(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2007/0105817 A1
`(43) Pub. Date:
`May 10, 2007
`Page et al.
`
`US 20070105817A1
`
`(54) USE OF CICLETANINE AND OTHER
`FURCDPYRONES FOR TREATMENT OF
`SYSTOLIC-PREDOMINANT
`HYPERTENSION, ISOLATED SYSTOLIC
`HYPERTENSION, ELEVATED PULSE
`PRESSURE, AND GENERAL
`HYPERTENSION
`
`(76) Inventors: Jim Page, Laramie, WY (US); Karen
`Page, Laramie, WY (US); Glenn V.
`Cornett, Palo Alto, CA (US)
`
`Correspondence Address:
`GREENBERG TRAURIG, LLP (SV2)
`2450 Colorado Avenue, Suite 400E
`Santa Monica, CA 90404 (US)
`
`(21) Appl. No.:
`
`11/356,158
`
`(22) Filed:
`
`Feb. 15, 2006
`Related U.S. Application Data
`(60) Provisional application No. 60/735,632, filed on Nov.
`9, 2005. Provisional application No. 60/758,524, filed
`on Jan. 11, 2006.
`
`Publication Classification
`
`(51) Int. Cl.
`(2006.01)
`A6II 3L/724
`(2006.01)
`A61K 31/4741
`(52) U.S. Cl. .............................................. 514/58: 514/302
`(57)
`ABSTRACT
`This invention provides therapeutic compositions of cicleta
`nine and other furopyridines for the treatment of elevated
`pulse pressure or isolated systolic hypertension, as well as
`general hypertension, in monotherapy and in combined
`therapy with other anti-hypertensive agents (such as organic
`and inorganic nitrogen donors, calcium channel blockers,
`diuretics, beta blockers, angiotensin receptor blockers, ACE
`inhibitors, aldosterone antagonists, renin inhibitors and cen
`trally-acting antihypertensives) cardiovascular agents (such
`as medications to treat heart failure) and oral antidiabetic
`agents (such as biguanides and glitaZones). Such composi
`tions include enantiomerically pure (positive or negative)
`embodiments, as well as enantiomeric mixtures other than a
`racemic mixture, and include daily dosages of less than 50
`mg. Further provided are methods of treatment of general or
`systolic hypertension, wherein patients are administered the
`inventive compositions, either a monotherapeutic furopyri
`dine composition, or a combination therapy, which includes
`a second agent in addition to the furopyridine, for treatment
`of general hypertension or systolic hypertension, and hyper
`tension-associated complications.
`
`Human Power of N Company
`EX1021
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`US 2007/01 05817 A1
`
`May 10, 2007
`
`USE OF CICLETANNE AND OTHER
`FURCDPYRONES FOR TREATMENT OF
`SYSTOLIC-PREDOMINANT HYPERTENSION,
`ISOLATED SYSTOLIC HYPERTENSION,
`ELEVATED PULSE PRESSURE, AND GENERAL
`HYPERTENSION
`
`RELATED APPLICATIONS
`0001. The present application claims priority to U.S.
`Provisional Patent Application Ser. No. 60/735,632 of Page
`et al., filed on Nov. 9, 2005, and to U.S. Provisional Patent
`Application Ser. No. 60/758524 of Page et al., filed on Jan.
`11, 2006, both applications entitled “The use of cicletanine
`and other furopyridines for the treatment of elevated pulse
`pressure and isolated Systolic hypertension'. The present
`application further claims priority to U.S. patent application
`Ser. No. 1 1/232,724, of Cornett and Page, filed on Sep. 21,
`2005, entitled “Enantiomer compositions of cicletanine,
`alone and in combination with other agents, for the treatment
`of diseases'.
`
`FIELD OF THE INVENTION
`0002 The field of this invention relates to the use of
`racemic and non-racemic furopyridine compounds and
`derivatives thereof, alone and in combination with other
`therapeutic agents, for prophylaxis and/or treatment of sys
`tolic predominant hypertension, isolated Systolic hyperten
`Sion, elevated pulse pressure, and general hypertension.
`
`BACKGROUND
`0003 Pulse pressure is the difference between systolic
`pressure and diastolic pressure; elevated pulse pressure is
`commonly the result of a disproportionately high systolic
`pressure. It is now believed that elevated systolic pressure,
`or the consequently elevated pulse pressure, is more strongly
`associated with cardiovascular adverse events than diastolic
`blood pressure (The Seventh Report of the Joint National
`Committee on Prevention, Detection and treatment of high
`Blood Pressure, NIH Publication No. 03-5233, May 2003).
`Current anti-hypertensive therapies are not fully satisfactory
`for the generally older population that suffers from this
`"isolated systolic hypertension'. The current standard of
`practice therapies tend either to be insufficiently effective at
`reducing blood pressure in a broad sense, or they tend to
`produce a lowering of both systolic and diastolic pressures,
`which leaves the pulse pressure relatively uneffected. Fur
`ther, the therapies that do show some ability to exert a
`differential effect, do not provide an adequate total reduction
`in Systolic blood pressure.
`0004 Highlighting the desirability of being able to thera
`peutically achieve a differential effect, or systolic-preferen
`tial effect, is recent evidence that excessive reduction in
`diastolic pressure may be associated with increased adverse
`cardiovascular and cerebrovascular adverse events. Another
`difficulty with some current hypertension therapies is that
`their efficacy does not persist over time. This loss of effec
`tiveness is generally attributed either to short serum half life,
`or to rapid development of tachyphylaxis, i.e., a loss in
`effectiveness of a drug after an initial use, or under continu
`ous use, that is ascribed to receptor desensitization or down
`regulation.
`0005 Current hypertension therapy, and therapies for
`isolated Systolic hypertension are incompletely satisfactory
`
`for other reasons as well. The problem presented by endot
`helial dysfunction, in particular the deficit of vascular nitric
`oxide (NO) remains a challenging factor in the pathology of
`hypertension, and currently available drugs for treatment of
`hypertension do not include within the scope of their mecha
`nisms of action an effective approach to treating endothelial
`dysfunction. New or improved forms of therapy that are
`directed preferentially toward reducing systolic blood pres
`Sure and pulse pressure, and which resolve any of the
`therapeutic deficiencies just described, would be a welcome
`addition to the healthcare market.
`
`SUMMARY OF THE INVENTION
`0006. This invention and its embodiments relate to the
`therapeutic use of racemic and non-racemic cicletanine,
`other furopyridines, salts thereof, esters thereof (including
`salts with HO coordinated bonds), other noncovalent
`derivatives, such as complexes, clathrates, and chelates
`thereof, as well as metabolic products derived from admin
`istered furopyridines which may, themselves, provide thera
`peutic benefit. These furopyridine-based compounds are
`used alone, in various combinations within the furopyridine
`genus, as well as collectively as a genus in combination with
`other agents, for treatment of systolic predominant hyper
`tension, isolated systolic hypertension, elevated pulse pres
`Sure, and general hypertension.
`0007 Embodiments of the invention include cicletanine
`treatment, at low-nanomolar concentrations, that are Sufi
`cient to correct deficits in vascular nitric oxide, and to do so
`safely and effectively, both as a furopyridine-based mono
`therapy, and in combination with other hypertension agents.
`More particularly, some embodiments of the invention fur
`ther provide for the use of cicletanine and other furopy
`ridines for the treatment of human systolic predominant
`hypertension, isolated systolic hypertension, elevated pulse
`pressure, and general hypertension in monotherapy and in
`combination with organic and inorganic nitrogen donors,
`nitric oxide synthase modulators, antioxidants, calcium
`channel blockers, beta blockers, angiotensin receptor block
`ers, ACE inhibitors, aldosterone antagonists, renin inhibi
`tors, centrally-acting antihypertensives, diuretics, and other
`compounds used to treat hypertension, cardiovascular dis
`eases (such as heart failure and angina), or metabolic dis
`CaSC.
`0008 Embodiments of the invention include a therapeu
`tic formulation comprising a furopyridine composition, Such
`composition referring to any formulation comprising one or
`more furopyridine compounds, including derivatives and
`metabolites of Such furopyridine compounds as they may
`arise in the body of a patient upon treatment with the
`furopyridine composition, as described above, or any com
`bination thereof. By way of example, one such furopyridine
`species is cicletanine : (+/-)-3-(4-chlorophenyl)-1,3-dihy
`dro-6-methylfuro-3,4-cpyridin-7-ol); another species is
`(+/-) 3-(4-fluorophenyl)-1,3-dihydro-7-hydroxy-6-methyl
`furop-3,4-c pyridine. In various embodiments, each of the
`one or more furopyridine compounds may be present in
`various enantiomeric proportions or profiles, including the
`Substantially pure positive (+) enantiomer, Substantially pure
`negative (-) enantiomer, a racemic mixture of the (+) and (-)
`enantiomers, and a non-racemic mixture of the (+) and (-)
`enantiomers. Such non-racemic mixtures may be weighted
`toward either the (+) and (-) enantiomer, varying, for
`
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`
`example from a (+) to (-) ratio from between an extreme of
`about 99 to 1 to the other extreme of 1 to 99.
`0009 Embodiments of the invention include total furo
`pyridine daily dosages of less than 50 mg, wherein the total
`dosage accounts for the combined dosage of positive (+) and
`negative (-) enantiomers of the furopyridine species.
`Cicletanine, for example, may be administered to a subject
`in amounts of about 25 mg, about 30 mg, about 35 mg, about
`40 mg. or about 45 mg. Other embodiments of the invention
`include compositions that comprise more than one furopy
`ridine species; in Such cases, embodiments further include
`those in which the daily dosage of the combined concen
`trations of the separate furopyridine species is less than the
`cicletanine-bioeduivalent of 50 mg, accounting for differ
`ences in molecular weight, potency, and bioavailability.
`0010 Further embodiments of the invention include
`combination therapies, wherein the above described furo
`pyridine compositions, at above identified daily dosages of
`less than 50 mg, are combined with other so-called second
`agents, such agents themselves being effective for the treat
`ment of hypertension. Such second agents may include, for
`example, organic and inorganic nitrates, calcium channel
`blockers, and diuretics.
`0011 Typically, embodiments of the invention are used
`as therapeutic formulations for human patients or subjects;
`these formulations may be appropriate for treatment of
`ongoing disease of any stage of progression or severity, as
`well as prophylaxis for patients medically considered to be
`at risk for the development of hypertensive disease. Embodi
`ments of the invention are also applicable to the veterinary
`uses. Typical embodiments of the formulation of the inven
`tion are for oral use; other embodiments are for administra
`tion by any conventional mode of administration, including
`injection, intravenous administration, and any form of
`parenteral administration. Embodiments of formulation of
`the invention may include non-medicinal constituents (i.e.,
`non-furopyridine and non-second therapeutic agent) that
`help the effectiveness or bioavailability of the biologically
`active agents. Such additives to the formulation may include
`absorption enhancers, tissue selectivity enhancers, tissue
`adhesion enhancers, polymers, and other agents to improve
`stability and bioavailability, half-life in vivo, duration of
`effect, and/or effectiveness of drug delivery to appropriate
`target tissues.
`0012 Embodiments of the invention also include meth
`ods of treatment, in which patients suffering from elevated
`pulse pressure, systolic predominant hypertension, or iso
`lated systolic hypertension are treated by the administration
`of the therapeutic compositions described herein. In some
`cases, patients with borderline systolic hypertension, or with
`generalized hypertension, or patients who are considered to
`be at risk of progressing toward isolated Systolic hyperten
`sion may benefit from treatment with these furopyridine
`compositions, and accordingly, embodiments of the inven
`tion include methods for treating these patients as well.
`0013 Various embodiments of the inventive treatment, in
`addition to the administration of furopyridine compositions
`at dosages described, may further include the generation of
`metabolites of the administered furopyridines in the body of
`the patient, where Such metabolites, themselves, may be
`responsible for- or contribute to medically beneficial effects.
`Formulations and methods of treatment with such formula
`
`tions, as provided by embodiments of the present invention,
`are understood to be therapeutically sufficient or effective
`when the treatment results in a clinically apparent improve
`ment in any clinical sign or symptom associated with any of
`the aforementioned forms of hypertension, as measured or
`assessed by a responsible health care professional, working
`in the bounds of currently accepted Standards of practice, or
`as perceived by a cognizant and reasonable patient being
`provided the inventive treatment.
`
`DESCRIPTION OF EMBODIMENTS OF THE
`INVENTION
`Furopyridine Treatment Preferentially Directed Toward Sys
`tolic Hypertension
`0014. In one embodiment of the invention, cicletanine
`(chemical name: it-3-(4-chlorophenyl)-1,3-dihydro-6-meth
`ylfuro-3,4-cpyridin-7-ol) or other furopyridine compounds
`are used (1) at doses resulting in serum blood level mea
`Surements below those usually associated with Substantial
`diuretic and direct vasodilatory effects, or (2) at doses near
`or below the currently-marketed minimum daily dosage of
`50 mg. These compounds, at these dosages, can exert
`differential effects on systolic and diastolic hypertension,
`with an effect on lowering systolic pressure and, in contrast,
`either a much smaller effect-, or an absence of a detectable
`effect on diastolic hypertension. In the cases of both mono
`therapy and combination therapy (i.e., in combination with
`a second agent, as described below), per embodiments of the
`invention, the furopyridine composition may also have one
`or more the following effects: exert protective effects on the
`vasculature, and/or reduce or slow the development of
`dementia, a common side effect of hypertension, as well as
`end-organ pathologies associated with diabetes.
`0015 The differential therapeutic effects on hyperten
`Sion, biased toward alleviating the systolic pressure and
`reversing endothelial dysfunction, may be applicable in
`patients with higher levels of systolic hypertension. For
`example, the effects are persistent over both the short term
`and the longer term: observable at time intervals 24 hours or
`more after dosing, developing over a period of a few weeks,
`and continuing at 12 weeks of continued daily dosing. It is
`believed that the effects are derived from mechanisms of
`action different from those of other currently available
`compounds that are applied to the treatment of systolic
`hypertension and elevated pulse pressure, and complemen
`tary to the effects of Such compounds. In particular, cicleta
`nine and other furopyridine compounds contribute to reduc
`ing the development of tachyphylaxis to organic and
`inorganic nitrogen donors.
`0016. The differential effects, or systolic-preferential
`effects, of embodiments of the invention are obtained at
`relatively low drug levels in blood, levels that minimize or
`avoid invoking other active mechanisms common to cicleta
`nine and other furopyridine compounds, as well as mini
`mizing the likelihood of eliciting tachphylaxis. In some
`patients, however, for example those with a mix of both
`systolic and diastolic hypertensive characteristics, higher
`dosing may be needed to adequately address the reducing of
`systolic and diastolic pressures, and pulse pressure, without
`unduly lowering diastolic pressures. Carefully tailored dos
`ing will allow adjustment of the individual effects of the
`cicletanine or other furopyridines, particularly (in the case of
`
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`US 2007/01 05817 A1
`
`May 10, 2007
`
`cicletanine) at daily dosages of less than 50 mg, and in
`combination with other therapeutic compounds (see 'second
`agent” description, below) to obtain one or more benefits
`Such as reduced tachyphylaxis, extended duration of action,
`improved side effect profile, improved convenience,
`enhanced organ protective effects, and modulation of sys
`tolic blood pressure, diastolic blood pressure, and pulse
`pressure.
`Daily Dosage Ranges of Furopyridine Compositions
`0017 Embodiments of the invention include total furo
`pyridine dosages of less than 50 mg per day, wherein the
`total dosage accounts for the combined dosage of positive
`(+) and negative (-) enantiomers of the furopyridine species.
`Cicletanine, for example, may be administered to a subject
`in amounts of about 25 mg, about 30 mg, about 35 mg, about
`37.5 mg, about 40 mg, about 42.5 mg, about 45 mg, or about
`47.5 mg. Some embodiments may include dosages either
`lower or higher than this particular range, depending on
`medical features particular to the patient. Such as age,
`weight, sex, affliction with conditions or complications other
`than hypertension, and/or interactions with other drugs.
`Daily dosages lower than 25 mg, may include, for example
`dosages stepping up from 1 Jug, to 3 Jug, to 10 Jug, to 30 Jug,
`to 100 ug, to 300 ug, to 1 mg, to 3 mg, to 10 mg. to 24 mg.
`Specific examples of lower daily dosages include about 5
`mg, about 7.5 mg, about 10 mg, about 12.5 mg, about 15 mg.
`about 17.5 mg, about 20 mg, and about 22.5 mg. Higher
`daily dosing may be needed for some patient populations
`due to impaired absorption or enhanced metabolism and
`excretion.
`0018. In some embodiments, the differential anti-hyper
`tensive effect is obtained with conventional oral dosing
`formulations, but other embodiments include formulations
`that provide reduced first-pass metabolism and/or more
`constant serum levels may provide more consistent effects.
`Such formulations include those designed, merely by way of
`example, to be depot injectable or implantable; formulations
`may be particularly adapted for transdermal, transmucosal,
`oral delayed release, oral delayed gastric discharge, or any
`other facilitator of pharmacokinetic effectiveness as known
`by practitioners of the art. Such and similar technologies
`may provide more predictable and consistent serum levels
`that are adequate to provide the desired differential anti
`hypertensive effect, but not so high as to diminish the
`differential anti-hypertensive effect by being beyond the
`level appropriate to the medical requirements of the indi
`vidual patient.
`0019. In some embodiments, this differential anti-hyper
`tensive effect is applicable and beneficial due to the high
`incidence of isolated systolic hypertension and elevated
`pulse pressures in the hypertensive population in general.
`Older hypertensive patients are particularly at risk, as iso
`lated systolic hypertension accounts for 54% of hypertensive
`patients of 50 to 59 years of age, and 87% of patients of 60
`or more years of age. Further, it is believed that elevated
`pulse pressure is more closely associated with adverse
`cardiovascular events than is diastolic blood pressure.
`Furopyridine Compositions Varying with Respect to Rela
`tive Enantiomeric Presence
`0020 Embodiments of the invention include composi
`tions of cicletanine or other furopyridines that vary in terms
`
`of the relative presence of positive (+) and (-) enantiomers
`(see below). These varied compositions may be used as a
`monotherapy or in combination therapy, with second agents,
`to treat human elevated pulse pressure, systolic predominant
`hypertenison, isolated systolic hypertension, or general
`hypertension. In general terms, these compositions varying
`with respect to their enantiomeric profile, can take the
`following forms:
`0021
`1. Pure (+) cicletanine or other furopyridine
`enantiomer,
`0022. 2. Non-racemic compositions of cicletanine
`(NRC) or other furopyridines, involving a mixture of
`(+) cicletanine or other furopyridine and (-) cicletanine
`or other furopyridine where the ratio of (+) to (-) is
`greater than 1:1,
`0023. 3. Racemic cicletanine: a mixture of (+) cicleta
`nine or other furopyridine and (-) cicletanine or other
`furopyridine where the ratio of (+) to (-) is 1:1,
`0024. 4. Non-racemic cicletanine (NRC) or other furo
`pyridine involving a mixture of (+) cicletanine or other
`furopyridine and (-) cicletanine or other furopyridine
`where the ratio of (+) to (-) is less than 1:1, and
`0025 5. Pure (-) cicletanine or other furopyridine
`enantiomer.
`0026. By enantiomeric compositions being “pure' is
`meant "substantially pure', i.e., pure by standard methods of
`analysis, including the respective margin of error in the
`method. In the case of non-racemic mixtures, in various
`embodiments, where the ratio of (+) to (-) is lesser or greater
`than 1:1, a wide range in relative presence is meant, for
`example, a range in ratios varying from one extreme of
`between about 1% (+) :: 99% (-) to the other extreme of
`about 99% (+) ::1% (-). More particularly, the ratio of (-)
`enantiomer: (+) enantiomer may, for example, be about
`95:5, about 90:10, about 80:20, about 70:30, about
`60:40, about 55:45, about 40:60, about 30:70, about
`20:80, about 10:90, or about 5:95. Other embodiments
`may include variations of these ratios, occupying the
`approximate midpoint range thereof.
`0027 Embodiments of the invention include treatment
`with furopyridines other than cicletanine. An example of
`such is (+/-) 3-(4-fluorophenyl)-1,3-dihydro-7-hydroxy-6-
`methylfurop-3,4-c pyridine. This compound can be pro
`duced in a racemic mixture and can be used in either purified
`enantiomer condition or in a weighted, non-racemic enan
`tiomeric mixture. Other furopyridine compounds have been
`identified, by Garay, et al., for example, (“Stimulation of K+
`fluxes by diuretic drugs in human red cells: Biochemical
`Pharmacology 33, #13, 2013-2020, 1984).
`0028. Those of ordinary skill in the art will recognize
`furopyridines as a genus, and that other furopyridine com
`pounds or species exist, and that other novel compounds
`may be synthesized in the future; all such furopyridines and
`their derivatives, as described above, are included as
`embodiments in the present invention. Embodiments of the
`invention further include compositions that include more
`than one furopyridine, each present at total dosage levels
`independent of the other within the constraints of total daily
`dosing as described herein, and each of which could be
`present, respectively, as one of the five enantiomeric profiles
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`described above. Compositional embodiments of medical
`treatment provided by the invention further include metabo
`lites of furopyridines that are made within the body follow
`ing administration of the furopyridines at the dosage levels
`described herein, even metabolites that are not currently
`known. And method of treatment embodiments of the inven
`tion include receiving the medically beneficial effects of
`such metabolites.
`Furopyridine Compositions Combined with Second Agents
`for Treatment of Hypertension
`0029 Embodiments of the present invention include
`combination therapies, wherein a furopyridine composition
`is combined with a second agent. "Second agent, as used
`herein, refers to any therapeutic agent other than the furo
`pyridine compositions. “Second agent' is also general term
`that may refer to a plurality of non-furopyridine agents, in
`that a combination therapy could include more than one
`second agent. Such second agents may be, by themselves,
`effective agents for lowering blood pressure, and/or treating
`any complications associated high blood pressure. Second
`agents may also include agents not established as conven
`tional agents for treatment of hypertension, particularly at
`dosages in which they are combined with the furopyridine
`compositions, but which, in combination with furopyridine
`compositions at the dosages described herein, the combina
`tion becomes an effective therapeutic formulation. As
`described herein, the furopyridine compositions used in
`combination with second agents are administered at daily
`dosages described above, and in all the enantiomeric varia
`tions described above.
`
`0030 Particular embodiments of the invention thus
`include a cicletanine composition (in its various enantio
`meric forms) in combination with one or more second
`agents. Such agents include, by way of example, organic and
`inorganic nitrates, calcium channel blockers, diuretics,
`angiotensin converting enzyme inhibitors, angiotensin
`receptor blockers, beta blockers, centrally-acting antihyper
`tensives, aldosterone antagonists, renin inhibitors, endothe
`lin receptor antagonists, other antihypertensives, and other
`agents used to treat disease states associated with endothelial
`dysfunction, including, by way of example, oral antidiabetic
`agents, lipid-lowering agents, and agents that increase high
`density lipoprotein (HDL) cholesterol levels. One still more
`particular embodiment of the invention is that of furopyri
`dine compositions in combination with calcium-channel
`blockers or nitrates (organic or inorganic), as these are
`currently preferred treatments for isolated systolic hyperten
`Sion. The mechanisms of furopyridine action and those of
`these second agents are different, and therefore complemen
`tary of each other; their combined broadly-defined antihy
`pertensive effect may be additive or synergistic.
`0031. In some embodiments, as with the monotherapy
`description above (i.e., monotherapeutic in that the furopy
`ridine composition is not combined with a non-furopyridine
`second agent), patients with borderline systolic hyperten
`Sion, or with generalized hypertension, or patients who are
`considered to be at risk of progressing toward isolated
`systolic hypertension may benefit from treatment with these
`combination therapies, and accordingly, embodiments of the
`invention include methods for treating these patients as well.
`
`EQUIVALENTS OF THE INVENTION
`0032. While particular embodiments of the invention and
`variations thereof have been described in detail, other modi
`fications 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 applica
`tions, modifications, and Substitutions may be made of
`equivalents without departing from the spirit of the inven
`tion or the scope of the claims. Various terms have been used
`in the description to convey an understanding of the inven
`tion; it will be understood that the meaning of these various
`terms extends to common linguistic or grammatical varia
`tions or forms thereof. It will also be understood that when
`therapeutic agents have been identified by trade names or
`common names, that these names are provided as contem
`porary examples, and the invention is not limited by Such
`literal scope, particularly when agents have been further
`described in terms of chemical class and/or by mechanism of
`action. Although the description offers biochemical theory
`and interpretation, 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 that have been set forth for purposes of
`exemplification, but is to be defined only by a fair reading
`of the appended claims, including the full range of equiva
`lency to which each element thereof is entitled.
`We claim:
`1. A formulation comprising a furopyridine composition,
`the composition comprising one or more furopyridine com
`pounds, wherein the daily dosage of the composition is less
`than 50 mg of cicletanine bioequivalent, the formulation
`sufficient for the treatment of any of systolic-predominant
`hypertension, isolated systolic hypertension, elevated pulse
`pressure, and general hypertension.
`2. The formulation of claim 1 wherein the furopyridine
`composition comprises one or more furopyridine deriva
`tives, the derivatives selected from the group consisting of
`salts, salts with HO coordinated bonds, esters, clathrates,
`and chelates.
`3. The formulation of claim 1 wherein the formulation is
`for oral use.
`4. The formulation of claim 1 wherein the daily dosage is
`between about 1 g and about 47.5 mg.
`5. The formulation of claim 1 wherein the daily dosage is
`between about 1 mg and about 45 mg.
`6. The formulation of claim 1 wherein the daily dosage is
`selected from the group consisting of about 5 mg, about 7.5
`mg, about 10 mg, about 12.5 mg, about 15 mg, about 20 mg.
`about 25 mg, about 30 mg, about 35 mg, about 37.5 mg.
`about 40 mg, and about 45 mg.
`7. The formulation of claim 1 wherein the furopyridine
`composition comprises cicletanine.
`8. The formulation of claim 1 wherein the enantiomeric
`profile of each of the one or more furopyridine compounds
`of the composition is selected from the group consisting of
`Substantially pure positive (+) enantiomer, Substantially pure
`negative (-) enantiomer, a racemic mixture of the (+) and (-)
`enantiomers, and a non-racemic mixture of the (+) and (-)
`enantiomers.
`9. The formulation of claim 1 further comprising at least
`one second therapeutic agent to form a combination therapy.
`10. The formulation of claim 9, wherein the second agent
`is selected from the group consisting of organic and inor
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`ganic nitrogen donors, nitric oxide synthase modulators,
`antioxidants, calcium channel blockers, beta blockers,
`angiotensin receptor blockers, ACE inhibitors, aldosterone
`antagonists, renin inhibitors, centrally-acting antihyperten
`sives, and diuretics.
`11. The formulation of claim 1 further comprising one or
`more bioavailability enhancers selected from the group
`consisting of absorption enhancers, tissue selectivity
`enhancers, tissue adhesion enhancers, and polymers.
`12. A method of treating a patient with any one or more
`of systolic-predominant hypertension, isolated systolic
`hypertension, and elevated pulse pressure, the method com
`prising administering the patient a formulation comprising a
`furopyridine composition, wherein the daily dosage of the
`composition is less than 50 mg cicletanine bioeduivalent.
`13. The method of claim 12, wherein the formulation
`further comprises a second therapeutic agent.
`
`14. The method of claim 12, wherein the treating of the
`patient further comprises deriving therapeutic benefit from
`any metabolite derived from the furopyridine composition in
`the body of the patient.
`15. A method of treating a patient with generalized
`hypertension by administering the patient a formulation
`comprising a furopyridine composition comprising one or
`more furopyridine compounds, wherein the daily dosage of
`the composition is less than 50 mg cicletanine equivalent.
`16. The method of claim 15, wherein the formulation
`further comprises a second therapeutic agent.
`17. The method of claim 15, wherein the treating of the
`patient further comprises deriving therapeutic benefit from
`any metabolite derived from the furopyridine composition in
`the body of the patient.
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