WO2008137043A1

WO2008137043A1 - Methods and compositions

Info

Publication number: WO2008137043A1
Application number: PCT/US2008/005639
Authority: WO
Inventors: Steven W. Bailey; June E. Ayling
Original assignee: South Alabama Medical Science Foundation
Priority date: 2007-05-02
Filing date: 2008-05-02
Publication date: 2008-11-13

Abstract

Disclosed are methods for treating hypertension in a subject, for reducing blood pressure in a subject, and for decreasing risk of stroke in a subject. The methods include administering to the subject an effective amount of at least one reduced folate. Also disclosed are pharmaceutical compositions that includes a first antihypertensive agent, the first antihypertensive agent being a reduced folate; and a second antihypertensive agent. Pharmaceutical compositions that include a reduced folate and an antidyslipidemia agent other than niacin are also described. Kits are also described.

Description

METHODS AND COMPOSITIONS

The present application claims the benefit of U.S. Provisional Patent Application Serial No. 60/927,229, filed May 2, 2007, which provisional patent application is hereby incorporated by reference.

The present invention was made with the support of the National Institutes of Health Grant No. HL068165. The Federal Government may have certain rights in this invention.

FIELD OF THE INVENTION

The present invention relates, generally, to methods and compositions for treating hypertension, for reducing blood pressure, and for reducing risk of stroke and, more particularly, to methods and compositions containing reduced folates and that use natural folates for treating hypertension, for reducing blood pressure, and for reducing risk of stroke.

BACKGROUND OF THE INVENTION

Hypertension is one of the most common worldwide diseases afflicting humans. Because of the associated morbidity and mortality and the cost to society, hypertension is an important public health challenge. Over the past several decades, extensive research, widespread patient education, and a concerted effort on the part of health care professionals have led to decreased mortality and morbidity rates from the multiple organ damage arising from years of untreated hypertension. Hypertension is the most important modifiable risk factor for coronary heart disease (the leading cause of death in North America) , stroke (the third leading cause), congestive heart failure, end-stage renal disease, and peripheral vascular disease.

In the United States, forty-three million people are estimated to have hypertension (e.g., defined, for adults humans, by a systolic blood pressure of 140 mm Hg or greater and/or diastolic blood pressure of 90 mm Hg or greater or defined as those taking antihypertensive medications) . The age-adjusted prevalence of hypertension varies from 18-32%, according to data from the National Health Examination Surveys.

The National High Blood Pressure Education Program (NHBPEP) has reported estimates of hypertension prevalence in United States. The hypertension survey was conducted from 1989-1994, and actual blood pressure and self-reported information was used. Hypertension was defined as noted above. The data indicate that 43.3 million adults suffered from hypertension in November 1991. The data further show that prevalence of hypertension increases with age, suggesting that, as the population ages, the number of adults suffering from hypertension will continue to grow. Internationally, national health surveys in various countries have shown a high prevalence of poor control of hypertension. These studies have reported that prevalence of hypertension is 22% in Canada, of which 16% is controlled; 26.3% in Egypt, of which 8% is controlled; and 13.6% in China, of which 3% is controlled. Hypertension is a worldwide epidemic; in many countries, 50% of the population older than 60 years has hypertension. Overall, approximately 20% of the world's adults are estimated to have hypertension. The 20% prevalence is for hypertension defined as blood pressure in excess of 140/90 mm Hg. The prevalence dramatically increases in patients older than 60 years, again suggesting that the numbers of individuals affected by hypertension will increase as the population ages. Currently, treatment of hypertension frequently includes the administration of diuretics and other antihypertensives and combinations of such diuretics and other antihypertensives. Many of the existing antihypertensives have significant and unpredictable side effects in various individuals, which can result in a reluctance to commence treatment, in non-compliance with the treatment protocol, and/or in a need to discontinue use of the antihypertensive or combination of antihypertensives . In view of the widespread prevalence of hypertension and the expectation of increased prevalence in an aging population and in view of the side effects associated with many existing antihypertensives, a need continues to exist for methods and compositions for treating hypertension and for reducing blood pressure, and the present invention is directed to addressing this need.

SUMMARY OF THE INVENTION

The present invention relates to a method for treating hypertension in a subject. The method includes administering to the subject an effective amount of at least one reduced folate . The present invention also relates to a method for reducing blood pressure in a subject. The method includes administering to the subject an effective amount of at least one reduced folate.

The present invention also relates to a method for decreasing risk of stroke in a subject. The method includes administering to the subject an effective amount of at least one reduced folate.

The present invention also relates to a pharmaceutical composition that includes a first antihypertensive agent, the first antihypertensive agent being a reduced folate; and a second antihypertensive agent .

The present invention also relates to a pharmaceutical composition that includes a reduced folate; and an antidyslipidemia agent other than niacin.

The present invention also relates to a kit . The kit includes a first pharmaceutical composition, wherein the first pharmaceutical composition includes a reduced folate; and the kit further includes a second pharmaceutical composition, wherein the second pharmaceutical composition includes an antidyslipidemia agent other than niacin.

The present invention also relates to a kit which includes a first pharmaceutical composition and a second pharmaceutical composition. The first pharmaceutical composition includes a first antihypertensive agent, the first antihypertensive agent being a reduced folate. The second pharmaceutical composition includes a second antihypertensive agent.

BRIEF DESCRIPTION OF THE DRAWING

Figure 1 is a bar graph illustrating the average effect on blood pressure following the treatment in accordance with a method of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention, in one aspect thereof, relates to a method for treating hypertension in a subject. The method includes administering to the subject an effective amount of at least one reduced folate.

The present invention, in another aspect thereof, relates to a method for reducing blood pressure in a subject. The method includes administering to the subject an effective amount of at least one reduced folate.

"Subject", as used herein, is meant to refer to any organism that would benefit from treatment of hypertension, reduction of blood pressure, and/or decreasing risk of stroke. Examples of suitable subjects include animals, such as mammals, domestic animals, bovine animals, equine animals, porcine animals, canine animals, feline animals, murine animals, horses, dogs, cats, rabbits, mice, rats, and the like. "Subject", as used herein, is also meant to include humans, such as male humans, female humans, pregnant female humans, nonpregnant female humans, adult humans, adolescent humans, and children. By way of illustration, suitable subjects include those who have blood pressure in a normal range (e.g., where the method reduces the risk of developing hypertension) . Suitable subjects also include those who have blood pressure in a prehypertensive range (e.g., where the method reduces the risk of developing hypertension or where the method reduces the subject's blood pressure to a values in a normal range) . Suitable subjects also include those who have blood pressure in a hypertensive range. As one skilled in the art will appreciate, "normal range", "prehypertensive range", and "hypertensive range" for a particular subject will depend on a number of factors, including the subject's species, age, etc. Illustratively, where the subject is a human adult, "normal range" is meant to refer to (i) a systolic blood pressure of under 120 mm Hg and (ii) a diastolic blood pressure of under 80 mm Hg,- "prehypertensive range" is meant to refer to (i) a systolic blood pressure of between 120 mm Hg and 139 mm Hg, inclusive, and a diastolic blood pressure of 89 mm Hg or less or (ii) a diastolic blood pressure of between 80 mm Hg and 89 mm

Hg, inclusive, and a systolic blood pressure of 139 mm Hg or less; and "hypertensive range" is meant to refer to (i) a systolic blood pressure of 140 mm Hg or greater or (ii) a diastolic blood pressure of 90 mm Hg or greater. Information regarding "normal" and other ranges for other human subjects (e.g., human subjects of particular ages (such as children, adolescents, etc.), human subjects of particular races, human subjects of particular ethnicities, etc.) can be found, for example, (i) from the data compiled by the National Institutes of Health's

National Heart Lung and Blood Institute (NHLBI) (e.g., at http : //www . nhlbi . nih . gov/guidelines/hypertension/ child_tbl.htm), which is hereby incorporated by reference) and (ii) in Muntner et al . , "Trends in Blood Pressure Among Children and Adolescents," J. Am. Med. Assoc.,

291 (17) :2107-2113 (2004), which is hereby incorporated by reference .

As used herein, "blood pressure" is meant to refer to values obtained by standard procedures, such as those described in Pickering et al . , "Recommendations for Blood Pressure Measurement in Humans and Experimental Animals: Part 1: Blood Pressure Measurement in Humans: a Statement for Professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research, " Circulation, 111 (5) : 697-716 (2005), which is hereby incorporated by reference.

By way of further illustration, suitable subjects include human adults who have a systolic blood pressure of under 120 mm Hg; human adults who have a diastolic blood pressure of under 80 mm Hg; human adults who have a systolic blood pressure of under 120 mm Hg and a diastolic blood pressure of under 80 mm Hg; human adults who have a systolic blood pressure of between 120 mm Hg and 139 mm Hg, inclusive; human adults who have a diastolic blood pressure of between 80 mm Hg and 99 mm Hg, inclusive; human adults who have a systolic blood pressure of between 120 mm Hg and 139 mm Hg, inclusive, and a diastolic blood pressure of between 80 mm Hg and 89 mm Hg, inclusive; human adults who have a systolic blood pressure of between 140 mm Hg and 159 mm Hg, inclusive; human adults who have a diastolic blood pressure of between 90 mm Hg and 99 mm Hg, inclusive; human adults who have a systolic blood pressure of between 140 mm Hg and 159 mm Hg, inclusive, and a diastolic blood pressure of between 90 mm Hg and 99 mm Hg, inclusive; human adults who have a systolic blood pressure of 160 mm Hg or greater; and/or human adults who have a diastolic blood pressure of 100 mm Hg or greater; human adults who have a systolic blood pressure of 160 mm Hg or greater and a diastolic blood pressure of 100 mm Hg or greater.

By way of further illustration, suitable subjects include human adults who have a systolic blood pressure of between 110 mm Hg and 115 mm Hg, inclusive; of between 115 mm Hg and 120 mm Hg, inclusive; of between 120 mm Hg and 125 mm Hg, inclusive; of between 125 mm Hg and 130 mm Hg, inclusive; of between 130 mm Hg and 135 mm Hg, inclusive; of between 135 mm Hg and 140 mm Hg, inclusive; of between 140 mm Hg and 145 mm Hg, inclusive; of between 145 mm Hg and 150 mm Hg, inclusive; of between 150 mm Hg and 155 mm Hg, inclusive; of between 155 mm Hg and 160 mm Hg, inclusive; of between 160 mm Hg and 165 mm Hg, inclusive; of between 165 mm Hg and 170 mm Hg, inclusive; of between 170 mm Hg and 175 mm Hg, inclusive; and/or of between 175 mm Hg and 180 mm Hg, inclusive.

Additionally or alternatively, these human adult subjects can have a diastolic blood pressure of between 70 mm Hg and 75 mm Hg, inclusive; of between 75 mm Hg and 80 mm Hg, inclusive; of between 80 mm Hg and 85 mm Hg, inclusive; of between 85 mm Hg and 90 mm Hg, inclusive; of between 90 mm Hg and 95 mm Hg, inclusive; of between 95 mm Hg and 100 mm Hg, inclusive; of between 100 mm Hg and 105 mm Hg, inclusive; of between 105 mm Hg and 110 mm Hg, inclusive; of between 110 mm Hg and 115 mm Hg, inclusive; and/or of between 115 mm Hg and 120 mm Hg.

Additionally or alternatively, the subject can be one who is folate deficient, or the subject can be one who is not folate deficient. As used herein, a subject is to be viewed as being folate deficient if the subject's homeostatic plasma level of reduced folate is below the norm for that subject. In the case of human subjects, a human subject is to be viewed, for the purposes of the present invention, as being folate deficient if the human subject's homeostatic plasma level of reduced folate is below 20 nanomolar. Conversely, for the purposes of the present invention, a human subject is to be viewed as not being folate deficient if the human subject's homeostatic plasma level of reduced folate is at or above 20 nanomolar. Still additionally or alternatively, the subject can be one who has a normal blood homocysteine level, or the subject can be one who has an elevated blood homocysteine level; the subject can be a human adult who has a blood homocysteine level of 15 micromoles per liter or less, or the subject can be a human adult who has a blood homocysteine level of greater than 15 micromoles per liter; the subject can be a human adult who has a blood homocysteine level of 12 micromoles per liter or less, or the subject can be a human adult who has a blood homocysteine level of greater than 12 micromoles per liter; the subject can be a human adult who has a blood homocysteine level of 10 micromoles per liter or less, or the subject can be a human adult who has a blood homocysteine level of greater than 10 micromoles per liter; and/or the subject can be a human adult who has a blood homocysteine level of 6.3 micromoles per liter or less, or the subject can be a human adult who has a blood homocysteine level of greater than 6.3 micromoles per liter. Still additionally or alternatively, the subject can be one who is at risk of having a stroke or who is at increased risk of having a stroke, such as in cases where the subject's risk of having a stroke is 20% or more (e.g., 30% or more, 40% or more, 50% or more, 75% or more, 100% or more (i.e. , twice or more) , 150% or more, 200% or more (thrice or more), 250% or more, etc.) than the stroke risk of the general population. Subjects who are at increased risk of having a stroke include those who have one or more risk factors that increase the risk of stroke. These risk factors include high blood pressure, tobacco use, diabetes mellitus, carotid, peripheral, or other artery diseases, atrial fibrillation, transient ischemic attacks, high red blood cell counts, sickle cell anemia, high blood cholesterol, high levels of LDL cholesterol, high levels of triglycerides, low levels of HDL cholesterol, physical inactivity, sedentary lifestyle, overweight, obesity, excessive alcohol use, cocaine use, advanced age (e.g., greater than 50, greater than 55, greater than 60, greater than 65, greater than 70, greater than 75, etc.), family history of stroke, individual history of prior stroke, individual history of prior heart attack, sex, race, ethnicity, menopause, prior or current use of oral contraceptives, and the like. By way of illustration, the subject can be one who has one, two, three, or more of the above-mentioned risk factors (e.g., a subject who is male, who is a smoker, and/or who has previously suffered from a stroke) ; or the subject can be one who does not have one, two, three, or more of the above- mentioned risk factors (e.g., a subject who does not suffer from atrial fibrillation, who does not have high blood cholesterol, and/or who has not previously suffered from a stroke) ; or the subject can be one who has some (e.g., one, two, three, or more) of the above-mentioned risk factors but who does not have one or more other risk factors (e.g., a subject who is obese and/or who is a smoker, but who has not previously suffered from a stroke) .

Still additionally or alternatively, the subject can be one who is not known to be suffering from cardiovascular disease, or the subject can be one who is known to be suffering from cardiovascular disease. For example, in certain embodiments, the subject is one who is not known to be suffering from coronary artery disease, while, in other embodiments, the subject is one who is known to be suffering from coronary artery disease. In this regard, coronary artery disease is defined as the presence of a >50% stenosis in at least one coronary artery identified by coronary arteriography within the last 5 years.

As one skilled in the art will appreciate, the subject can be one who meets none, exactly one, exactly two, exactly three, exactly four, one or more, two or more, three or more, four or more, etc. of the aforementioned criteria. By way of illustration, the subject can be one who has a normal blood homocysteine level and who is not known to be suffering from coronary artery disease. By way of further illustration, the subject can be one who has an elevated blood homocysteine level and who is known to be suffering from coronary artery disease. By way of still further illustration, the subject can be one who has an elevated blood homocysteine level and who is not known to be suffering from coronary artery disease. "Treating", as used herein, is meant to include any measurable or otherwise observable reduction in hypertension, for example, as determined by blood pressure measurements taken prior to and after administration of the reduced folate. The reduction can be temporary, or it can be sustained. Illustratively, the reduction can be for a period of 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, 1 day, 2 days, 4 days, one week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 9 months, 1 year, 2 years, 5 years, 10 years, the subject's lifetime. The reduction can be indicated by a measurable decrease in systolic blood pressure, in diastolic blood pressure, or in both systolic blood pressure and diastolic blood pressure. The reduction can be indicated, for example, by a decrease in systolic blood pressure and/or diastolic blood pressure of 2 mm Hg or more, of 5 mm Hg or more, of 10 mm Hg or more, etc. The reduction can be indicated, for example, by a decrease in systolic blood pressure and/or diastolic blood pressure to an extent such that a hypertensive subject becomes "prehypertensive" or

"normal" or by a decrease in systolic blood pressure and/or diastolic blood pressure to an extent such that a prehypertensive subject becomes "normal". The measurable or otherwise observable reduction in hypertension can be measured or otherwise observed in a single subject or in a group of subjects. For example, the measurable or otherwise observable reduction in hypertension can be measured or otherwise observed in a group of subjects whose number and degree of reduction are sufficiently great to provide a statistically significant result. It will be appreciated that, within a group of subjects, certain members of the group may experience a greater decrease in systolic blood pressure and/or diastolic blood pressure than other members of the group; and some members of the group may not experience any decrease in systolic blood pressure and/or diastolic blood pressure; and some members of the group may even experience an increase in systolic blood pressure and/or diastolic blood pressure. Despite this, each member of the group is to be viewed as having been "treated" in accordance with the method of the present invention, if, as a result of the administration of reduced folate, the group, as a whole, experiences a statistically significant reduction in blood pressure. "Treating", as used herein, is meant to include prophylactic treatment, for example, as in the case where the reduced folate is administered to a subject (e.g., a subject who has a blood pressure in a normal range) to prevent or reduce the likelihood of the subject's becoming prehypertensive or hypertensive. Examples of subjects who may benefit from such prophylactic treatment include individuals who suffer from diseases, disorders, syndromes, or other conditions which are known to cause a blood pressure increase; women who have previously suffered from pre-eclampsia; women who have previously suffered from pre-eclampsia and who are not presently pregnant; women who have previously suffered from pre-eclampsia and who are pregnant again; women who have previously suffered from pregnancy- induced hypertension; human subjects over the age of 50 (e.g., over the age of 55, over the age of 60, over the age of 65, over the age of 70, and/or over the age of 75), such as human subjects over the age of 50 who suffer from (or who have a family history of) diseases, disorders, syndromes, or other conditions which are known to cause a blood pressure increase.

As will be apparent from the discussion above, the treatment contemplated herein is meant to include treatment of chronic hypertensive conditions. However, the methods of the present invention can also be used to treat acute forms of hypertension (such as acute emergency^' hypertension, malignant hypertension, and the like) , and "treating", as used herein, is meant to encompass the treatment of such acute forms of hypertension . As will also be apparent from the discussion above, the treatment contemplated herein is meant to include treatment of systemic hypertensive conditions. However, the methods of the present invention can also be used to treat the other kinds of hypertension, such as pulmonary hypertension. Pulmonary hypertension is not defined by the usual systemic blood pressure measurements discussed above, but by pressures measured within the lung itself. These are typically much lower (e.g., normal typically less than 25 mm Hg) . Although it may be first recognized by symptoms of fatigue, exertional dyspnea, and, occasionally, chest discomfort and temporary fainting, pulmonary hypertension is typically diagnosed by measurement of the pressure in the pulmonary artery. Accordingly, "treating", as used herein, is meant to encompass the treatment of pulmonary hypertension and other such non-systemic forms of hypertension .

"Reducing risk of stroke", as used herein, is meant to refer to complete elimination of as well as any measurable reduction (e.g., a reduction of 1% or more, such as 2% or more, 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, etc.) in the likelihood of the incidence or severity of stroke in an individual subject or in a population of subjects. Reduction in stroke risk can be ascertained, for example, in a population of subjects. Where the subjects are human, reduction in stroke risk can be ascertained, for example, in a population of humans or in a population of model animals. Examples of populations of subjects include the general population as well as sub-populations having one or more specified characteristics, for example, sub-populations having a specified age range (e.g., subjects over the age of 30, subjects over the age of 40, subjects over the age of 50, subjects over the age of 60, subjects over the age of 65, subjects over the age of 70, subjects over the age of 75, subjects over the age of 80, etc.); sub-populations having one or more specified lifestyle characteristics (e.g., subjects who exercise regularly, subjects who do not exercise regularly, subjects who have non- sedentary lifestyles, subjects who have sedentary lifestyles, smokers, non-smokers, etc.); sub-populations having specified sex, race, and/or ethnicity (e.g., male subjects, female subjects, subjects of Asian descent, subjects of non-Asian descent, subjects of African descent, subjects of non-African descent, etc.); sub- populations having one or more specified medical conditions (e.g., overweight subjects, non-overweight subjects, obese subjects, non-obese subjects, subjects suffering from atrial fibrillation, subjects not suffering from atrial fibrillation, hypertensive subjects, non-hypertensive subjects, subjects having high blood pressure, subjects not having high blood pressure, diabetic subjects, non-diabetic subjects, etc.); sub- populations having a specified stroke history (e.g., subjects who have previously had a stroke, subjects who have not previously had a stroke, subjects who have previously had an ischemic stroke, subjects who have not previously had an ischemic stroke, subjects who have previously had a hemorrhagic stroke, subjects who have not previously had a hemorrhagic stroke, etc.) ; and sub- populations having two or more of the aforementioned characteristics . The reduced folates can be administered on a regular basis, for example, once per day, multiple times per day (e.g., twice per day, thrice per day, four times per day, six times per day, etc.), or continuously (e.g., as in the case where the reduced folate is administered in a time-release formulation) .

The reduced folate can be administered routinely (e.g., daily) to the subject so that the subject's homeostatic plasma level of reduced folate is elevated to a value above that at which the subject would be considered to be folate deficient. For the purposes of the present invention, the homeostatic level is the concentration of reduced folate in the plasma from blood, as measured while fasting and prior to administration of reduced folate in accordance with the present invention. For example, in the case of human subjects, reduced folate can be administered routinely (e.g., daily) to the human subject so as to increase the human subject's homeostatic plasma level of reduced folate to a value greater than 20 nanomolar, such as greater than about 30 nanomolar, greater than 40 nanomolar, greater than about 50 nanomolar, greater than 60 nanomolar, greater than about 70 nanomolar, greater than about 80 nanomolar, greater than about 90 nanomolar, greater than about 100 nanomolar, greater than about 150 nanomolar, greater than about 200 nanomolar, greater than about 250 nanomolar, greater than about 300 nanomolar, greater than about 350 nanomolar, greater than about 400 nanomolar, greater than about 450 nanomolar, greater than about 500 nanomolar, greater than about 600 nanomolar, greater than about 700 nanomolar, greater than about 800 nanomolar, greater than about 900 nanomolar, greater than about 1 micromolar, greater than about 2 micromolar, etc. Once the subject's homeostatic plasma level of reduced folate is elevated to a value above that at which the subject would be considered to be folate deficient, the administration of reduced folate can be continued so as to maintain the subject's homeostatic plasma level at such elevated values for a period of 1 day, 2 days, 4 days, one week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 9 months, 1 year, 2 years, 5 years, 10 years, the subject's lifetime. By increasing the subject's homeostatic plasma level of reduced folate to a level that is higher than has been considered in the art to be sufficient, the method of the present invention can be used to treat hypertension in a subject and/or to reduce blood pressure in the subject.

Additionally or alternatively, and particularly in cases where the subject suffers from an acute form of hypertension, the reduced folates can be administered so as to maintain plasma concentrations above homeostatic levels for the period of time during which therapeutic effects are desired, for example, for a period of 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16 hours, and/or 1 day and/or for the period of time needed to reduce the subject's blood pressure to a non-acute level. Plasma levels need not be determined for each individual, but, rather, they can be projected on the basis of pharmacokinetic data from a group of subjects. In the case of human subjects, reduced folate can be administered so as to attain and/or maintain the subject's plasma level of reduced folate at a value greater than 20 nanomolar, such as greater than about 30 nanomolar, greater than 40 nanomolar, greater than about 50 nanomolar, greater than 60 nanomolar, greater than about 70 nanomolar, greater than about 80 nanomolar, greater than about 90 nanomolar, greater than about 100 nanomolar, greater than about 150 nanomolar, greater than about 200 nanomolar, greater than about 250 nanomolar, greater than about 300 nanomolar, greater than about 350 nanomolar, greater than about 400 nanomolar, greater than about 450 nanomolar, greater than about 500 nanomolar, greater than about 600 nanomolar, greater than about 700 nanomolar, greater than about 800 nanomolar, greater than about 900 nanomolar, greater than about 1 micromolar, greater than about 2 micromolar, etc. As discussed above, the method of the present invention involves administering at least one reduced folate to the subject. Suitable reduced folates include: tetrahydrofolic acid, 5 -methyl -tetrahydrofolic acid, 5- formyl-tetrahydrofolic acid, 10-formyl-tetrahydrofolic acid, 5 , 10 -methylene-tetrahydrofolic acid, 5 , 10-methenyl- tetrahydrofolic acid, 5-formimino- tetrahydrofolic acid, 7 , 8-dihydrofolic acid, and polyglutamyl derivatives thereof . These can be administered as their natural isomers: (6S) -tetrahydrofolic acid, 5-methyl - (6S) - tetrahydrofolic acid, 5-formyl- (6S) -tetrahydrofolic acid, 10-formyl- (6R) -tetrahydrofolic acid, 5 , 10-methylene- (6R) - tetrahydrofolic acid, 5 , 10-methenyl- (6R) -tetrahydrofolic acid, 5-formimino- (6S) -tetrahydrofolic acid, and polyglutamyl derivatives thereof. The aforementioned natural isomers can be administered in combination with a corresponding non-natural isomer ( (6R) -tetrahydrofolic acid, 5-methyl- (6R) -tetrahydrofolic acid, 5-formyl- (6R) - tetrahydrofolic acid, 10-formyl- (6S) -tetrahydrofolic acid, 5, 10-methylene- (6S) -tetrahydrofolic acid, 5,10- methenyl- (6S) -tetrahydrofolic acid, 5-formimino- (6R) - tetrahydrofolic acid, and polyglutamyl derivatives thereof), or they can be administered alone (i.e., substantially free from the corresponding non-natural isomer) . Illustratively, suitable reduced folates include racemic tetrahydrofolic acid, racemic 5-methyl - tetrahydrofolic acid, racemic 5-formyl-tetrahydrofolic acid, racemic 10-formyl-tetrahydrofolic acid, racemic 5 , 10 -methylene-tetrahydrofolic acid, racemic 5,10- methenyl-tetrahydrofolic acid, racemic 5-formimino- tetrahydrofolic acid, and polyglutamyl derivatives thereof .

As indicated above, the reduced folates can be administered in combination (e.g., a mixture of 5-formyl- tetrahydrofolic acid and 5 -methyl -tetrahydrofolic acid), and "reduced folate" is meant to include such mixtures. "Reduced folate" is also meant to include polyglutamyl derivatives; as well as monoalkyl, dialkyl, monobenzyl , and/or dibenzyl esters of the reduced folate ' s glutamate side chain. It is believed that monoalkyl, dialkyl, monobenzyl, and/or dibenzyl esters of the reduced folate's glutamate side chain are especially useful in topical formulations, such as in transdermal patches and other transdermal delivery formulations.

In certain embodiments, the reduced folate is a reduced folate other than racemic 5-formyl- tetrahydrofolic acid. In certain embodiments, the reduced folate is a combination of reduced folates, at least one of which is a reduced folate other than racemic 5-formyl-tetrahydrofolic acid. In certain embodiments, the reduced folate is a combination of reduced folates, none of which is racemic 5-formyl-tetrahydrofolic acid. In certain embodiments, the reduced folate is a reduced folate other than 5-formyl-tetrahydrofolic acid. In certain embodiments, the reduced folate is a combination of reduced folates, at least one of which is a reduced folate other than 5-formyl-tetrahydrofolic acid. In certain embodiments, the reduced folate is a combination of reduced folates, none of which is 5-formyl - tetrahydrofolic acid. In certain embodiments, the reduced folate is a reduced folate other than racemic tetrahydrofolic acid. In certain embodiments, the reduced folate is a combination of reduced folates, at least one of which is a reduced folate other than racemic tetrahydrofolic acid. In certain embodiments, the reduced folate is a combination of reduced folates, none of which is racemic tetrahydrofolic acid. In certain embodiments, the reduced folate is a reduced folate other than tetrahydrofolic acid. In certain embodiments, the reduced folate is a combination of reduced folates, at least one of which is a reduced folate other than tetrahydrofolic acid. In certain embodiments, the reduced folate is a combination of reduced folates, none of which is tetrahydrofolic acid. In certain embodiments, the reduced folate is a reduced folate other than racemic 5-formyl - tetrahydrofolic acid and other than racemic tetrahydrofolic acid. In certain embodiments, the reduced folate is a combination of reduced folates, at least one of which is a reduced folate other than racemic 5-formyl- tetrahydrofolic acid and other than racemic tetrahydrofolic acid. In certain embodiments, the reduced folate is a combination of reduced folates, none of which is racemic 5-formyl-tetrahydrofolic acid and none of which is racemic tetrahydrofolic acid. In certain embodiments, the reduced folate is a reduced folate other than 5-formyl -tetrahydrofolic acid and other than tetrahydrofolic acid. In certain embodiments, the reduced folate is a combination of reduced folates, at least one of which is a reduced folate other than 5- formyl-tetrahydrofolic acid and other than tetrahydrofolic acid. In certain embodiments, the reduced folate is a combination of reduced folates, none of which is 5-formyl-tetrahydrofolic acid and none of which is tetrahydrofolic acid.

The reduced folates can be either in the form of a free acid or in the form of a salt, and "reduced folate", as used herein, is also meant to encompass both the free acid and salt forms. Examples of suitable salt forms include hydrochloride, sodium, potassium, and magnesium salts. As yet another example, the reduced folate can be in the form of a calcium salt. The salt form and crystal structure of the reduced folate somewhat affects the reduced folate's stability and solubility, and this can be optimized depending on the needs for a particular formulation. Suitable salt forms also include those in which the counter ion is an organic amine base. The pH of the final composition can also be optimized according to the stability properties of the particular reduced folate used and the other components present in the formulation (if any), as is well understood in the arts of nutrient processing and folate compounds.

The reduced folate can be administered alone or in a pharmaceutical, supplement, or other composition containing, in addition to the reduced folate, one or more other components. Examples of suitable dosage forms include enteral (e.g., oral, intragastric, or transpyloric) , parenteral (intramuscular, intravenous, intraperitoneal, rectal, vaginal, and subcutaneous), topical, and ocular dosage forms. As used herein, "pharmaceutical composition" is meant to include compositions that include at least one non-over-the- counter ("non-OTC") component (e.g., a composition that include at least one non-OTC drug, a medical food, etc.) . Illustratively, the reduced folate can be administered orally, such as in the form of an orally- administered supplement or an in the form of an orally- administered pharmaceutical composition. For example, pills, tablets, chewable tablets, capsules, powders, syrups, suspensions, solutions, chewable gums, liquid- filled candies, suckable candies, and soft chews are suitable forms for administration of reduced folates for treating hypertension in a subject and/or for reducing blood pressure in a subject. Time delay, slow-release, and enterically-protected formulations can also be used. Suitable dosage forms for orally administered reduced folate include tablets, dispersible powders, granules, capsules, suspensions, syrups, and elixirs. Inert diluents and carriers for tablets include, for example, lactose and talc. Tablets may also contain granulating and disintegrating agents, such as starch and alginic acid; binding agents, such as starch, gelatin, and acacia; and lubricating agents, such as magnesium stearate, stearic acid, and talc. Tablets may be uncoated or may be coated by known techniques to delay disintegration and absorption. Inert diluents and carriers which may be used in capsules include, for example, calcium phosphate, and kaolin. Suspensions, syrups, and elixirs may contain conventional excipients, for example, methyl cellulose, tragacanth, sodium alginate; wetting agents, such as lecithin and polyoxyethylene stearate; and preservatives, such as ethyl -p-hydroxybenzoate . Other inert ingredients can also be present in the dosage forms for oral administration .

As discussed above, dosage forms for oral administration can include inert materials, such as fillers, binding agents, stabilizers, sweeteners, including nutritive sweeteners (e.g. sucrose, sorbitol, and other polyols) and non-nutritive sweeteners (e.g. saccharin, aspartame, and acesulfame K), colorants, flavors, buffers, salts, coatings, and the like that are known to those skilled in the art of supplement and pharmaceutical formulation. For example, in cases where pharmaceutical compositions are to be produced, one would use inert materials or other excipients that are pharmaceutically acceptable.

Additionally or alternatively, the oral dosage forms or other compositions can also include one or more additional (i.e., in addition to the reduced folate) biologically active materials.

Examples of such additional biologically active materials that can be present in the composition include: other vitamins and/or nutrients (e.g., vitamin Bl; vitamin B2 ; vitamin B3 ; vitamin B5 ; vitamin B6 ; vitamin B12 ; vitamin C; vitamin A and its precursors, such as beta-carotene; vitamin D; vitamin E including vitamin E isomeric forms and derivatives; vitamin K; biotin,- pantothenic acid; methionine; choline; taurine; carnitine; acetyl-carnitine; sugars; lipids; amino acids, such as glutamine, arginine, and methionine; and proteins) , and minerals (e.g., boron, calcium, phosphorus, chromium, copper, manganese, magnesium, nickel, sodium, molybdenum, potassium, iron, selenium, silicon, vanadium, and zinc) . By way of illustration, in certain embodiments, the reduced folate is administered in a composition that comprises the reduced folate and that comprises one or more other vitamins. By way of further illustration, in certain embodiments, the reduced folate is administered in a composition that comprises the reduced folate and that is substantially free of any other vitamin. By way of further illustration, in certain embodiments, the reduced folate is administered in a composition that comprises the reduced folate and that is substantially free of any other vitamin other than ascorbic acid (e.g., in a composition that comprises the reduced folate, that comprises ascorbic acid, and that is substantially free of all other vitamins) . As used herein, a composition is to be deemed to be substantially free of a particular vitamin if the composition contains no measurable amount of the particular vitamin or if the composition contains less than 10% (e.g., less than 9%, less than 8%, less than 5%, less than 2%, less than 1%, etc.) of the U.S. adult RDA for the particular vitamin per gram of composition.

As further illustration, the additional biologically active materials which can be present in compositions that are useful in the methods of the present invention include essential nutrients, such as those that have been compiled in a number of published sources, including Modern Nutrition in Health and Disease, 8th ed., Shils et al . , eds . , Philadelphia : Lea and Febiger (1994) ; and Modern Nutrition in Health and Disease, 10th ed., Shils et al . , eds., Philadelphia:

Lippincott Williams & Wilkins (2005), which are hereby incorporated by reference.

As yet further illustration, suitable additional biologically active materials which can be present in compositions that are useful in the methods of the present invention include one or more antihypertensive agents. Examples of suitable antihypertensive agents include diuretics, such as loop diuretics (e.g., bumetanide, ethacrynic acid, and furosemide) (which can be particularly useful in cases involving renal insufficiency) , potassium-sparing diuretics (e.g., amiloride, triamterene, and spironolactone) (which can be particularly useful in cases involving primary hyperaldosteronism) , and thiazide diuretics (e.g., chlortalidone, epitizide, hydrochlorothiazide, chlorothiazide, bendroflumethiazide, indapamide, metolazone, and polythiazide) (which can be particularly useful in cases involving uncomplicated hypertension, systolic hypertension (e.g., in the elderly) , and/or diabetes without neuropathy) ; beta- andrenergic antagonists (e.g., atenolol, betaxolol , bisoprolol, metoprolol, nadolol, pindolol, propranolol, and timolol) which can be particularly useful in cases involving post -myocardial infarction, uncomplicated hypertension, and/or diabetes without neuropathy) ; angiotensin-converting enzyme ("ACE") inhibitors (e.g., benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril) (which can be particularly useful in cases involving diabetes, heart failure, and/or uncomplicated hypertension); angiotensin II antagonists (e.g., candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan) (which can be particularly useful in cases involving diabetes, heart failure, and/or uncomplicated hypertension); calcium channel blockers, such as nondihydropyridines (e.g., diltiazem and verapamil) (which can be particularly useful in cases involving uncomplicated hypertension) and nondihydropyridines (e.g., amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, and nitrendipine) (which can be particularly useful in cases involving systolic hypertension and/or uncomplicated hypertension) ; alpha-andrenergic antagonists (e.g., doxazosin, phentolamine , indoramin, phenoxybenzamine, prazosin, terazosin, and tolazoline) (which can be particularly useful in cases involving uncomplicated hypertension) ; combined alpha- and beta- andrenergic antagonists (e.g., bucindolol, carvedilol, and labetalol); central alpha agonists and other centrally acting agents (e.g., clonidine, methyldopa, reserpine, guanabenz, guanethidine, and guanfacine) ; vasodilators (e.g., sodium nitroprusside, hydralazine, and minoxidil); and aldosterone receptor antagonists (e.g., spironolactone and eplerenone) . Examples of suitable combinations of antihypertensive agents include combinations of ACE inhibitors and calcium channel blockers (e.g., amlodipine/benzazepril , enalapril/ felodipine, and trandolapril/verapamil) ; combinations of ACE inhibitors and diuretics (e.g., benzazepril/ hydroclorothiazide, captopril/hydroclorothiazide, enalapril/hydroclorothiazide, 1isinopril/hydroclorothiazide, moexipril/hydroclorothiazide, and quinapril/ hydroclorothiazide) ; combinations of angiotensin II antagonists and diuretics (e.g., candesartan/ hydroclorothiazide , eprosartan/hydroclorothiazide , irbesartan/hydroclorothiazide , losartan/hydroclorothiazide , telmisartan/hydroclorothiazide, and valsartan/ hydroclorothiazide); beta blockers and diuretics (e.g., atenolol/chlortalidone, bisoprolol/hydroclorothiazide, metoprolol/hydroclorothiazide , nadolol/hydroclorothiazide, and timolol/hydroclorothiazide) ; combinations of centrally acting agents and diuretics (e.g., methyldopa/ hydroclorothiazide, reserpine/chlortalidone, and reserpine/hydroclorothiazide) ; and combinations of two diuretics (e.g., amiloride/hydroclorothiazide , triamterene/ hydroclorothiazide, and spironolactone/hydroclorothiazide) .

As still further illustration, the additional biologically active materials which can be present in compositions that are useful in the methods of the present invention include one or more antidyslipidemia agents. Examples of suitable antidyslipidemia agents include cholesterol -lowering drugs and other antihyperlipidemia agents, such as those belonging to the class of agents commonly referred to as "statins". Examples of statins that can be used in the compositions of the present invention include simvastatin (available commercially from Merck as ZOCOR™) , lovastatin (available commercially from Merck as MEVACOR™) , fluvastatin (available commerically from Novartis as LESCOL™) , pravastatin (available commercially from Bristol -Meyers Squibb as PRAVACHOL™) , atorvastatin (available commercially from Parke-Davis/Pfizer as LIPITOR™) , and cerivastatin (available commercially from Bayer as BAYCOL™] . The statin or statins can be included in the composition in amounts that are effective to reduce a subject's serum cholesterol level (e.g., in amounts that are effective to reduce a subject's serum LDL cholesterol levels by more than about 5%, by more than 5%, by more than about 10%, by more than 10%, by more than about 20%, by more than 20%, by more than about 30%, by more than 30%, by more than about 35%, by more than

35%, etc.; and/or in amounts that are effective to reduce a subject's total serum cholesterol by more than about 5%, by more than 5%, by more than about 10%, by more than 10%, by more than about 15%, by more than 15%, by more than about 20%, by more than 20%, by more than about 25%, by more than 25%, etc., in subjects with moderately elevated or high serum cholesterol and/or triglyceride levels. Examples of other suitable antidyslipidemia agents include bile acid-binding resins, such as cholestyramine (e.g., QUESTRAN™, QUESTRAN™ Lite), colestipol (e.g., COLESTID™) ; fibric acid analogs, such as clofibrate (e.g., ATROMID-5™) and gemfibrozil (e.g., LOPID™) ; and niacin. Examples of suitable combinations of antidyslipidemia agents include combinations of a statin and a bile acid-binding resin; and combinations of a statin and a fibric acid analog. Illustratively, the compositions of the present invention can include, in addition to the reduced folate, a antidyslipidemia agent other than niacin, such as (i) in the case where the composition includes a reduced folate, an antidyslipidemia agent other than niacin, and niacin (e.g., a reduced folate, a statin, and niacin; a reduced folate, a bile acid-binding resin, and niacin; a reduced folate, a fibric acid analog, and niacin); and (ii) in the case where the composition includes a reduced folate, an antidyslipidemia agent other than niacin, and no niacin (e.g., a reduced folate, a statin, and no niacin; a reduced folate, a bile acid-binding resin, and no niacin; a reduced folate, a fibric acid analog, and no niacin) .

As yet further illustration, the additional biologically active materials which can be present in compositions that are useful in the methods of the present invention can include aspirin. For example, in certain embodiments of the method of the present invention, the reduced folate is administered in a composition that includes the reduced folate and one or more additional antihypertensive agents, such as those described above. The amount of additional antihypertensive agent present in the composition can be, for example, from about 10% to about 150% (e.g., from 10% to 150%, from about 20% to about 135%, from 20% to 135%, from about 50% to about 125%, from 50% to 125%, from about 75% to about 110%, from 75% to 110%, and/or about 100%) of the dose range or ranges that are typically used and/or can be used for the particular additional antihypertensive agent or agents (i.e., the dose range or ranges that are typically used when the particular additional antihypertensive agent or agents are used in the absence of the reduced folate) . Details regarding the use of antihypertensive agents to affect hypertension and blood pressure are presented, for example, in Tables 6 and 7 in Piascik, "The Therapy of Hypertension, " University of Kentucky (available at http://www.uky.edu/~mtp/pha824hy/PHA824hy.html); and in the Physicians' Desk Reference, which are hereby incorporated by reference.

As further example, in other embodiments of the method of the present invention, the reduced folate is administered in a composition that includes the reduced folate and one or more antidyslipidemia agents, such as those described above. The amount of antidyslipidemia agent present in the composition can be, for example, from about 10% to about 150% (e.g., from 10% to 150%, from about 20% to about 135%, from 20% to 135%, from about 50% to about 125%, from 50% to 125%, from about 75% to about 110%, from 75% to 110%, and/or about 100%) of the dose range or ranges that are typically used for the particular antidyslipidemia agent or agents (i.e., the dose range or ranges that are typically used when the particular antidyslipidemia agent or agents are used in the absence of the reduced folate) . For example, the reduced folate can be administered in a composition that includes the reduced folate and from about 1 mg to about 30 mg (e.g., from 10 mg to 20 mg) of simvastatin. As noted above, other statins can be used, and mixtures of statins can also be used. By way of example, the concentration of the selected statin (s) can be within the range of from about 1 microgram to about 120 milligram (e.g., from about 10 microgram to about 60 milligram; from about 1000 microgram to about 30 milligram) of the selected statin (s) per dose. Details regarding the use of antidyslipidemia agents are presented, for example, in McKenney, "New Guidelines for Managing Hypercholesterolemia," J. Amer. Pharm. Assn., 41(4): 596- 607 (2001); and in the Physicians' Desk Reference, which are hereby incorporated by reference.

As an alternative to administering the aforementioned additional biologically active materials (e.g., other vitamins and/or nutrients and/or minerals, aspirin, essential nutrients, antihypertensive agents, and/or antidyslipidemia agents) as part of a composition which includes the reduced folate, one or more of the additional biologically active material (s) can be administered separately from the reduced folate, for example, in a separate dosage form (as in the case where the reduced folate is administered orally in a first tablet and an additional biologically active material is administered orally in a second tablet) ; by a different route (e.g., as in the case where the reduced folate is administered orally and an additional biologically active material is administered non-orally or as in the case where the reduced folate is administered non-orally and an additional biologically active material is administered orally); etc. Where one or more of the additional biologically active material (s) are administered separately from the reduced folate, the administration can be carried out at the same time, at substantially the same time, or at different times. Where the additional biologically active material (s) are administered separately from the reduced folate, the additional biologically active material (s) and the reduced folate can be packaged separately, or, alternatively, they can be packaged in the form of a kit, for example as further described hereinbelow.

The reduced folate can also be administered orally as a food that is fortified with one or more reduced folates. Foods can be single-component foods, for example, fruits and fruit juices (e.g., orange juice), dairy products (e.g., milk), vegetables (e.g., spinach), other such single-component foods. Foods can also be multi -component preparations made from two or more single-component foods. Typically, foods contain various concentrations of endogenous reduced folates. Depending on the nature of the processing needed, the fortification is often optimally performed after any especially destructive processing steps, as is well know in the art of food fortification. Since the amount endogenous reduced folates present in the food can vary, it can be advantageous to know the final amount (number of moles) of reduced folate in the food or food preparation, as quantified, for example, by analysis of a sample of a product batch. Many analytical methods (such as microbial growth dependence, folate binding protein based assays, HPLC and GC) are available for measurement of the reduced folate content of foods, food preparations, and supplements.

Irrespective of whether the reduced folate is administered orally to a human subject in the form of a supplement, in the form of a pharmaceutical composition, in the form of a fortified food, or in the form of a food preparation, the total amount of reduced folate administered per dose can be in the range of from about 0.45 micromoles to about 200 micromoles (based on the natural isomer component, if the reduced folate is present as a mixture of isomers) , such as from 0.45 micromoles to 200 micromoles, from about 0.9 micromoles to about 200 micromoles, from 0.9 micromoles to 200 micromoles, from about 1.8 micromoles to about 200 micromoles, from 1.8 micromoles to 200 micromoles, from about 0.45 micromoles to about 150 micromoles, from about 0.9 micromoles to about 150 micromoles, from about 1.8 micromoles to about 150 micromoles, from about 0.45 micromoles to about 100 micromoles, from about 0.9 micromoles to about 100 micromoles, from about 1.8 micromoles to about 100 micromoles, from about 0.45 micromoles to about 50 micromoles, from about 0.9 micromoles to about 50 micromoles, from about 1.8 micromoles to about 50 micromoles, from 0.45 micromoles to 2.27 micromoles, from 0.9 micromoles to 2.27 micromoles, from 2.27 micromoles to 100 micromoles, from 2.27 micromoles to 200 micromoles, from about 0.45 micromoles to 2.27 micromoles, from about 0.9 micromoles to 2.27 micromoles, from 2.27 micromoles to about 100 micromoles, and/or from 2.27 micromoles to about 200 micromoles. In certain embodiments, the total amount of reduced folate administered per dose is in the range of from about 0.45 micromoles to 68 micromoles, such as from 0.45 micromoles to 68 micromoles, from about 0.45 micromoles to about 65 micromoles, from 0.45 micromoles to 65 micromoles, from about 0.45 micromoles to about 60 micromoles, from 0.45 micromoles to 60 micromoles, from about 0.45 micromoles to about 55 micromoles, from 0.45 micromoles to 55 micromoles, from about 0.45 micromoles to about 45 micromoles, from about 0.45 micromoles to 45 micromoles, from 0.45 micromoles to 45 micromoles, from about 0.45 micromoles to about 40 micromoles, from 0.45 micromoles to 40 micromoles, from about 0.45 micromoles to about 35 micromoles, and/or from 0.45 micromoles to 35 micromoles, from about 2.27 micromoles to 68 micromoles, such as from 2.27 micromoles to 68 micromoles, from about 2.27 micromoles to about 65 micromoles, from 2.27 micromoles to 65 micromoles, from about 2.27 micromoles to about 60 micromoles, from 2.27 micromoles to 60 micromoles, from about 2.27 micromoles to about 55 micromoles, from 2.27 micromoles to 55 micromoles, from about 2.27 micromoles to about 50 micromoles, from 2.27 micromoles to 50 micromoles, from about 2.27 micromoles to about 45 micromoles, from about 2.27 micromoles to 45 micromoles, from 2.27 micromoles to 45 micromoles, from about 2.27 micromoles to about 40 micromoles, from 2.27 micromoles to 40 micromoles, from about 2.27 micromoles to about 35 micromoles, and/or from 2.27 micromoles to 35 micromoles, wherein, again, these values are based on the natural isomer component, if the reduced folate is present as a mixture of isomers.

As discussed above, oral administration can be carried out in a single dose, multiple doses, or continuously. The amount of reduced folate contained in a single dose will, of course, depend in part on the dosing regimen and the total amount of reduced folate to be administered to the subject in a given period of time (e.g., per day) . Suitable daily dosage ranges of reduced folates include: from about 0.45 micromoles to about 15 micromoles, from about 0.9 micromoles to about 15 micromoles, from 0.9 micromoles to 15 micromoles, from about 1 micromoles to about 15 micromoles, from about 2 micromoles to about 12 micromoles, from about 3 micromoles to about 10 micromoles, from about 5 micromoles to about 8 micromoles, etc.

Dosage forms suitable for parenteral administration include solutions, suspensions, dispersions, emulsions, and the like. They may also be manufactured in the form of sterile solid compositions which can be dissolved or suspended in sterile injectable medium immediately before use. They may contain suspending or dispersing agents known in the art. Examples of parenteral administration are intramuscular, intravenous, rectal, and subcutaneous administration.

As mentioned above, the reduced folates can be administered via routes other than oral and parenteral routes. For example, the reduced folates can be administered to the eye in the form of drops, creams, or gel solutions or suspensions adapted for ocular application. The reduced folates can also be administered via the lungs, for example, as in the case where the reduced folate is administered intranasally, e.g., via a liquid spray or via an aerosol. For administration to the respiratory tract by inhalation, the reduced folate can be delivered from an insufflator, nebulizer, or a pressurized pack or other convenient means of delivering an aerosol spray. Pressurized packs may include a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the reduced folate can be in the form of a dry powder composition, for example, a powder mix of the reduced folate and a suitable powder base such as lactose or starch. The powder composition can be presented in unit dosage form in, for example, capsules, cartridges, or gelatin or blister packs, from which the powder may be administered with the aid of an inhalator or insufflator. For intranasal administration, the reduced folate can be administered via a liquid spray, such as via a plastic bottle atomizer. Typical of these are the Mistometer

(Wintrop) and the Medihaler (Riker) . The reduced folates can also be administered topically, for example, in a conventional topical cream, lotion, spray, gel matrix, and/or via a transdermal patch or other transdermal delivery device. Topical formulations can benefit from incorporation of delivery systems that enhance skin penetration (e.g., liposomes, etc.), as is known in the art. Illustratively, topical dosage forms that are applied regularly (e.g., daily) can be formulated so as to contain from about 0.05 micromoles to about 1 millimole, such as from 0.05 micromoles to 1 millimole, from about 0.1 micromoles to about 0.8 millimoles, from about 0.5 micromoles to about 0.5 millimoles, from about 1 micromole to about 0.4 millimoles, from about 50 micromoles to about 0.4 millimoles, from about 0.1 millimoles to about 0.3 millimole and/or about 0.2 millimoles of reduced folate (based on the natural isomer component, if the reduced folate is present as a mixture of isomers) per coverage area. As further illustration, transdermal patches or other topical formulations employing a transdermal delivery device, can be formulated so as to contain from about 1.5 micromoles to about 6 millimoles, such as from 1.5 micromoles to 6 millimoles, from about 3 micromoles to about 6 millimoles, from about 15 micromoles to about 6 millimoles, from about 30 micromoles to about 6 millimoles, from about 1.5 millimoles to about 6 millimoles, from about 3 millimoles to about 6 millimoles, about 4 millimoles, about 5 millimoles, and/or about 6 millimoles of reduced folate (based on the natural isomer component, if the reduced folate is present as a mixture of isomers) .

Further details regarding formulating the compositions described hereinabove, such as compositions for topical, enteral, and parenteral administration, can be found, for example, in Handbook of Pharmaceutical Excipients , 3rd Edition (2000), American Pharmaceutical Association; The Theory and Practice of Industrial Pharmacy, 3rd Edition, Lachman et al . 1986; Pharmaceutical Dosage Forms: Tablets Volume Edition, Christopher T, edition, 1995; and Remington's Pharmaceutical Sciences, 2000, which are hereby incorporated by reference.

It will be appreciated that the actual preferred amount of reduced folate to be administered according to the present invention will vary according to the particular reduced folate, the particular composition formulated, and the mode of administration. Many factors that may modify the action of the reduced folate (e.g., body weight, sex, diet, time of administration, route of administration, rate of excretion, condition of the subject, drug combinations, and reaction sensitivities and severities) can be taken into account by those skilled in the art. Administration can be carried out continuously or periodically within the maximum tolerated dose. Optimal administration rates for a given set of conditions can be ascertained by those skilled in the art using conventional dosage administration tests. The present invention also relates to pharmaceutical compositions which include a first antihypertensive agent and a second antihypertensive agent. The first antihypertensive agent is a reduced folate (such as one of the reduced folates discussed above, or combinations thereof), and suitable amounts of reduced folate in the pharmaceutical composition include those discussed above (e.g., from about 0.45 micromoles to about 200 micromoles of reduced folate per dose, from about 0.45 micromoles to 68 micromoles of reduced folate per dose, from about 0.45 micromoles to about 65 micromoles of reduced folate per dose, from about 0.45 micromoles to about 50 micromoles of reduced folate per dose, from about 0.45 micromoles to 45 micromoles of reduced folate per dose, from about 0.45 micromoles to about 40 micromoles of reduced folate per dose, from about 2.27 micromoles to about 200 micromoles of reduced folate per dose, from about 2.27 micromoles to 68 micromoles of reduced folate per dose, from about 2.27 micromoles to about 65 micromoles of reduced folate per dose, from about 2.27 micromoles to about 50 micromoles of reduced folate per dose, from about 2.27 micromoles to 45 micromoles of reduced folate per dose, from about 2.27 micromoles to about 40 micromoles of reduced folate per dose, etc.) . By way of illustration, in certain embodiments, the reduced folate is selected from the group consisting of tetrahydrofolic acid, 5 -methyl - tetrahydrofolic acid, 5-formyl-tetrahydrofolic acid, 10- formyl-tetrahydrofolic acid, 5 , 10-methylene- tetrahydrofolic acid, 5 , 10 -methenyl-tetrahydrofolic acid, 5-formimino-tetrahydrofolic acid, 7 , 8-dihydrofolic acid, and polyglutamyl derivatives thereof; in certain embodiments, the reduced folate is selected from the group consisting of (6S) -tetrahydrofolic acid, 5 -methyl - (6S) -tetrahydrofolic acid, 5-formyl- (6S) -tetrahydrofolic acid, 10-formyl- (6R) -tetrahydrofolic acid, 5,10- methylene- (6R) -tetrahydrofolic acid, 5 , 10-methenyl - (6R) - tetrahydrofolic acid, 5-formimino- (6S) -tetrahydrofolic acid, and polyglutamyl derivatives thereof; in certain embodiments, the reduced folate is selected from the group consisting of racemic tetrahydrofolic acid, racemic 5-methyl-tetrahydrofolic acid, racemic 5-formyl - tetrahydrofolic acid, racemic 10-formyl -tetrahydrofolic acid, racemic 5 , 10-methylene- tetrahydrofolic acid, racemic 5 , 10 -methenyl -tetrahydrofolic acid, racemic 5- formimino-tetrahydrofolic acid, and polyglutamyl derivatives thereof; in certain embodiments, the reduced folate is 5-methyl-tetrahydrofolic acid; in certain embodiments, the reduced folate is 5 , 10-methylene- tetrahydrofolic acid; in certain embodiments, the reduced folate is not tetrahydrofolic acid and is not 5-formyl - tetrahydrofolic acid; etc. The second antihypertensive agent can be selected from those discussed above (e.g., from a group consisting of diuretics, beta-andrenergic antagonists, angiotensin-converting enzyme inhibitors, angiotensin II antagonists, calcium channel blockers, alpha-andrenergic antagonists, combined alpha- and beta- andrenergic antagonists, centrally acting agents, vasodilators, aldosterone receptor antagonists, and combinations thereof) . Examples of suitable diuretics, beta-andrenergic antagonists, angiotensin-converting enzyme inhibitors, angiotensin II antagonists, calcium channel blockers, alpha-andrenergic antagonists, combined alpha- and beta-andrenergic antagonists, centrally acting agents, vasodilators, aldosterone receptor antagonists include those which are discussed above in the context of the methods of the present invention.

The pharmaceutical composition of the present invention can also include other components (i.e., in addition to the reduced folate and second antihypertensive agent), such as inert materials and/or biologically active materials. For example, the composition can further include one or more other vitamins (such as those discussed above) . Additionally or alternatively, the pharmaceutical composition can further include an antidyslipidemia agent (such as one, two, or more of the antidyslipidemia agent discussed above in the context of the methods of the present invention) .

The present invention also relates to pharmaceutical compositions which include a reduced folate and an antidyslipidemia agent other than niacin. Examples of reduced folates suitable for use in the pharmaceutical compositions include those discussed above or combinations thereof, and suitable amounts of reduced folate in the pharmaceutical composition include those amounts discussed above and suitable amounts of reduced folate in the pharmaceutical composition include those discussed above (e.g., from about 0.45 micromoles to about 200 micromoles of reduced folate per dose, from about 0.45 micromoles to 68 micromoles of reduced folate per dose, from about 0.45 micromoles to about 65 micromoles of reduced folate per dose, from about 0.45 microraoles to about 50 micromoles of reduced folate per dose, from about 0.45 micromoles to 45 micromoles of reduced folate per dose, from about 0.45 micromoles to about 40 micromoles of reduced folate per dose, from about 2.27 micromoles to about 200 micromoles of reduced folate per dose, from about 2.27 micromoles to 68 micromoles of reduced folate per dose, from about 2.27 micromoles to about 65 micromoles of reduced folate per dose, from about 2.27 micromoles to about 50 micromoles of reduced folate per dose, from about 2.27 micromoles to 45 micromoles of reduced folate per dose, from about 2.27 micromoles to about 40 micromoles of reduced folate per dose, etc.) . By way of illustration, in certain embodiments, the reduced folate is selected from the group consisting of tetrahydrofolic acid, 5-methyl- tetrahydrofolic acid, 5-formyl -tetrahydrofolic acid, 10- formyl- tetrahydrofolic acid, 5 , 10-methylene- tetrahydrofolic acid, 5 , 10-methenyl-tetrahydrofolic acid, 5-formimino- tetrahydrofolic acid, 7 , 8-dihydrofolic acid, and polyglutamyl derivatives thereof; in certain embodiments, the reduced folate is selected from the group consisting of (6S) -tetrahydrofolic acid, 5 -methyl - (6S) -tetrahydrofolic acid, 5-formyl- (6S) -tetrahydrofolic acid, 10-formyl- (6R) -tetrahydrofolic acid, 5,10- methylene- (6R) -tetrahydrofolic acid, 5 , 10-methenyl- (6R) - tetrahydrofolic acid, 5-formimino- (6S) -tetrahydrofolic acid, and polyglutamyl derivatives thereof; in certain embodiments, the reduced folate is selected from the group consisting of racemic tetrahydrofolic acid, racemic 5-methyl -tetrahydrofolic acid, racemic 5-formyl- tetrahydrofolic acid, racemic 10-formyl- tetrahydrofolic acid, racemic 5 , 10-methylene-tetrahydrofolic acid, racemic 5 , 10-methenyl -tetrahydrofolic acid, racemic 5- formimino-tetrahydrofolic acid, and polyglutamyl derivatives thereof; in certain embodiments, the reduced folate is 5 -methyl -tetrahydrofolic acid; in certain embodiments, the reduced folate is 5 , 10-methylene- tetrahydrofolic acid; in certain embodiments, the reduced folate is not tetrahydrofolic acid and is not 5-formyl- tetrahydrofolic acid; etc. The antidyslipidemia agent can be selected from a group consisting of statins, bile acid-binding resins, fibric acid analogs, and combinations thereof. For example, in certain embodiments, the pharmaceutical composition includes reduced folate and a statin. The pharmaceutical composition can further include (i.e., in addition to the reduced folate and statin) a second, third, etc. antidyslipidemia agent; and the second, third, etc. can be selected from a group consisting of statins, bile acid-binding resins, fibric acid analogs, niacin, and combinations thereof. For example, in certain embodiments, the pharmaceutical composition includes reduced folate, one or more statins (each in a antidyslipidemia effective amount) , and niacin (in a antidyslipidemia effective amount) .

The aforementioned pharmaceutical compositions (i.e., those including a reduced folate and an antidyslipidemia agent other than niacin) can be substantially free from niacin or not. As used in this context, "substantially free from niacin" is meant to refer to compositions in which the level of niacin present in the composition is insufficient to have an appreciable (e.g., a measurable and/or significant) antidyslipidemia effect. Illustratively, compositions containing no niacin; containing niacin in an amount that is equal to or less than 500% of the FDA's DV for niacin for the subject; containing niacin in an amount that is equal to or less than 400% of the FDA's DV for niacin for the subject; containing niacin in an amount that is equal to or less than 300% of the FDA's DV for niacin for the subject; containing niacin in an amount that is equal to or less than 200% of the FDA's DV for niacin for the subject; containing niacin in an amount that is equal to or less than the FDA's DV for niacin for the subject; containing niacin in an amount of less than 100 mg (dry- weight) ; containing niacin in an amount of less than 80 mg (dry weight) ; containing niacin in an amount of less than 60 mg (dry weight) ; containing niacin in an amount of less than 40 mg (dry weight) ; and/or containing niacin in an amount of less than 20 mg (dry weight) are to be deemed to be "substantially free from niacin". As used herein, "FDA's DV" is meant to refer to the U.S. Food and Drug Administration's Daily Value, which, for niacin, is 20 mg/day.

The subject pharmaceutical compositions of the present invention can also include other components (i.e., in addition to the reduced folate and antidyslipidemia agent), such as inert materials and/or biologically active materials. For example, the composition can further include one or more other vitamins (such as those discussed above) . Additionally or alternatively, the pharmaceutical composition can further include an antihypertensive agent (such as one, two, or more of the antihypertensive agents discussed above in the context of the methods of the present invention) . As used in this context, "substantially free from niacin" is meant to refer to compositions in which the level of niacin present in the composition is insufficient to have an appreciable antidyslipidemia effect.

The present invention is further illustrated by the following non- limiting example. EXAMPLE

Example 1 -- Acute and Chronic Effects of Folic Acid and 5-Methyl-6S-Tetrahγdrofolate on Blood Pressure and Endothelial Function

Several studies have pointed to a relationship between elevated total plasma homocysteine and hypertension. Moreover, a number of reports have demonstrated that folic acid can lower blood pressure in specific classes of subjects (e.g. smokers), although a few such trials did not show this effect (e.g. diabetics) . Folate has also been observed to improve endothelial function, usually measured by flow mediated dilation ("FMD"), although this finding is most often seen in patients with vascular disease, and less so in healthy subjects. We have conducted a trial comparing the effect of 10 weeks treatment with folic acid (at 2.5 mg/d or 5.0 mg/d) , with 5-methyl-6S-tetrahydrofolate ("5- MTHF") (at 5.0 mg/d), or placebo in predominantly healthy individuals. Subjects were included if they previously did not consume more than 0.1 mg of folic acid per day from supplements or breakfast cereals, and had fasting homocysteine levels in the top quintile at screening. Blood pressure was measured after 10 min relaxation while sitting (average = 129/83 at baseline) . FMD was then measured by ultrasound of the brachial artery at baseline, 90 min after the first dose, after 10 weeks treatment, and finally 90 min after administration of the last dose. Blood samples were taken after each of the four FMD measurements. Plasma total folate was determined by microbiological assay and unmetabolized folic acid by column-switching HPLC with fluorescence detection after post -column coulometric oxidation. Among compliant subjects (judged by counting remaining capsules) , total plasma folate increased by 68 nM, 82 nM, 141 nM, and 0.7 nM in the 2.5 mg/d folic acid, 5.0 mg/d folic acid, 5.0 mg/d 5-MTHF, and placebo treatment arms, respectively. Diastolic blood pressure decreased in all the folate treatment arms, but only subjects taking 5- MTHF reached statistical significance (P = 0.02 relative to placebo, 0.05 relative to 5 mg/d folic acid) . No significant changes in FMD were seen with the first dose or chronic treatment with any folate, consistent with previous studies in healthy subjects. However, the last dose of 5-MTHF (but not of folic acid) induced a considerable increase in FMD 90 min later (P < 0.02) . Among individuals in the 5-MTHF treatment arm this improved endothelial function was correlated with their overall decrease in blood pressure.

Figure 1 sets forth some of the results from this experiment . More particularly, Figure 1 is a bar graph illustrating the average effect on blood pressure after 10 weeks of treatment with 2.5 mg/d or 5.0 mg/d of folic acid or "5.0 mg/d" (actually 11.3 micromoles) of 5- methyl-6S-tetrahydrofolate ("5-MTHF") . Only the last of these produced a statistically significant change.

Although the invention has been described in detail for the purpose of illustration, it is understood that such detail is solely for that purpose, and variations can be made therein by those skilled in the art without departing from the spirit and scope of the invention which is defined by the claims that are set forth below.

Claims

WHAT IS CLAIMED IS:

1. A method for treating hypertension in a subject, said method comprising: administering to the subject an effective amount of at least one reduced folate.

2. A method according to claim 1, wherein the reduced folate is 5-methyl - tetrahydrofolic acid.

3. A method according to claim 1, wherein the reduced folate is 5-methyl - (6S) -tetrahydrofolic acid.

4. A method according to claim 1, wherein the reduced folate is racemic 5 -methyl -tetrahydrofolic acid.

5. A method according to claim 1, wherein the reduced folate is selected from the group consisting of tetrahydrofolic acid, 5-methyl-tetrahydrofolic acid, 5-formyl- tetrahydrofolic acid, 10 -formyl -tetrahydrofolic acid, 5,10- methylene-tetrahydrofolic acid, 5 , 10 -methenyl-tetrahydrofolic acid, 5-formimino- tetrahydrofolic acid, 7 , 8-dihydrofolic acid, and polyglutamyl derivatives thereof.

6. A method according to claim 1, wherein the reduced folate is selected from the group consisting of (6S) - tetrahydrofolic acid, 5-methyl- (6S) -tetrahydrofolic acid, 5- formyl- (6S) -tetrahydrofolic acid, 10-formyl- (6R) - tetrahydrofolic acid, 5 , 10-methylene- (6R) -tetrahydrofolic acid, 5 , 10-methenyl- (6R) -tetrahydrofolic acid, 5-formimino- (6S) -tetrahydrofolic acid, and polyglutamyl derivatives thereof .

7. A method according to claim 1, wherein the reduced folate is selected from the group consisting of racemic tetrahydrofolic acid, racemic 5-methyl-tetrahydrofolic acid, racemic 5-formyl -tetrahydrofolic acid, racemic 10- formyl-tetrahydrofolic acid, racemic 5 , 10-methylene- tetrahydrofolic acid, racemic 5 , 10-methenyl-tetrahydrofolic acid, racemic 5-formimino- tetrahydrofolic acid, and polyglutamyl derivatives thereof.

8. A method according to claim 1, wherein the reduced folate is selected from the group consisting of racemic tetrahydrofolic acid, racemic 5-methyl-tetrahydrofolic acid, racemic 10-formyl-tetrahydrofolic acid, racemic 5,10- methylene-tetrahydrofolic acid, racemic 5 , 10-methenyl- tetrahydrofolic acid, racemic 5-formimino-tetrahydrofolic acid, and polyglutamyl derivatives thereof.

9. A method according to claim 1, wherein the reduced folate is 5 , 10 -methylene-tetrahydrofolic acid.

10. A method according to claim 1, wherein the reduced folate is not tetrahydrofolic acid and is not 5- formyl -tetrahydrofolic acid.

11. A method according to claim 1, wherein the subject is one who has blood pressure in a pre-hypertensive range .

12. A method according to claim 1, wherein the subject is one who has blood pressure in a hypertensive range.

13. A method according to claim 1, wherein the subject is one who has a systolic blood pressure of under 120 mm Hg .

14. A method according to claim 1, wherein the subject is one who has a diastolic blood pressure of under 80 mm Hg .

15. A method according to claim 1, wherein the subject is one who has a systolic blood pressure of under 120 mm Hg and a diastolic blood pressure of under 80 mm Hg.

16. A method according to claim 1, wherein the subject is one who has a systolic blood pressure of between 120 mm Hg and 139 mm Hg, inclusive.

17. A method according to claim 1, wherein the subject is one who has a diastolic blood pressure of between 80 mm Hg and 99 mm Hg, inclusive.

18. A method according to claim 1, wherein the subject is one who has a systolic blood pressure of between 120 mm Hg and 139 mm Hg, inclusive, and a diastolic blood pressure of between 80 mm Hg and 89 mm Hg, inclusive.

19. A method according to claim 1, wherein the subject is one who has a systolic blood pressure of between 140 mm Hg and 159 mm Hg, inclusive.

20. A method according to claim 1, wherein the subject is one who has a diastolic blood pressure of between 90 mm Hg and 99 mm Hg, inclusive.

21. A method according to claim 1, wherein the subject is one who has a systolic blood pressure of between 140 mm Hg and 159 mm Hg, inclusive, and a diastolic blood pressure of between 90 mm Hg and 99 mm Hg, inclusive.

22. A method according to claim 1, wherein the subject is one who has a systolic blood pressure of 160 mm Hg or greater.

23. A method according to claim 1, wherein the subject is one who has a diastolic blood pressure of 100 mm Hg or greater.

24. A method according to claim 1, wherein the subject is one who has a systolic blood pressure of 160 mm Hg or greater and a diastolic blood pressure of 100 mm Hg or greater .

25. A method according to claim 1, wherein the subject is one who is not known to be suffering from coronary artery disease.

26. A method according to claim 1, wherein the subject is one who has an elevated blood homocysteine level.

27. A method according to claim 1, wherein the subject is one who is not known to be suffering from coronary artery disease and who has an elevated blood homocysteine level .

28. A method according to claim 1, wherein the reduced folate is administered orally.

29. A method according to claim 1, wherein the reduced folate is administered orally in time-release formulation.

30. A method according to claim 1, wherein the reduced folate is administered in a composition that comprises the reduced folate and that is substantially free of any other vitamin other than ascorbic acid.

31. A method according to claim 1, wherein the reduced folate is administered in a pharmaceutical composition that comprises the reduced folate.

32. A method according to claim 31, wherein the pharmaceutical composition further comprises, in addition to the reduced folate, one or more additional biologically active materials .

33. A method according to claim 31, wherein the pharmaceutical composition further comprises, in addition to the reduced folate, one or more antihypertensive agents, one or more antidyslipidemia agents, or both.

34. A method according to claim 31, wherein the pharmaceutical composition further comprises, in addition to the reduced folate, one or more antihypertensive agents.

35. A method according to claim 31, wherein the pharmaceutical composition further comprises, in addition to the reduced folate, one or more antidyslipidemia agents.

36. A method according to claim 31, wherein the pharmaceutical composition further comprises, in addition to the reduced folate, one or more one or more antihypertensive agents and one or more antidyslipidemia agents.

37. A method according to claim 1, wherein the reduced folate is administered under conditions effective to establish and/or maintain a homeostatic plasma level of reduced folate greater than 50 nanomolar.

38. A method according to claim 1, wherein the reduced folate is administered under conditions effective to establish and/or maintain a homeostatic plasma level of reduced folate greater than about 80 nanomolar.

39. A method according to claim 1, wherein the reduced folate is administered at a daily dose of from about 0.45 micromoles to about 15 micromoles .

40. A method according to claim 1, wherein the reduced folate is administered in a dose containing from about 0.45 micromoles to about 200 micromoles.

41. A method according to claim 1, wherein the reduced folate is administered in a dose containing from about 0.45 micromoles to 68 micromoles.

42. A method according to claim 1, wherein the reduced folate is administered in a dose containing from about 0.45 micromoles to about 65 micromoles.

43. A method according to claim 1, wherein the reduced folate is administered in a dose containing from about 0.45 micromoles to about 50 micromoles.

44. A method according to claim 1, wherein the reduced folate is administered in a dose containing from about 2.27 micromoles to about 50 micromoles.

45. A method according to claim 1, wherein the reduced folate is administered in a dose containing from about 0.45 micromoles to 45 micromoles.

46. A method according to claim 1, wherein the reduced folate is administered in a dose containing from about 0.45 micromoles to about 40 micromoles.

47. A method for decreasing risk of stroke in a subject, said method comprising: treating hypertension in the subject using a method according to claim 1.

48. A method for reducing blood pressure in a subject, said method comprising: administering to the subject an effective amount of at least one reduced folate.

49. A method according to claim 48, wherein the reduced folate is 5-methyl -tetrahydrofolic acid.

50. A method according to claim 48, wherein the reduced folate is 5-methyl - (6S) -tetrahydrofolic acid.

51. A method according to claim 48, wherein the reduced folate is racemic 5-methyl-tetrahydrofolic acid.

52. A method according to claim 48, wherein the reduced folate is selected from the group consisting of tetrahydrofolic acid, 5-methyl-tetrahydrofolic acid, 5-formyl- tetrahydrofolic acid, 10-formyl-tetrahydrofolic acid, 5,10- methylene- tetrahydrofolic acid, 5 , 10-methenyl- tetrahydrofolic acid, 5-formimino-tetrahydrofolic acid, 7 , 8-dihydrofolic acid, and polyglutamyl derivatives thereof.

53. A method according to claim 48, wherein the reduced folate is selected from the group consisting of (6S) - tetrahydrofolic acid, 5-methyl- (6S) -tetrahydrofolic acid, 5- formyl- (6S) -tetrahydrofolic acid, 10-formyl- (6R) - tetrahydrofolic acid, 5 , 10 -methylene- (6R) -tetrahydrofolic acid, 5 , 10-methenyl- (6R) -tetrahydrofolic acid, 5-formimino- (6S) -tetrahydrofolic acid, and polyglutamyl derivatives thereof .

54. A method according to claim 48, wherein the reduced folate is selected from the group consisting of racemic tetrahydrofolic acid, racemic 5 -methyl -tetrahydrofolic acid, racemic 5-formyl -tetrahydrofolic acid, racemic 10- formyl- tetrahydrofolic acid, racemic 5 , 10-methylene- tetrahydrofolic acid, racemic 5 , 10-methenyl -tetrahydrofolic acid, racemic 5-formimino- tetrahydrofolic acid, and polyglutamyl derivatives thereof.

55. A method according to claim 48, wherein the reduced folate is selected from the group consisting of racemic tetrahydrofolic acid, racemic 5-methyl-tetrahydrofolic acid, racemic 10-formyl - tetrahydrofolic acid, racemic 5,10- methylene- tetrahydrofolic acid, racemic 5 , 10-methenyl - tetrahydrofolic acid, racemic 5-formimino-tetrahydrofolic acid, and polyglutamyl derivatives thereof.

56. A method according to claim 48, wherein the reduced folate is 5 , 10-methylene-tetrahydrofolic acid.

57. A method according to claim 48, wherein the reduced folate is not tetrahydrofolic acid and is not 5- formyl- tetrahydrofolic acid.

58. A method according to claim 48, wherein the subject is one who has blood pressure in a normal range.

59. A method according to claim 48, wherein the subject is one who has blood pressure in a prehypertensive range .

60. A method according to claim 48, wherein the subject is one who has blood pressure in a hypertensive range

61. A method according to claim 48, wherein the subject is one who has a systolic blood pressure of under 120 mm Hg .

62. A method according to claim 48, wherein the subject is one who has a diastolic blood pressure of under 80 mm Hg .

63. A method according to claim 48, wherein the subject is one who has a systolic blood pressure of under 120 mm Hg and a diastolic blood pressure of under 80 mm Hg.

64. A method according to claim 48, wherein the subject is one who has a systolic blood pressure of between 120 mm Hg and 139 mm Hg, inclusive.

65. A method according to claim 48, wherein the subject is one who has a diastolic blood pressure of between 80 mm Hg and 99 mm Hg, inclusive.

66. A method according to claim 48, wherein the subject is one who has a systolic blood pressure of between 120 mm Hg and 139 mm Hg, inclusive, and a diastolic blood pressure of between 80 mm Hg and 89 mm Hg, inclusive.

67. A method according to claim 48, wherein the subject is one who has a systolic blood pressure of between 140 mm Hg and 159 mm Hg, inclusive.

68. A method according to claim 48, wherein the subject is one who has a diastolic blood pressure of between 90 mm Hg and 99 mm Hg, inclusive.

69. A method according to claim 48, wherein the subject is one who has a systolic blood pressure of between 140 mm Hg and 159 mm Hg, inclusive, and a diastolic blood pressure of between 90 mm Hg and 99 mm Hg, inclusive.

70. A method according to claim 48, wherein the subject is one who has a systolic blood pressure of 160 mm Hg or greater.

71. A method according to claim 48, wherein the subject is one who has a diastolic blood pressure of 100 mm Hg or greater.

72. A method according to claim 48, wherein the subject is one who has a systolic blood pressure of 160 mm Hg or greater and a diastolic blood pressure of 100 mm Hg or greater .

73. A method according to claim 48, wherein the subject is one who is not known to be suffering from coronary artery disease.

74. A method according to claim 48, wherein the subject is one who has an elevated blood homocysteine level.

75. A method according to claim 48, wherein the subject is one who is not known to be suffering from coronary- artery disease and who has an elevated blood homocysteine level .

76. A method according to claim 48, wherein the reduced folate is administered orally.

77. A method according to claim 48, wherein the reduced folate is administered orally in time-release formulation .

78. A method according to claim 48, wherein the reduced folate is administered in a composition that comprises the reduced folate and that is substantially free of any other vitamin other than ascorbic acid.

79. A method according to claim 48, wherein the reduced folate is administered in a pharmaceutical composition that comprises the reduced folate.

80. A method according to claim 79, wherein the pharmaceutical composition further comprises, in addition to the reduced folate, one or more additional biologically active materials .

81. A method according to claim 79, wherein the pharmaceutical composition further comprises, in addition to the reduced folate, one or more antihypertensive agents, one or more antidyslipidemia agents, or both.

82. A method according to claim 79, wherein the pharmaceutical composition further comprises, in addition to the reduced folate, one or more antihypertensive agents.

83. A method according to claim 79, wherein the pharmaceutical composition further comprises, in addition to the reduced folate, one or more antidyslipidemia agents.

84. A method according to claim 79, wherein the pharmaceutical composition further comprises, in addition to the reduced folate, one or more one or more antihypertensive agents and one or more antidyslipidemia agents.

85. A method according to claim 48, wherein the reduced folate is administered under conditions effective to establish and/or maintain a homeostatic plasma level of reduced folate greater than 50 nanomolar.

86. A method according to claim 48, wherein the reduced folate is administered under conditions effective to establish and/or maintain a homeostatic plasma level of reduced folate greater than about 80 nanomolar.

87. A method according to claim 48, wherein the reduced folate is administered at a daily dose of from about 0.45 micromoles to about 15 micromoles .

88. A method according to claim 48, wherein the reduced folate is administered in a dose containing from about 0.45 micromoles to about 200 micromoles.

89. A method according to claim 48, wherein the reduced folate is administered in a dose containing from about 0.45 micromoles to 68 micromoles.

90. A method according to claim 48, wherein the reduced folate is administered in a dose containing from about 0.45 micromoles to about 65 micromoles.

91. A method according to claim 48, wherein the reduced folate is administered in a dose containing from about 0.45 micromoles to about 50 micromoles.

92. A method according to claim 48, wherein the reduced folate is administered in a dose containing from about 2.27 micromoles to about 50 micromoles.

93. A method according to claim 48, wherein the reduced folate is administered in a dose containing from about 0.45 micromoles to 45 micromoles.

94. A method according to claim 48, wherein the reduced folate is administered in a dose containing from about 0.45 micromoles to about 40 micromoles.

95. A method for decreasing risk of stroke in a subject, said method comprising: reducing blood pressure in the subject using a method according to claim 48.

96. A method for decreasing risk of stroke in a subject, said method comprising: administering to the subject an effective amount of at least one reduced folate.

97. A method according to claim 96, wherein the reduced folate is 5-methyl-tetrahydrofolic acid.

98. A method according to claim 96, wherein the reduced folate is 5-methyl- (6S) - tetrahydrofolic acid.

99. A method according to claim 96, wherein the reduced folate is racemic 5-methyl-tetrahydrofolic acid.

100. A method according to claim 96, wherein the reduced folate is selected from the group consisting of tetrahydrofolic acid, 5-methyl-tetrahydrofolic acid, 5-formyl - tetrahydrofolic acid, 10-formyl-tetrahydrofolic acid, 5,10- methylene-tetrahydrofolic acid, 5 , 10-methenyl- tetrahydrofolic acid, 5-formimino-tetrahydrofolic acid, 7 , 8-dihydrofolic acid, and polyglutamyl derivatives thereof.

101. A method according to claim 96, wherein the reduced folate is selected from the group consisting of (6S) - tetrahydrofolic acid, 5 -methyl- (6S) -tetrahydrofolic acid, 5- formyl- (6S) -tetrahydrofolic acid, 10-formyl- (6R) - tetrahydrofolic acid, 5 , 10-methylene- (6R) -tetrahydrofolic acid, 5 , 10-methenyl- (6R) -tetrahydrofolic acid, 5-formimino- (6S) -tetrahydrofolic acid, and polyglutamyl derivatives thereof .

102. A method according to claim 96, wherein the reduced folate is selected from the group consisting of racemic tetrahydrofolic acid, racemic 5-methyl -tetrahydrofolic acid, racemic 5-formyl -tetrahydrofolic acid, racemic 10- formyl- tetrahydrofolic acid, racemic 5 , 10-methylene- tetrahydrofolic acid, racemic 5 , 10-methenyl-tetrahydrofolic acid, racemic 5-formimino-tetrahydrofolic acid, and polyglutamyl derivatives thereof.

103. A method according to claim 96, wherein the reduced folate is selected from the group consisting of racemic tetrahydrofolic acid, racemic 5-methyl -tetrahydrofolic acid, racemic 10-formyl -tetrahydrofolic acid, racemic 5, 10- methylene- tetrahydrofolic acid, racemic 5 , 10-methenyl - tetrahydrofolic acid, racemic 5-formimino-tetrahydrofolic acid, and polyglutamyl derivatives thereof.

104. A method according to claim 96, wherein the reduced folate is 5 , 10-methylene- tetrahydrofolic acid.

105. A method according to claim 96, wherein the reduced folate is not tetrahydrofolic acid and is not 5- formyl-tetrahydrofolic acid.

106. A method according to claim 96, wherein the subject is one who has blood pressure in a pre-hypertensive range .

107. A method according to claim 96, wherein the subject is one who has blood pressure in a hypertensive range

108. A method according to claim 96, wherein the subject is one who has a systolic blood pressure of under 120 mm Hg .

109. A method according to claim 96, wherein the subject is one who has a diastolic blood pressure of under 80 mm Hg .

110. A method according to claim 96, wherein the subject is one who has a systolic blood pressure of under 120 mm Hg and a diastolic blood pressure of under 80 mm Hg.

111. A method according to claim 96, wherein the subject is one who has a systolic blood pressure of between 120 mm Hg and 139 mm Hg, inclusive.

112. A method according to claim 96, wherein the subject is one who has a diastolic blood pressure of between 80 mm Hg and 99 mm Hg, inclusive.

113. A method according to claim 96, wherein the subject is one who has a systolic blood pressure of between 120 mm Hg and 139 mm Hg, inclusive, and a diastolic blood pressure of between 80 mm Hg and 89 mm Hg, inclusive.

114. A method according to claim 96, wherein the subject is one who has a systolic blood pressure of between 140 mm Hg and 159 mm Hg, inclusive.

115. A method according to claim 96, wherein the subject is one who has a diastolic blood pressure of between 90 mm Hg and 99 mm Hg, inclusive.

116. A method according to claim 96, wherein the subject is one who has a systolic blood pressure of between 140 mm Hg and 159 mm Hg, inclusive, and a diastolic blood pressure of between 90 mm Hg and 99 mm Hg, inclusive.

117. A method according to claim 96, wherein the subject is one who has a systolic blood pressure of 160 mm Hg or greater.

118. A method according to claim 96, wherein the subject is one who has a diastolic blood pressure of 100 mm Hg or greater.

119. A method according to claim 96, wherein the subject is one who has a systolic blood pressure of 160 mm Hg or greater and a diastolic blood pressure of 100 mm Hg or greater.

120. A method according to claim 96, wherein the subject is one who is not known to be suffering from coronary artery disease.

121. A method according to claim 96, wherein the subject is one who has an elevated blood homocysteine level.

122. A method according to claim 96, wherein the subject is one who is not known to be suffering from coronary- artery disease and who has an elevated blood homocysteine level .

123. A method according to claim 96, wherein the reduced folate is administered orally.

124. A method according to claim 96, wherein the reduced folate is administered orally in time-release formulation.

125. A method according to claim 96, wherein the reduced folate is administered in a composition that comprises the reduced folate and that is substantially free of any other vitamin other than ascorbic acid.

126. A method according to claim 96, wherein the reduced folate is administered in a pharmaceutical composition that comprises the reduced folate.

127. A method according to claim 126, wherein the pharmaceutical composition further comprises, in addition to the reduced folate, one or more additional biologically active materials .

128. A method according to claim 126, wherein the pharmaceutical composition further comprises, in addition to the reduced folate, one or more antihypertensive agents, one or more antidyslipidemia agents, or both.

129. A method according to claim 126, wherein the pharmaceutical composition further comprises, in addition to the reduced folate, one or more antihypertensive agents.

130. A method according to claim 126, wherein the pharmaceutical composition further comprises, in addition to the reduced folate, one or more antidyslipidemia agents.

131. A method according to claim 126, wherein the pharmaceutical composition further comprises, in addition to the reduced folate, one or more one or more antihypertensive agents and one or more antidyslipidemia agents.

132. A method according to claim 96, wherein the reduced folate is administered under conditions effective to establish and/or maintain a homeostatic plasma level of reduced folate greater than 50 nanomolar.

133. A method according to claim 96, wherein the reduced folate is administered under conditions effective to establish and/or maintain a homeostatic plasma level of reduced folate greater than about 80 nanomolar.

134. A method according to claim 96, wherein the reduced folate is administered at a daily dose of from about 0.45 micromoles to about 15 micromoles.

135. A method according to claim 96, wherein the reduced folate is administered in a dose containing from about 0.45 micromoles to about 200 micromoles.

136. A method according to claim 96, wherein the reduced folate is administered in a dose containing from about 0.45 micromoles to 68 micromoles.

137. A method according to claim 96, wherein the reduced folate is administered in a dose containing from about 0.45 micromoles to about 65 micromoles.

138. A method according to claim 96, wherein the reduced folate is administered in a dose containing from about 0.45 micromoles to about 50 micromoles.

139. A method according to claim 96, wherein the reduced folate is administered in a dose containing from about 2.27 micromoles to about 50 micromoles.

140. A method according to claim 96, wherein the reduced folate is administered in a dose containing from about 0.45 micromoles to 45 micromoles.

141. A method according to claim 96, wherein the reduced folate is administered in a dose containing from about 0.45 micromoles to about 40 micromoles.

142. A pharmaceutical composition comprising: a first antihypertensive agent, said first antihypertensive agent being a reduced folate; and a second antihypertensive agent .

143. A pharmaceutical composition according to claim 142, wherein the reduced folate is selected from the group consisting of tetrahydrofolic acid, 5 -methyl - tetrahydrofolic acid, 5- formyl -tetrahydrofolic acid, 10- formyl-tetrahydrofolic acid, 5 , 10-methylene-tetrahydrofolic acid, 5 , 10 -methenyl-tetrahydrofolic acid, 5-formimino- tetrahydrofolic acid, 7 , 8 -dihydrofolic acid, and polyglutamyl derivatives thereof.

144. A pharmaceutical composition according to claim 142, wherein the reduced folate is selected from the group consisting of ( 6S) - tetrahydrofolic acid, 5 -methyl - (6S) - tetrahydrofolic acid, 5- formyl- (6S) -tetrahydrofolic acid, 10- formyl- (6R) -tetrahydrofolic acid, 5 , 10-methylene- (6R) - tetrahydrofolic acid, 5 , 10-methenyl- (6R) -tetrahydrofolic acid, 5-formimino- (6S) -tetrahydrofolic acid, and polyglutamyl derivatives thereof.

145. A pharmaceutical composition according to claim 142, wherein the reduced folate is selected from the group consisting of racemic tetrahydrofolic acid, racemic 5- methyl -tetrahydrofolic acid, racemic 5-formyl -tetrahydrofolic acid, racemic 10-formyl- tetrahydrofolic acid, racemic 5,10- methylene-tetrahydrofolic acid, racemic 5 , 10-methenyl - tetrahydrofolic acid, racemic 5-formimino-tetrahydrofolic acid, and polyglutamyl derivatives thereof.

146. A pharmaceutical composition according to claim 142, wherein the reduced folate is 5-methyl- tetrahydrofolic acid.

147. A pharmaceutical composition according to claim 142, wherein the reduced folate is 5 , 10-methylene- tetrahydrofolic acid.

148. A pharmaceutical composition according to claim 142, wherein the reduced folate is not tetrahydrofolic acid and is not 5-formyl -tetrahydrofolic acid.

149. A pharmaceutical composition according to claim 142, wherein the second antihypertensive agent is selected from a group consisting of diuretics, beta- andrenergic antagonists, angiotensin-converting enzyme inhibitors, angiotensin II antagonists, calcium channel blockers, alpha-andrenergic antagonists, combined alpha- and beta-andrenergic antagonists, centrally acting agents, vasodilators, aldosterone receptor antagonists, and combinations thereof.

150. A pharmaceutical composition according to claim 142, wherein said pharmaceutical composition further comprises an antidyslipidemia agent.

151. A pharmaceutical composition according to claim 142, wherein said pharmaceutical composition comprises from about 0.45 micromoles to about 200 micromoles of reduced folate.

152. A pharmaceutical composition according to claim 142, wherein said pharmaceutical composition comprises from about 0.45 micromoles to 68 micromoles of reduced folate.

153. A pharmaceutical composition according to claim 142, wherein said pharmaceutical composition comprises from about 0.45 micromoles to about 65 micromoles of reduced folate.

154. A pharmaceutical composition according to claim 142, wherein said pharmaceutical composition comprises from about 0.45 micromoles to about 50 micromoles of reduced folate .

155. A pharmaceutical composition according to claim 142, wherein said pharmaceutical composition comprises from about 2.27 micromoles to about 50 micromoles of reduced folate.

156. A pharmaceutical composition according to claim 142, wherein said pharmaceutical composition comprises from about 0.45 micromoles to 45 micromoles of reduced folate.

157. A pharmaceutical composition according to claim 142, wherein said pharmaceutical composition comprises from about 0.45 micromoles to about 40 micromoles of reduced folate.

158. A pharmaceutical composition comprising: a reduced folate; and an antidyslipidemia agent other than niacin.

159. A pharmaceutical composition according to claim 158, wherein the reduced folate is selected from the group consisting of tetrahydrofolic acid, 5 -methyl - tetrahydrofolic acid, 5-formyl-tetrahydrofolic acid, 10- formyl-tetrahydrofolic acid, 5 , 10-methylene- tetrahydrofolic acid, 5 , 10-methenyl-tetrahydrofolic acid, 5-formimino- tetrahydrofolic acid, 7 , 8-dihydrofolic acid, and polyglutamyl derivatives thereof.

160. A pharmaceutical composition according to claim 158, wherein the reduced folate is selected from the group consisting of (6S) -tetrahydrofolic acid, 5-methyl - (6S) - tetrahydrofolic acid, 5-formyl- (6S) -tetrahydrofolic acid, 10- formyl- (6R) -tetrahydrofolic acid, 5 , 10-methylene- (6R) - tetrahydrofolic acid, 5 , 10-methenyl- (6R) -tetrahydrofolic acid, 5-formimino- (6S) -tetrahydrofolic acid, and polyglutamyl derivatives thereof.

161. A pharmaceutical composition according to claim 158, wherein the reduced folate is selected from the group consisting of racemic tetrahydrofolic acid, racemic 5- methyl -tetrahydrofolic acid, racemic 5-formyl-tetrahydrofolic acid, racemic 10-formyl- tetrahydrofolic acid, racemic 5,10- methylene- tetrahydrofolic acid, racemic 5 , 10-methenyl- tetrahydrofolic acid, racemic 5-formimino-tetrahydrofolic acid, and polyglutamyl derivatives thereof.

162. A pharmaceutical composition according to claim 158, wherein the reduced folate is 5 -methyl - tetrahydrofolic acid.

163. A pharmaceutical composition according to claim 158, wherein the reduced folate is 5 , 10-methylene- tetrahydrofolic acid.

164. A pharmaceutical composition according to claim 158, wherein the reduced folate is not tetrahydrofolic acid and is not 5-formyl -tetrahydrofolic acid.

165. A pharmaceutical composition according to claim 158, wherein the antidyslipidemia agent is selected from a group consisting of statins, bile acid-binding resins, fibric acid analogs, and combinations thereof.

166. A pharmaceutical composition according to claim 158, wherein the antidyslipidemia agent is a statin.

167. A pharmaceutical composition according to claim 158, wherein the pharmaceutical composition is substantially free from niacin.

168. A pharmaceutical composition according to claim 158, wherein said pharmaceutical composition comprises from about 0.45 micromoles to about 200 micromoles of reduced folate.

169. A pharmaceutical composition according to claim 158, wherein said pharmaceutical composition comprises from about 0.45 micromoles to 68 micromoles of reduced folate.

170. A pharmaceutical composition according to claim 158, wherein said pharmaceutical composition comprises from about 0.45 micromoles to about 65 micromoles of reduced folate.

171. A pharmaceutical composition according to claim 158, wherein said pharmaceutical composition comprises from about 0.45 micromoles to about 50 micromoles of reduced folate.

172. A pharmaceutical composition according to claim 158, wherein said pharmaceutical composition comprises from about 2.27 micromoles to about 50 micromoles of reduced folate.

173. A pharmaceutical composition according to claim 158, wherein said pharmaceutical composition comprises from about 0.45 micromoles to 45 micromoles of reduced folate.

174. A pharmaceutical composition according to claim 158, wherein said pharmaceutical composition comprises from about 0.45 micromoles to about 40 micromoles of reduced folate.

175. A kit comprising: a first pharmaceutical composition, wherein the first pharmaceutical composition includes a reduced folate; and a second pharmaceutical composition, wherein the second pharmaceutical composition includes an antidyslipidemia agent other than niacin.

176. A kit comprising: a first pharmaceutical composition, wherein said first pharmaceutical composition comprises a first antihypertensive agent, the first antihypertensive agent being a reduced folate; and a second pharmaceutical composition, wherein said second pharmaceutical composition comprises a second antihypertensive agent.