 mg to 400 mg
more particularly: 10 to 325 mg
Beta Blockers 2.5 mg - 1800 mg
particularly: 5 mg - 1500 mg
more particularly: 10 mg - 1250 mg
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Dihydropyridine Calcium Blockers 0.5 mg to 225 mg
particularly: 1.5 to 175 mg
more particularly: 2.5 mg to 125 mg
Diltiazem 100 mg - 1000 mg
particularly: 200 mg - 750 mg
more particularly: 300 mg - 600 mg
Verapamil 200 mg - 700 mg
particularly: 300 mg - 600 mg
more particularly: 350 mg - 500 mg
Nitrogen Donors 0.1 to 250 mg
particularly: 0.2 to 200 mg
more particularly: 0.5 to 150 mg
Diuretics 1.25 mg to 1000 mg
particularly: 2.5 mg to 800 mg
more particularly: 5 mg to 600 mg
Hyperglycemics
Glitazones 1 mg to 600 mg
particularly: 2.5 mg to 500 mg
more particularly: 5 mg to 400 mg
Alphaglucosidase Inhibitors 10 mg to 600 mg
particularly: 20 to 500 mg
more particularly: 25 mg to 400 mg
Biguanines 75 mg to 5000 mg
particularly: 150 mg to 3500 mg
more particularly: 250 mg to 2500 mg
Sulfonylureas 0.5 mg to 5000 mg
particularly: 1 mg to 4000 mg
more particularly: 5 mg to 3000 mg
Hypolipidemics
HMG CoA Reductase Inhibitors 3 mg to 300 mg
particularly: 5 mg to 150 mg
more particularly: 10 mg to 100 mg
Fibrates 10 to 2000 mg
particularly: 20 to 1600 mg
more particularly: 40 mg to 1250 mg
Nicotinic Acid 12.5 mg to 4000 mg
particularly: 25 mg to 3000 mg
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more particularly: 50 mg to 2500 mg
Ezetimibe 2.5 to 50 mg
particularly: 5 to 40 mg
more particularly: 10 mg to 30 mg
Treatment of Metabolic Syndrome
[00146] Cicletanine, due to its multiple therapeutic effects, may also be used
in
accordance with preferred embodiments of the present invention as a treatment
for
metabolic syndrome (sometimes also known as "pre-diabetes" or "syndrome X").
The
National Cholesterol Education Program (NCEP) at the NIH lists the following
as
"factors that are generally accepted as being characteristic of [metabolic]
syndrome"
(Third Report of the Expert Panel on Detection, Evaluation, and Treatment of
High
Blood Cholesterol in Adults (Adult Treatment Panel III; also known as ATP
III). Nov. 19,
2002. National Heart, Lung and Blood Institute (NHLBI), National Institutes of
Health):
abdominal obesity; atherogenic dyslipidemia; raised blood pressure; insulin
resistance± glucose intolerance; prothrombotic state; proinflammatory
state.
[00147] For purposes, of diagnosis, the metabolic syndrome is identified by
the
presence of three or more of the components listed in Table 5 below:
Table 5 Clinical Identification of the Metabolic Syndrome*
Risk Factor Defining Level
Abdominal Obesity Waist Women >88 cm (>35"); Men >102 cm (>40")
Circumferencet
Tri I cerides >_150 m /dl
HDL cholesterol Women <50 mg/dL; Men <40 mg/dl
Blood pressure 2:130/85 mmHg
Fasting glucose ?110 mg/dl
* The ATP III panel did not find adequate evidence to recommend routine
measurement
of insulin resistance (e.g., plasma insulin), proinflammatory state (e.g.,
high-
sensitivity C-reactive protein), or prothrombotic state (e.g., fibrinogen or
PAI-1) in the
diagnosis of the metabolic syndrome.
t Some males can develop multiple metabolic risk factors when the waist
circumference is only marginally increased, e.g., 94-102 cm (37"-39"). Such
persons may have a strong genetic contribution to insulin resistance. They
should
benefit from changes in life habits, similarly to men with categorical
increases in
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waist circumference.
[00148] Cicletanine as a combination therapy with another drug (such as an ACE
inhibitor or an angiotensin II receptor antagonist, or an OAD or a Lipid-
lowering agent),
holds promise addressing these five factors.
Abdominal Obesity
[00149] Abdominal obesity, and perhaps obesity in general, is likely to be one
step
upstream on the causal chain of metabolic syndrome from the point of action of
cicletanine. In a review article (Hall J. E. 2003 Hypertension 41:625-33), the
author
charts an accepted view of the role of obesity in hypertension.
[00150] Obesity increases renal sodium reabsorption and impairs pressure
natriuresis
by activation of the renin-angiotensin and sympathetic nervous systems and by
altered
intrarenal physical forces. Chronic obesity also causes marked structural
changes in the
kidneys that eventually lead to a loss of nephron function, further increases
in arterial
pressure, and severe renal injury in some cases. Although there are many
unanswered
questions about the mechanisms of obesity hypertension and renal disease, this
is one
of the most promising areas for future research, especially in view of the
growing,
worldwide "epidemic" of obesity.
[00151] Cicletanine has also been shown to enhance natriuresis, thereby
countering at
least one of the hypertensive effects of obesity cited above (Garay R. P. et
al. 1995 Eur
J Pharmacol 274:175-180).
Triglycerides
[00152] Reported results from human trials (Tarrade T. & Guinot P. 1988 Drugs
Exp
Clin Res 14:205-14) include an account of favorable effects upon triglyceride
levels in
patients receiving higher (150-200 mg/day) of cicletanine. Average
triglyceride levels fell
from 128 to 104 mg/dl over 12 months. HDL cholesterol. In another a study, in
Dahl sait-
sensitive rats with salt-induced hypertension, reported in 1997, cicletanine
treatment
significantly decreased low-density lipoprotein (LDL) cholesterol and
increased high-
density lipoprotein (HDL) cholesterol (Uehara Y. et al. 1997 Blood Press 3:180-
7).
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Blood Pressure
[00153] Cicletanine is an effective treatment for hypertension (high blood
pressure), as
cited in numerous articles (see above) and is approved for the treatment of
hypertension in several European countries. Cicietanine has been demonstrated
as
effective both as a monotherapy (Tarrade T. & Guinot P. 1988 Drugs Exp Clin
Res
14:205-14) and in combination with other antihypertensive drugs (Tarrade T. et
al. 1989
Arch Mal Coeur Vaiss 82 Spec No 4:103-8).
Fasting Glucose
[00154] Fasting glucose is used to assess glucose tolerance. Cicletanine
exhibits either
a neutral or healthy effect on glucose tolerance. Even at lower doses (50-100
mg per
day), cicletanine therapy results in maintained or improved levels of glucose
tolerance
(Tarrade T. & Guinot P. 1988 Drugs Exp Clin Res 14:205-14). At higher doses
(150-200
mg per day; still within the therapeutic/safety range), the positive effect of
cicletanine on
glucose tolerance becomes more pronounced (Witchitz S. & Gryner S. 1989 Arch
Mal
Coeur Vaiss 82 Spec No 4:145-9). These positive or neutral effects of
cicletanine are in
contrast to other antihypertensives, particularly diuretics and beta blockers,
which tend
to have a deleterious effects upon glucose tolerance and plasma lipids (Brook
R. D.
2000 Curr Hypertens Rep 2:370-377).
[00155] This favorable comparison of cicletanine with conventional diuretics
(per
glucose and lipid metabolism) underscores the promise of cicletanine as a
component
of combination therapy with OADs and lipid-lowering agents, as it should yield
advantages in comparison with the same drugs administered individually.
EXAMPLES
[00156] Animal models of diabetes and hypertension are useful for
demonstrating the
efficacy of embodiments of the present invention. Human clinical studies with
both sick
and normal subjects are important, of course, for demonstrating efficacy in
people. In
the sections that follow, examples are provided of animal models and
procedures, as
well as human studies.
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Animal Models
[00157] The persons skilled in the pertinent arts are fully enabled to select
a relevant
test model to optimize the hereinbefore and hereinafter indicated therapeutic
indications. Representative studies are carried out with a combination of
cicletanine and
a second agent (e.g., antihypertensive agent such as calcium channel blockers,
ACE
inhibitors, angiotensin II receptor antagonists, etc.) applying the following
methodology.
Various animal models of diabetes and hypertensive disease are used to
evaluate the
combination therapy of the present invention. A dozen of such models are
listed in
Table 6.
Table 6. List of Animal Models
1 Rat model of experimental diabetic nephropathy (uninephrectomized
streptozotocin-induced diabetic rats), see Villa et al. (Am J Hypertens 1997
10:202-8)
2 Rat model exhibiting diabetic hypertension with renal impairment disclosed
by
Kohzuki et al. (Am J Hypertens 2000 13:298-306 and J Hypertens 1999 17:695-
700)
3 Rat model of hypertension in Dahl-S rats fed a high-salt (4% NaCI) diet
disclosed
by Uehara Y. et al. (J Hypertens 1991 9:719-28)
4 Sabra rat model of salt-susceptibility previously developed by Prof. Ben-
Ishay
from the Hebrew University in Jerusalem, which has been transferred to the Rat
Genome Center in Ashkelon
Cohen-Rosenthal Diabetic (Non-Insulin-Dependent) Hypertensive (CRDH) Rat
Model for study of diabetic retinopathies www.tau.ac.il/medicine/conf2002/M/M-
11.doc;
6 BB rat (insulin-dependent diabetes mellitus), FHH rat (Fawn hooded
hypertensive, ESRD model), GH rat (genetically hypertensive rat), GK rat
(noninsulin-dependent diabetes mellitus, ESRD model), SHR (spontaneously
hypertensive rat), SR/MCW (salt resistant), SS/MCW (salt sensitive, syndrome-X
model) lgr.mcw.edu/lgr_overview.html
7 A mild hyperglycemic effect of pregnancy on the offspring of type I diabetes
can
be studied with a rat model established using streptozotocin-induced diabetic
pregnant rats transplanted with a controlled number of islets of Langerhans
8 Zucker diabetic fatty rat (type II)
9 Transgenic mice overexpressing the rate-limiting enzyme for hexosamine
synthesis, glutamine: F6P amidotransferase (GFA), which results in
hyperinsulinemia and insulin resistance (model of type II NIDDM)
A two kidney, one clipped rat model of hypertension in STZ-induced diabetes in
SD rats;
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11 A spontaneously diabetic rat with polyuria, polydipsia, and mild obesity
developed by selective breeding (Tokushima Research Institute; Otsuka
Pharmaceutical, Tokushima, Japan) and named OLETF. The characteristic
features of OLETF rats are 1) late onset of hyperglycemia (after 18 wk of
age); 2)
a chronic course of disease; 3) mild obesity; 4) inheritance by males; 5)
hyperplastic foci of pancreatic islets; and 6) renal complication (Kawano et
al.
1992 Diabetes 41:1422-1428)
12 A spontaneously hypertensive rat (SHR); Taconic Farms, Germantown, N.Y.
(Tac:N(SHR)fBR), as disclosed in U.S. Pat. No. 6,395,728.
Experimental Procedures in Animal Studies
[00158] A radiotelemetric device (Data Sciences International, Inc., St. Paul,
Minn.) is
implanted into the lower abdominal aorta of all test animals. Test animals are
allowed to
recover from the surgical implantation procedure for at least 2 weeks prior to
the
initiation of the experiments. The radiotransmitter is fastened ventrally to
the
musculature of the inner abdominal wall with a silk suture to prevent
movement.
Cardiovascular parameters are continuously monitored via the radiotransmitter
and
transmitted to a receiver where the digitized signal is then collected and
stored using a
computerized data acquisition system. Blood pressure (mean arterial, systolic
and
diastolic pressure) and heart rate are monitored in conscious, freely moving
and
undisturbed animals in their home cages. The arterial blood pressure and heart
rate are
measured every 10 minutes for 10 seconds and recorded. Data reported for each
rat
represent the mean values averaged over a 24-hour period and are made up of
the 144
- 10 minute samples collected each day. The baseline values for blood pressure
and
heart rate consist of the average of three consecutive 24-hour readings taken
prior to
initiating the drug treatments. All rats are individually housed in a
temperature and
humidity controlled room and are maintained on a 12 hour light/dark cycle.
[00159] In addition to the cardiovascular parameters, determinations of body
weight,
insulin, blood glucose, urinary thromboxane/PGI2 ratio (Hishinuma et al.
2001
Prostaglandins, Leukotrienes and Essential Fatty Acids 65:191-196), blood
lipids,
plasma creatinine, urinary albumin excretion, also are recorded in all rats.
Since all
treatments are administered in the drinking water, water consumption is
measured five
times per week. doses of cicletanine and the second agent (e.g.,
antihypertensive
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agents such as calcium channel blockers, ACE inhibitors, angiotensin II
receptor
antagonists, OADs, or lipid-lowering agents) for individual rats are then
calculated
based on water consumption for each rat, the concentration of drug substance
in the
drinking water, and individual body weights. All drug solutions in the
drinking water are
made up fresh every three to four days.
[00160] Upon completion of the 6 week treatment, rats are anesthetized and the
heart
and kidneys are rapidly removed. After separation and removal of the atrial
appendages, left ventricle and left plus right ventricle (total) are weighed
and recorded.
Left ventricular and total ventricular mass are then normalized to body weight
and
reported. All values reported for blood pressure and cardiac mass represent
the group
mean±SEM. The kidneys are dissected for morphological investigation of
glomeruloscierosis, renal tubular damage and intrarenal arterial injury.
[00161] Cicletanine and the second agent (e.g., calcium channel blockers, ACE
inhibitors, angiotensin II receptor antagonists, oral anti-diabetics, oral
lipid-lowering
agents, etc.) are administered via the drinking water either alone or in
combination to
rats from beginning at 18 weeks of age and continued for 6 weeks. Based on a
factorial
design, seven (7) treatment groups are used to evaluate the effects of
combination
therapy on the above-mentioned indices of hypertension, diabetes and
nephropathies,
as listed below in Table 7.
Table 7. Experimental Groups
Cicletanine Second Agent
1 high dose cicietanine alone in drinking no second agent
water (concentration of about 250 -
1000 mg/liter)
2 no cicietanine high dose of the second agent, in
drinking water (e.g., concentration of
about 100 - 500 mg/liter);
3 low dose cicletanine (10 - 250 low dose the second agent, in drinking
mg/liter) plus ... water (e.g., 1 - 100 mg/liter)
4 high dose cicletanine plus ... high dose
high dose cicletanine plus ... low dose
6 low dose cicletanine plus ... high dose
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7 vehicle control group on regular drinking water.
[00162] Thus, 4 groups of rats receive combination therapy. The relative
dosages of
cicietanine and the second agent can be varied by the skilled practitioner
depending on
the known pharmacologic actions of the selected drugs. Accordingly, the high
and low
dosages indicated are provided here only as examples and are not limiting on
the
dosages that may be selected and tested.
[00163] Representative studies are carried out with a combination of
cicletanine and
other agents, in particular, calcium channel blockers, ACE inhibitors and
angiotensin II
receptor antagonists, oral anti-diabetics, or lipid-lowering agents. Diabetic
renal disease
is the leading cause of end-stage renal diseases. Hypertension is a major
determinant
of the rate of progression of diabetic diseases, especially diabetic
nephropathy. It is
known that a reduction of blood pressure may slow the reduction of diabetic
nephropathy and proteinuria in diabetic patients, however dependent on the
kind of
antihypertensive administered. In diabetic rat models, the presence of
hypertension is
an important determinant of renal injury, manifesting in functional changes
such as
albuminuria and in ultrastructural injury, as detailed in the studies cited
above.
Accordingly, the use of these animal models are well-applied in the art and
suitable for
evaluating effects of drugs on the development of diabetic renal diseases.
There is a
strong need to achieve a significant increase of the survival rate by
treatment of
hypertension in diabetes especially in non-insulin dependent diabetes mellitus
(NIDDM).
It is known that calcium channel blockers are not considered as first line
antihypertensives e.g., in NIDDM treatment. Though some kind of reduction of
blood
pressure may be achieved with calcium channel blockers, they may not be
indicated for
the treatment of renal disorders associated with diabetes.
[00164] Diabetes is induced in hypertensive rats aged about 6 to 8 weeks
weighing
about 250 to 300 g by treatment e.g. with streptozotocin. The drugs are
administered by
twice daily average. Untreated diabetic hypertensive rats are used as control
group
(group 1). Other groups of diabetic hypertensive rats are treated with 40
mg/kg of
cicletanine (group 2), with high dose of the second agent (group 3) and with a
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combination of 25 mg/kg of cicletanine and low dose of the second agent (group
4). On
a regular basis, besides other parameters the survival rate after 21 weeks of
treatment
is monitored. In week 21 of the study, survival rates are determined. As
discussed
above, the dosages can be modified by the skilled practitioner without
departing from
the scope of the above studies. The particularly beneficial effect on glycemic
control
provided by the treatment of the invention is indicated to be a synergistic
effect relative
to the control expected for the sum of the effects of the individual active
agents.
[00165] Glycemic control may be characterized using conventional methods, for
example by measurement of a typically used index of glycemic control such as
fasting
plasma glucose or glycosylated hemoglobin (Hb A1 c). Such indices are
determined
using standard methodology, for example those described in: Tuescher A,
Richterich,
P., Schweiz. Med. Wschr. 101 (1971), 345 and 390 and Frank P., 'Monitoring the
Diabetic Patent with Glycosolated Hemoglobin Measurements', Clinical Products
1988.
[00166] In a one aspect, the dosage level of each of the active agents when
used in
accordance with the treatment of the invention will be less than would have
been
required from a purely additive effect upon glycemic control. There is also an
indication
that the treatment of the invention will effect an improvement, relative to
the individual
agents, in the levels of advanced glycosylation end products (AGEs), leptin
and serum
lipids including total cholesterol, HDL-cholesterol, LDL-cholesterol including
improvements in the ratios thereof, in particular an improvement in serum
lipids
including total cholesterol, HDL-cholesterol, LDL-cholesterol including
improvements in
the ratios thereof, as well as an improvement in blood pressure.
[00167] To determine the effect of a compound suitable for use in methods and
compositions of the invention on glucose and insulin levels, rats are
administered a
combination of cicietanine with an oral antidiabetic, after being
experimentally induced
with type I diabetes, and their urine and blood glucose and insulin levels are
determined. Male Sprague-Dawley (Charles River Laboratories, Montreal, Canada)
rats
weighing approximately 200 g are randomly separated into control and
experimental
groups. All experimental animals are given an intravenous injection of 0.1 M
citrate
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buffered streptozotocin (pH 4.5) at a dosage of 65 mg/kg of body weight to
induce
diabetes mellitus. All control animals receive an intravenous injection of 0.1
M citrate
buffer (pH 4.5) alone.
[00168] One experimental group of rats also receives daily doses of
cicietanine. A
second experimental group receives daily sub-therapeutic doses of an oral
antidiabetic
or lipid-lowering agent. A third experimental group receives both daily doses
of
cicletanine and a daily sub-therapeutic dose of an oral antidiabetic or lipid-
lowering
agent. All animals are fed rat chow and water ad libitum. Plasma glucose
levels are
done using the Infinity Glucose Reagent (Sigma Diagnostics, St. Louis, Mo.).
[00169] The experimentaf group of rats that receive daily doses of both daily
doses of
cicletanine and a daily dose of an oral antidiabetic or lipid-lowering agent
show reduced
levels of glucose and insulin in blood and urine samples when compared with
the group
of rats that receive daily sub-therapeutic doses of the oral antidiabetic or
lipid-lowering
agent without receiving daily doses of cicletanine.
[00170] To determine the effect of a composition suitable for use in methods
of the
invention on glucose and insulin levels, as well as increases in systolic
blood pressure,
rats having type II diabetes are administered cicletanine, either alone or in
combination
with sucrose and/or an oral antidiabetic agent, and their systolic blood
pressure, urine
and blood glucose and insulin levels are determined. Acarbose is known to
reduce
blood pressure in sucrose induced hypertension in rats (Madar Z, et al., Isr J
Med Sci
33:153-159).
[00171] As described by Madar et al. (Isr J Med Sci 33:153-159), a high
sucrose or
fructose diet for a prolonged period is one technique used to induce Type II
diabetes,
specifically hypertension associated with hyperglycemia and. hyperinsulinemia
in
animals. Male Sprague-Dawley (Charles River Laboratories, Montreal, Canada)
rats
weighing approximately 200 g are randomly separated into the following seven
groups,
with each group having 5 animals, as listed below in Table 8.
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Table 8. Experimental Groups
1 control group: fed a normal diet and provided with drinking water.
2 sucrose group: fed 35% sucrose (35 g sucrose/100 ml of drinking water/day)
with an average intake of 150 mI/rat/day.
3 Sucrose + cicletanine group: fed sucrose as in (2) above and cicletanine.
4 Sucrose + OAD group: fed sucrose as in (2) above and administered a
therapeutic dose of an OAD.
Sucrose + cicletanine + OAD group: fed sucrose as in (2) above, cicletanine,
and administered a therapeutic dose of an OAD.
6 Sucrose + cicletanine + OAD group: fed sucrose as in (2) above, cicletanine,
and administered subthreshold (subtherapeutic) dose of an OAD.
7 Sucrose + OAD group: fed sucrose as in (2) above and a subthreshold
(subtherapeutic) dose of an OAD.
[00172] Total duration of the study is 16 weeks. Plasma insulin levels are
measured
using Rat Insulin RIA Kit (Linco Research Inc., St. Charles, Mo.). Plasma
glucose levels
are done using the Infinity Glucose Reagent ((Sigma Diagnostics, St. Louis,
Mo.).
Blood pressure is measured using the tail cuff method (see, Madar et al. Isr J
Med Sci
33:153-159). The results of this study show that when rats are treated with a
combination of cicietanine and a therapeutic dose of an OAD a decrease in
systolic
pressure is significantly greater when compared to rats treated with
cicletanine or an
OAD alone.
[00173] In one embodiment, the present invention to provides a pharmaceutical
combination composition, e.g. for the treatment or prevention of a condition
or disease
selected from the group consisting of hypertension, (acute and chronic)
congestive
heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy,
diabetic
cardiac myopathy, supraventricular and ventricular arrhythmias, atrial
fibrillation or atrial
flutter, myocardial infarction and its sequelae, atherosclerosis, angina
(whether unstable
or stable), renal insufficiency (diabetic and non-diabetic), heart failure,
angina pectoris,
diabetes, secondary aldosteronism, primary and secondary pulmonary
hyperaldosteronism, primary and pulmonary hypertension, renal failure
conditions, such
as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular
sclerosis,
proteinuria of primary renal disease, and also renal vascular. hypertension,
diabetic
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retinopathy, the management of other vascular disorders, such as migraine,
Raynaud's
disease, luminal hyperplasia, cognitive dysfunction (such as Alzheimer's), and
stroke,
comprising (i) a prostacyclin inducer and (ii) a second agent, particularly an
antihypertensive agent, such as calcium channel blocker, an ACE inhibitor or
an
angiotensin II receptor antagonist, an oral antidiabetic agent, such as a
sulfonurea, a
biguanide, an alpha-glucosidase inhibitor, a triazolidinedione and a
meglitinides, or a
lipid-lowering agent.
[00174] In this composition, components (i) and (ii) can be obtained and
administered
together, one after the other or separately in one combined unit dose form or
in two
separate unit dose forms. The unit dose form may also be a fixed combination.
The
determination of the dose of the active ingredients necessary to achieve the
desired
therapeutic effect is within the skill of those who practice in the art. The
dose depends
on the warm-blooded animal species, the age and the individual condition and
on the
manner of administration. In one preferred embodiment, an approximate daily
dosage of
cicletanine in the case of oral administration is about 10 - 500 mg/kg/day and
more
particularly about 30 - 100 mg/kg/day.
[00175] The following example illustrates an oral formulation of one
embodiment of the
combination invention described above; however, it is not intended to limit
its extent in
any manner. An example of a formulation of an oral tablet containing
cicietanine and a
second agent, such as an antihypertensive, anti-diabetic, or a lipid-lowering
agent is as
follows. Tablets are formed by roller compaction (no breakline), 200 mg
cicletanine+5
mg second agent, with pharmacologically acceptable excipients selected from
the group
consisting of Avicel PH 102 (filler), PVPP-XL (disintegrant), Aerosil 200
(glidant), and
magnesium-stearate (lubricant). Alternatively, an oral tablet containing
cicletanine and a
second agent may be prepared by wet-granulation followed by compression in a
high-
speed rotary tablet press, followed by film-coating.
Human Clinical Studies
[00176] Certain aspects of the present invention are embodied and illustrated
in the
following examples. While each of the combinations depicted below involve
total
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dosages of 100 mg, therapeutic dosages may range from 2 mg to 2000 mg.
Additionally, the medication combinations set forth below may be combined into
single-
dosage forms with other agents, including medications for hypertension such as
but not
limited to the following classes of agents: angiotensin receptor blockers,
angiotensin
converting enzyme (ACE) inhibitors, beta blockers, calcium-channel blockers,
and
diuretics. Additionally, the (+) or (-) enantiomers of Cicletanine may be
individually
combined into single-dosage forms with other agents useful in treating
diabetes, lipid
and blood-glucose disorders, and metabolic syndrome.
Human Study Example 1
[00177] A non-racemic combination drug is formulated into a pill of mixed
composition
comprising approximately 90 mg of the (+) enantiomer of Cicletanine and is
combined
with 10 mg of the (-) enantiomer of Cicletanine and is administered orally,
once a day,
to subjects suffering from uncomplicated hypertension (that is hypertension
without
complications such as diabetes, kidney disease, or metabolic syndrome). The
nonracemic formulated drug is administered, alone or in combination with drugs
from
other classes, either as a first-line drug or as a drug given in addition to
or as a
replacement for a previous/current drug given for hypertension.
[00178] When this non-racemic formulation is administered to appropriate
subjects
(including, but not limited to, those suggested above) blood pressure
favorably falls and
a positive effect upon metabolic parameters (in particular, blood glucose
levels, glucose
tolerance, blood triglyceride levels, blood cholesterol [total, LDL and HDL]
levels) will
either be positive or neutral, as compared to controls.
[00179] These results indicate that the non-racemic drug formulation above has
a
predominantly-diuretic effect, while having some vasorelaxant and organ-
protective
effects. Additionally, the potassium-lowering effect and the effect of this
drug upon lipids
and cholesterol is healthier and less pronounced than that of the thiazide-
type diuretics.
Human Study Example ll
[00180] A non-racemic combination drug is formulated into a pill of mixed
composition
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of approximately 80 mg of the (+) enantiomer of Cicletanine and is combined
with 20 mg
of the (-) enantiomer of Cicletanine and is administered orally, once a day,
to subjects
suffering symptoms from one or more of the following descriptions:
uncomplicated
hypertension, either alone or combined with drugs from other classes, or with
hypertension in the presence of mildly-elevated triglycerides, cholesterol, or
blood
glucose; but not in the presence of actual metabolic syndrome. The formulated
drug is
administered either as a first-line drug or as a drug given in addition to, or
as a
replacement for a previous/current drug given for hypertension.
[00181] When this non-racemic formulation is administered to appropriate
subjects
(including but not limited to those suggested above) blood pressure falls
favorably and
effects upon metabolic parameters (in particular, blood glucose levels,
glucose
tolerance, blood triglyceride levels, blood cholesterol [total, LDL and HDL]
levels) are
positive or remain neutral to minimal.
[00182] These results indicate that the non-racemic drug formulation above has
a
predominantly-diuretic effect, while having some vasorelaxant and organ-
protective
effects. Additionally, the potassium-lowering effect and the effect of this
drug upon lipids
and cholesterol are healthier and less pronounced than that of the thiazide-
type
diuretics.
Human Study Example 111
[00183] A non-racemic combination drug is formulated into a pill of mixed
composition
of approximately 70 mg of the (+) enantiomer of Cicletanine combined with 30
mg of the
(-) enantiomer of Cicletanine and is administered orally once a day to
subjects suffering
symptoms from one or more of the following descriptions: uncomplicated
hypertension,
either alone or combined with drugs from other classes or hypertension in the
presence
of mildly or moderately-elevated triglycerides, cholesterol or blood glucose,
but not in
the presence of actual metabolic syndrome. The drug is administered either as
a first-
line drug or as a drug given in addition to or as a replacement for a
previous/current
drug given for hypertension.
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[00184] When this non-racemic formulation is administered to appropriate
subjects
(including, but not limited to those suggested above) blood pressure falls
favorably, and
effects upon metabolic parameters (in particular, blood glucose levels,
glucose
tolerance, blood triglyceride levels, blood cholesterol [total, LDL and HDL]
levels) are
positive or remain neutral to minimal.
[00185] These results indicate that the non-racemic drug formulation above has
a
predominantly-diuretic effect, while having some vasorelaxant and organ-
protective
effects. The diuretic effects, however, will be more pronounced than the
others.
Additionally, the potassium-lowering effect and the effect of this drug upon
lipids and
cholesterol are healthier and less pronounced than that of the thiazide-type
diuretics.
Human Study Example IV
[00186] A non-racemic combination drug is formulated into a pill of mixed
composition
of approximately 60 mg of the (+) enantiomer of Cicletanine combined with 40
mg of the
(-) enantiomer of Cicletanine and is administered orally, once a day, to
subjects
suffering symptoms from one or more of the following descriptions:
hypertension in the
presence of mildly or moderately-elevated triglycerides, cholesterol, or blood
glucose
both in and out of the presence of actual metabolic syndrome. The drug is
administered
either as a first-line drug or as a drug given in addition to, or as a
replacement for a
previous/current drug given for hypertension.
[00187] When this non-racemic formulation is administered to appropriate
subjects
(including, but not limited to those suggested above) blood pressure falls
favorably and
effects upon metabolic parameters (in particular, blood glucose levels,
glucose
tolerance, blood triglyceride levels, blood cholesterol [total, LDL and HDL]
levels) are
positive or remain neutral to minimal.
[00188] These results indicate that the non-racemic drug formulation above
have a
predominantly-diuretic effect, as well as vasorelaxant and organ-protective
effects. The
diuretic effects, however, are more pronounced than the other effects.
Additionally, the
potassium-lowering effect and the effect of this drug upon lipids and
cholesterol will be
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healthier and less pronounced than that of the thiazide-type diuretics.
Human Study Example V
[00189] A non-racemic combination drug is formulated into a pill of mixed
composition
of approximately 40 mg of the (+) enantiomer of Cicletanine combined with 60
mg of the
(-) enantiomer of Cicletanine and is administered orally, once a day, to
subjects
suffering symptoms from one or more of the following descriptions:
uncomplicated
hypertension, either alone or combined with drugs from other classes;
hypertension in
the presence of mildly or moderately-elevated triglycerides, cholesterol or
blood
glucose; hypertension in the presence of diabetes or metabolic syndrome;
diabetes or
metabolic syndrome in the presence of prehypertension (at least 120/80) or
borderline
hypertension; and with complications of diabetes. The drug is administered
either as a
first-line drug or as a drug given in addition to, or as a replacement for a
previous/current drug given for hypertension, diabetes, blood-lipid disorder,
or other
metabolic syndrome (or a component thereof).
[00190] When this non-racemic formulation is administered to appropriate
subjects
(including, but not limited to those suggested above) blood pressure falls
favorably, and
effects upon metabolic parameters (in particular, blood glucose levels,
glucose
tolerance, blood triglyceride levels, blood cholesterol [total, LDL and HDL)
levels) are
positive or remain neutral to minimal.
[00191] These results indicate that the non-racemic drug formulation above has
a
diuretic effect, as well as vasorelaxant and organ-protective effects. The
diuretic effects,
however, are more pronounced than the other effects. Additionally, the
potassium-
lowering effect and the effect of this drug upon lipids and cholesterol is
healthier and
less pronounced than that of the thiazide-type diuretics.
Human Study Example VI
[00192] A non-racemic combination drug is formulated into a pill of mixed
composition
of approximately 30 mg of the (+) enantiomer of Cicletanine combined with 70
mg of the
(-) enantiomer of Cicletanine and is administered orally, once a day, to
subjects
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suffering symptoms from one or more of the following descriptions:
uncomplicated
hypertension, either alone or combined with drugs from other classes;
hypertension in
the presence of mildly or moderately-elevated triglycerides, cholesterol or
blood
glucose; hypertension in the presence of diabetes or metabolic syndrome;
diabetes or
metabolic syndrome in the presence of prehypertension (at least 120/80) or
borderline
hypertension; and with disorders of lipid (triglycerides, cholesterol, etc.)
metabolism;
impaired glucose tolerance, or with complications of diabetes. The drug is
administered
either as a first-line drug or as a drug given in addition to, or as a
replacement for a
previous/current drug given for hypertension, diabetes, blood-lipid disorders,
or
metabolic syndrome (or a component thereof).
[00193] When this non-racemic formulation is administered to appropriate
subjects
(including, but not limited to those suggested above) blood pressure falls
favorably and
effects upon metabolic parameters (in particular, blood glucose levels,
glucose
tolerance, blood triglyceride levels, blood cholesterol [total, LDL and HDL]
levels) are
positive or remain neutral to minimal.
[00194] These results indicate that the non-racemic drug formulation above has
a
diuretic effect, as well as vasorelaxant and organ-protective effects. The
organ
protective effects, however, are more pronounced than the other effects.
Additionally,
the potassium-lowering effect and the effect of this drug upon lipids and
cholesterol is
healthier and less pronounced than that of the thiazide-type diuretics.
Human Study Example Vll
[00195] A non-racemic combination drug is formulated into a pill of 'mixed
composition
of approximately 20 mg of the (+) enantiomer of Cicletanine combined with 80
mg of the
(-) enantiomer of Cicletanine and is administered orally, once a day, to
subjects
suffering symptoms from one or more of the following descriptions:
uncomplicated
hypertension, either alone or combined with drugs from other classes;
hypertension in
the presence of mildly or moderately-elevated triglycerides, cholesterol or
blood
glucose; hypertension in the presence of diabetes or metabolic syndrome;
diabetes or
metabolic syndrome in the presence of prehypertension (at least 120/80) or
borderline
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hypertension; and with disorders of lipid (triglycerides, cholesterol, etc.)
metabolism;
impaired glucose tolerance, or with complications of diabetes. The drug is
administered
either as a first-line drug or as a drug given in addition to, or as a
replacement for a
previous/current drug given for hypertension, diabetes, blood-lipid disorders,
or
metabolic syndrome (or a component thereof).
[00196] When this non-racemic formulation is administered to appropriate
subjects
(including, but not limited to those suggested above) blood pressure falls
favorably and
effects upon metabolic parameters (in particular, blood glucose levels,
glucose
tolerance, blood triglyceride levels, blood cholesterol [total, LDL and HDL]
levels) are
positive or remain neutral to minimal.
[00197] These results indicate that the non-racemic drug formulation above has
a
diuretic effect, as well as vasorelaxant and organ-protective effects. The
vasorelaxant
and organ protective effects, however, are more pronounced than the diuretic
effect.
Additionally, the potassium-lowering effect and the effect of this drug upon
lipids and
cholesterol are healthier and less pronounced than that of the thiazide-type
diuretics.
Human Study Example Vlll
[00198] A non-racemic combination drug is formulated into a pill of mixed
composition
of approximately 10 mg of the (+) enantiomer of Cicletanine combined with 90
mg of the
(-) enantiomer of Cicletanine and is administered orally, once a day, to
subjects
suffering symptoms from one or more of the following descriptions:
uncomplicated
hypertension, either alone or combined with drugs from other classes;
hypertension in
the presence of mildly or moderately-elevated triglycerides, cholesterol or
blood
glucose; hypertension in the presence of diabetes or metabolic syndrome;
diabetes or
metabolic syndrome in the presence of prehypertension (at least 120/80) or
borderline
hypertension; and with disorders of lipid (triglycerides, cholesterol, etc.)
metabolism;
impaired glucose tolerance, or with complications of diabetes. The drug is
administered
either as a first-line drug or as a drug given in addition to, or as a
replacement for a
previous/current drug given for hypertension, diabetes, blood-lipid disorders,
or
metabolic syndrome (or a component thereof).
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[00199] When this non-racemic formulation is administered to appropriate
subjects
(including, but not limited to those suggested above) blood pressure falls
favorably and
effects upon metabolic parameters (in particular, blood glucose levels,
glucose
tolerance, blood triglyceride levels, blood cholesterol [total, LDL and HDL]
levels) are
positive or remain neutral to minimal.
[00200] These results indicate that the non-racemic drug formulation above has
a
diuretic effect, as well as vasorelaxant and organ-protective effects. The
vasorelaxant
and organ protective effects, however, are more pronounced than the diuretic
effect.
Additionally, the potassium-lowering effect and the effect of this drug upon
lipids and
cholesterol are healthier and less pronounced than that of the thiazide-type
diuretics.
Understanding the invention
[00201] While a number of preferred embodiments of the invention and
variations thereof have
been described in detail, other modifications and methods of using the
disclosed therapeutic
combinations will be apparent to those of skill in the art. Accordingly, it
should be understood
that various applications, modifications, and substitutions may be made of
equivalents without
departing from the spirit of the invention or the scope of the claims. Various
terms have been
used in the description to convey an understanding of the invention. It will
be understood that a
corresponding description of these various terms applies to common linguistic
or grammatical
variations or forms of these various terms. It will also be understood that
therapeutic agents
have been identified by trade names, but that these names are provided as
contemporary
examples, and the invention is not limited by such literal scope, particularly
when agents have
been further described in terms of their chemical class and mechanism of
action. Although the
description is generous in its offering of biochemical theory and
interpretation of available data
in describing the invention, it should be understood that such theory and
interpretation do not
bind or limit the claims. Further, it should be understood that the invention
is not limited to the
embodiments set forth herein for purposes of exemplification, but is to be
defined only by a fair
reading of the appended claims, including the full range of equivalency to
which each element
thereof is entitled.
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