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United States Patent |
5,281,424
|
Morris, Jr.
,   et al.
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January 25, 1994
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Treatment of hypertension
Abstract
Novel methods are provided for treating hypertension in humans which
comprise administering therapeutic amounts of pharmaceutically-acceptable
non-halide salts of potassium. Preferred salts are potassium bicarbonate
GOVERNMENT SUPPORT
This invention was made with Government support under Grant No. M01-RR0079
awarded by the National Institutes of Health. The Government has certain
rights in this invention.
Inventors:
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Morris, Jr.; R. Curtis (San Francisco, CA);
Sebastian; Anthony (San Francisco, CA)
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Assignee:
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The Regents of the University of California (Alameda, CA)
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Appl. No.:
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708827 |
Filed:
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May 29, 1991 |
Intern'l Class: |
A61K 033/10 |
Field of Search: |
424/78,127,601,679,717,722,9
206/569
128/672
|
References Cited
Other References
Beilin, Clin. and Exper'tal Pharm. and Phys., 15: 215-23, (1988).
de Wesselow et al., Quart. J. Med., 8: 361-374, (1939).
Kolata, Science, 218: 361-62, (1982).
Luft et al., Am. J. Clin. Nutr., 45: 1289-94, (1987).
Maxwell et al., Med. Clinics N. America, 71 (5): 859-874, (1987).
Miller et al. (I), Hyperten. 10: 437-422, (1987).
Miller et al., (II)., Clin. and Exper. Theor. and Prac. A8 (4 and 5):
823-827, (1986).
Priddle, Can. Med. Assoc. J. 25: 5-8, (1931).
Singh et al., Acta. Cardiologica. XLII: 103-113, (1987).
Skrabal et al., Clinical Science 59: 157s-160s, (1980).
Skrabal et al., The Lancet, 895-900, (1981).
Smith et al., Br. Med. J., 290: 110-112, (1985).
Sugimoto et al., Hyperten. 11: 579-585, (1988).
Suppa et al., J. Hyperten. 6: 787-790, (1988).
Tannen, Annals of Int. Med., 98 (Part 2): 773-780, (1983).
Tannen, Kid Int. 32(S22): 242-248, (1987).
Tobian et al., (I) Hypertension. 6(supp I): I-170-I-176, (1984).
Tobian (II) J. Hyperten. 4 (Supp 4): S67-S76, (1986).
Tobian (III), Can. J. Physiol. Pharmacol. G4: 840-848, (1986).
Tobian (IV), Nutr. Rev. 46(8): 273-283, (1988).
Treasure et al., Hyperten. 5: 864-872, (1983).
Ullian et al., Sem. Nephr. 7(3): 329-252, (1987).
Witzgall et al., J. of Hypertens., 4:201-205, (1986).
Zoccali et al., J. of Hypertens., 3(1): 67-72, (1985).
Cappuccio et al., J. of Hypertens. 9(5): 465-473, (1991).
Overlack et al., Klin Wochenschr, 69(Supp XXV): 79-83 (1991).
Morgan, T. "Hypertension Treated By Salt Restriction", The Lancet, Feb. 4,
1978, pp. 227-230.
Morgan, "The effect of potassium and bicarbonate ions on the rise in blood
pressure caused by sodium chlorides", Clin. Sci. 63:407s-409s (1982).
Myers J., Morgan T., "The Effect of Sodium Intake on The Blood Pressure
Related to Age and Sex", Clin. and Exper. Hyper.--Theory and Practice,
A5(1), 99-118 (1983).
Morgan T. et al., "The Role of Potassium in Control of Blood Pressure",
Drugs 28: Suppl. 1, pp. 188-195 (1984).
Morgan, T. et al., "The role of sodium restriction in the management of
hypertension", Can. J. Physiol. Pharmacol. vol. 64, 1986.
Morgan et al., "Factors That Determine The Response Of People With Mild
Hypertension To A Reduced Sodium Intake", Clin. and Exper.--Theory and
Practice, A8(6), pp. 941-962 (1986).
Morgan, T. et al., "Compliance and the Elderly Hypertensive", Drugs 31
(Suppl. 4) pp. 174-183 (1986).
Chalmers, et al., "Australian National Health and Medical Research Council
Dietary Salt Study in Mild Hypertension", J. of Hypertension 4 (Suppl.
6):S629-S637 (1986).
Morgan et al., "Comparative Studies of Reduced Sodium and High Potassium
Diet in Hypertension", Nephron 47: Suppl. 1, pp. 21-26 (1987).
Nowson, Morgan, "Change in Blood Pressure in Relation to Change in
Nutrients Effected By Manipulation of Dietary Sodium and Potassium",
Clinical and Experimental Pharmacology & Physiology 15, pp. 225-242
(1988).
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Primary Examiner: Kulkosky; Peter F.
Attorney, Agent or Firm: Townsend and Townsend Khourie and Crew
Goverment Interests
GOVERNMENT SUPPORT
This invention was made with Government support under Grant No. M01-RR0079
awarded by the National Institutes of Health. The Government has certain
rights in this invention.
Parent Case Text
This is a continuation of application Ser. No. 07/577,846, filed Aug. 31,
1990, now abandoned, which is a continuation of application Ser. No.
07/420,596, filed Oct. 17, 1989, now abandoned, which is a
continuation-in-part of U.S. patent application Ser. No. 260,856, filed
Oct. 21, 1988 now abandoned.
Claims
What is claimed is:
1. A method for treating hypertension in a person on a diet having a normal
range of salt content, which comprises orally administering to such a
person a composition containing potassium bicarbonate as the principal
active ingredient for treating hypertension, the potassium bicarbonate
being administered in an amount sufficient to have a measurable blood
pressure lowering effect on the person treated but not in an amount
sufficient to induce undesirable toxic effects.
2. The method of claim 1, wherein the potassium bicarbonate is administered
in an amount sufficient to measurably lower the blood pressure of the
person treated.
3. The method of claim 1, for treating a person who has hypertension or a
person who has normal blood pressure but is susceptible to hypertension,
with said potassium bicarbonate-containing composition.
4. The method of claim 1, for treating a person who has hypertension with
said potassium bicarbonate-containing composition.
5. The method of claim 1, wherein the composition is administered as a
dietary supplement.
6. The method of claim 1, wherein the composition is administered in an
amount containing from about 50-300 mmoles of the potassium bicarbonate/70
kg body weight/24 hours.
7. The method of claim 1, wherein the composition includes a
pharmaceutically-acceptable carrier.
8. The method of claim 1, wherein the composition is substantially free of
potassium chloride.
9. The method of claim 1, wherein potassium bicarbonate is substantially
the only active ingredient for treating hypertension in said composition.
10. The method of claim 1, wherein the person is on a diet having a salt
content ranging from a moderately-restricted salt intake of about 75 meq.
of NaCl per day to a salt intake of about 300 meq. of NaCl per day or
higher.
11. A method for treating hypertension in a person aged 40-65 who is on a
diet having a normal range of salt content, which comprises orally
administering to such a person a composition containing potassium
bicarbonate as the principal active ingredient for treating hypertension,
the potassium bicarbonate being administered in an amount sufficient to
have a measurable blood pressure lowering effect on the person treated but
not in an amount sufficient to induce undesirable toxic effects.
12. The method of claim 11, wherein the potassium bicarbonate is
administered in an amount sufficient to measurably lower the blood
pressure of the person treated.
13. The method of claim 11, for treating a person who has hypertension or a
person who has normal blood pressure but is susceptible to hypertension,
with said potassium bicarbonate-containing composition.
14. The method of claim 11, for treating a person who has hypertension with
said potassium bicarbonate-containing composition.
15. The method of claim 11, wherein the composition is administered as a
dietary supplement.
16. The method of claim 11, wherein the composition is administered in an
amount containing from about 50-300 mmoles of the potassium bicarbonate/70
kg body weight/24 hours.
17. The method of claim 11, wherein the composition includes a
pharmaceutically-acceptable carrier.
18. The method of claim 11, wherein the composition is substantially free
of potassium chloride.
19. The method of claim 11, wherein potassium bicarbonate is substantially
the only active ingredient for treating hypertension in said composition.
20. The method of claim 11, wherein the person is on a diet having a salt
content ranging from a moderately-restricted salt intake of about 75 meq.
of NaCl per day to a salt intake of about 300 meq. of NaCl per day or
higher.
21. A method of diagnosing hypertension in a person on a diet having a
normal range of salt content, said person being susceptible to or
suffering from hypertension, which comprises measuring such person's blood
pressure to obtain a first value, orally administering to such a person a
composition containing potassium bicarbonate as the principal active
ingredient for treating hypertension, the potassium bicarbonate being
administered in an amount sufficient to have a measurable blood pressure
lowering effect on the person's blood pressure but not sufficient to
induce undesirable toxic effects, measuring the person's blood pressure to
obtain a second value, and comparing said first and second values to
determine whether to initiate anti-hypertension therapy.
22. The method of claim 21, wherein said composition is administered in an
amount and for a time sufficient to cause a measurable lowering of blood
pressure in a person who is responsive to potassium bicarbonate therapy or
prophylaxis.
23. The method of claim 21, wherein the composition is administered in an
amount containing from about 50-300 mmoles of the potassium bicarbonate/70
kg body weight/24 hours.
24. The method of claim 21, wherein the composition is substantially free
of potassium chloride.
25. The method of claim 21, wherein potassium bicarbonate is substantially
the only active ingredient for treating hypertension in said composition.
Description
FIELD OF THE INVENTION
This invention concerns novel methods for treating and diagnosing
hypertension in humans and, more particularly, involves administration of
pharmaceutically-acceptable non-halide potassium salts, such as potassium
bicarbonate, in a variety of dietary and pharmaceutical compositions.
BACKGROUND OF THE INVENTION
Hypertension is an insidious disease which affects many people.
Hypertension is generally defined as an abnormally increased blood
pressure. It is clinically recognized as an elevation of systolic arterial
blood pressure of 150 mm Hg or greater and/or an elevation of diastolic
arterial blood pressure of 90 mm Hg or higher. Certain risk factors, e.g.,
hypercholesterolemia, diabetes, smoking, and a familial history of
vascular disease, in conjunction with hypertension may predispose
individuals to arteriosclerosis and consequent cardiovascular morbidity
and mortality.
During the past three decades, morbidity and mortality resulting directly
or indirectly from hypertension have fallen with the development of
effective pharmacological agents. Several anti-hypertensive drugs that act
predominantly on the peripheral sympathetic nervous system, adrenergic
receptors, autonomic ganglia, and/or on the renin-angiotensin system have
been described and include, for instance, propranolol, methyldopa,
clonidine, and prazosin, to name but a few. Diuretic agents have also
become a mainstay in anti-hypertensive therapy, and include thiazides and
closely related phthalimidine derivatives, e.g., chlorthalidone. Others,
such as hydralazine, act as vasodilators by causing the direct relaxation
of arteriolar vascular smooth muscle.
In general, however, drug therapy for hypertension is reserved for those
individuals whose blood pressure cannot be maintained in an acceptable
range by non-pharmacological means. Of the non-pharmacological treatments
for hypertension, weight reduction and salt (sodium chloride) restriction
have been considered to be the most successful. Restricting dietary salt,
although of somewhat limited and unpredictable effect, can in some cases
reduce diastolic blood pressure to an extent comparable to that achieved
by treatment with some of the pharmacologic agents.
Patients whose cause of hypertension is not readily apparent are said to
have "essential hypertension." This group comprises approximately 95% of
the patients treated for hypertension. Patients with essential
hypertension whose blood pressure decreases with restriction of dietary
sodium chloride and increases with its subsequent supplementation are
characterized as having "salt-sensitivity" or, more precisely, "sodium
chloride-sensitive" hypertension. Fujita et al., Am. J. Med. (1980) 69:334
and Kurtz et al., N. Engl. J. Med. (1987) 317:1043. Certain elements of
the population have been reported to be more salt-sensitive than others,
and thus exhibit greater blood pressure changes when subjected to
different dietary intakes of NaCl (see, for example, Weinberger, et al.,
J. Am. Coll. Nutr. 1:139-148, 1982; Luft, et al., Am. J. Med. 72:726-736,
1982; Dustan, et al., Am. J. Med. Sci. 295:378-383, 1988; and Sullivan, et
al., Am. J. Med. Sci. 295:370-377, 1988.
The prevalent view is that the capacity of sodium chloride to increase
blood pressure depends only on its sodium component and that, hence, all
commonly ingested sodium salts have this capacity (Sodium and Potassium in
Foods and Drugs: NAK Conference Proceedings, White and Crocco, eds., Amer.
Med. Assn., Chicago, 1980; Willis, ed., FDA Drug Bulletin (1983) 13:25). A
standard pharmacological textbook, Goodman and Gilman, The Pharmacological
Basis of Therapeutics, 7th Ed., 1985, recommends that sodium restriction
should be encouraged for hypertensive patients and used as a definitive
therapy if effective.
Some studies have suggested that the anion component of a dietary sodium
salt may determine the extent to which that sodium salt induces an
increase in blood pressure. Kurtz et al., Science (1983) 222:1139;
Whitescarver et al., Science (1984) 223:1430; and Kurtz et al., New Engl.
J. Med., (1987), 317:1043. These studies suggest that both the sodium and
chloride ions of NaCl are required for its capacity to increase blood
pressure.
The results of clinical and epidemiological studies suggest that the amount
of potassium in the diet may also be an important determinant of blood
pressure in patients with hypertension and, in some instances, in
normotensive subjects. It has been observed that increasing potassium
intake by the administration of a dietary supplement of potassium tends to
lower blood pressure. (Addison, et al., Can. Med. Assoc. 18:281-285, 1928;
Morgan, et al., Clin. Sci. 63:407s-409s, 1982; Holly, et al., Lancet
2:1384-1387, 1981; Fujita, et al., Hypertension 6:184-192, 1984;
MacGregor, et al., J. Cardiovasc. Pharmacol. 6:S244-S249, 1984, Siani et
al., Br. Med. J. 294:1453-1456; and Obel, J. Cardiovasc. Pharmacol.
14:294-296, 1989). The anti-hypertensive effect of increasing potassium
intake, however, has usually been small and variable.
In one experimental program, the blood pressure-lowering effect of dietary
potassium supplementation was insignificant in patients on moderately
restricted NaCl diets. Smith, et al., Br. Med. J. (1985) 290:110. Indeed,
no anti-hypertensive effect of potassium was observed in studies by some
investigators. See, Richards et al., Lancet (1984) 1:757 and Skrabal et
al., Klin. Wochenschr. (1984) 62:124.
The possible use of a potassium salt other than potassium chloride, namely
potassium citrate, to treat hypertension has also been suggested in the
technical literature. Addison, Id. In that report, summarizing experiments
on five subjects on "salt-poor diets", potassium citrate was said to
exhibit a blood pressure lowering effect. Addison claimed that potassium
citrate was more effective than potassium chloride in two of the three
patients in whom he compared the hypotensive effect of the two potassium
salts. In neither of these two instances, however, does the reported data
justify the claim that potassium citrate was more effective than potassium
chloride in reducing blood pressure. Indeed, to our knowledge, potassium
citrate has not been recommended as a therapy for hypertension in any
publication in the medical literature in the sixty years since the date of
the Addison paper.
What is still urgently needed is an effective method for treating essential
hypertension which utilizes a potassium compound that may be conveniently
administered, preferably as a dietary supplement, which avoids concomitant
administration of chloride, which is relatively easy to manufacture in
bulk, and which may be made available at comparatively low cost. The
present invention fulfills these and other related needs.
SUMMARY OF THE INVENTION
The present invention involves a novel method for ameliorating or
preventing hypertension in humans afflicted with or predisposed to
hypertension, which method comprises administering a therapeutically- or
prophylactically-effective amount of a composition of a
pharmaceutically-acceptable potassium salt in which the anion component is
not a chloride or other halide. The potassium salt may be selected from
the group consisting of potassium bicarbonate, potassium phosphate, or an
alkalinizing potassium salt of a carboxylic acid, e.g., potassium
gluconate and potassium citrate, among others. In particularly preferred
embodiments the salts are potassium bicarbonate and potassium phosphate.
The non-halide potassium salt may be administered to ameliorate or prevent
hypertension in any of several therapeutically- or
prophylactically-acceptable forms and by a variety of routes. The
compositions may conveniently be formulated and administered as a dietary
supplement. An effective dosage of potassium bicarbonate is typically
about 50-250 millimoles (mmoles) per 70 kg body weight per day.
In accordance with this invention it is particularly preferred to
administer the non-halide potassium salt as a dietary supplement to
patients on nutritionally adequate whole-foods diets that have "normal"
salt (NaCl) contents (about 75 to 300 meq. of Na per day). It has been
found that administration of the potassium salt in this way is
particularly effective in ameliorating hypertension.
Moreover, administration of the non-halide potassium salt is believed to
attenuate increases of blood pressure otherwise induced by dietary NaCl in
salt-sensitive individuals. The non-halide potassium therapy thus protects
salt-sensitive individuals against extreme blood pressure elevations which
might otherwise occur when they are on high salt diets.
Also provided as part of the invention are methods for diagnosing
individuals susceptible to or suffering from hypertension which is or will
be amenable to treatment with a non-halide potassium salt.
DESCRIPTION OF THE FIGURES
FIG. 1 is a graph showing the results of administering 200 mmoles of
potassium bicarbonate per 70 kg. body weight per day in four oral doses on
each of 15 days to two male patients having essential hypertension. In the
graph each patient's mean arterial pressure (MAP) is plotted against time
for a pre-treatment "Control" period, a "KHCO.sub.3 " treatment period,
and a "Recovery" period. Filled bars represent the differences between the
control average MAP for the 10-day steady-state control period
(represented by the horizontal line) for one patient, and unfilled bars
represent the data for the second patient. Bars above the zero line
indicate MAP values exceeding the control period average, and bars below
the line indicate MAP values lower than the control period average;
FIG. 2 is a graph similar to FIG. 1, showing the results of administering
approximately 100 mmoles of potassium bicarbonate per 70 kg. body weight
per day for eight days to five normotensive males. The bar for each day
represents the average change in the MAP value for the group from the
control period; and
FIG. 3 is another graph similar to FIGS. 1 and 2, containing separate plots
of the average systolic and diastolic MAP values against time for six
post-menopausal normotensive women.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
In accordance with the present invention, novel methods are provided for
preventing or ameliorating hypertension, which comprises administering to
subjects a potassium salt in which the anion component is other than
chloride or other halide in amounts sufficient to provide the desired
physiological benefit while avoiding amounts sufficient to induce
undesirable toxic effects.
As used herein, the terms "treatment" or "treating" relate to any treatment
of hypertensive disease, and include: (1) preventing hypertension from
occurring in a subject who may be predisposed to the disease but who has
not yet been diagnosed as having it; (2) inhibiting the disease, i.e.,
arresting its development; or (3) ameliorating or relieving the symptoms
of the disease, i.e., causing regression of the hypertensive state.
One hypothesis for the results achieved by the present treatment, offered
by way of explanation but not limitation, is that the increase of chloride
or other halide upon the administration of potassium chloride or the like,
induces physiological changes that antagonize or otherwise counter or mask
the anti-hypertensive effect of potassium. Accordingly, subjects who do
not exhibit a lowering of blood pressure in response to the administration
of potassium chloride or bromide may show a response to a non-halide salt
of potassium, and patients who have shown some anti-hypertensive response
to potassium chloride or bromide may show a substantially greater response
when a non-halide potassium salt is used instead.
The non-halide potassium salts which may be employed in the process of the
present invention are those which exhibit the ability to decrease the
systolic or diastolic blood pressure of an individual without significant
undesirable side effects. A number of pharmaceutically-acceptable salts
are known, several of which are set forth in Berg et al., J. Pharmaceut.
Sci. (1977) 66:1, which is incorporated herein by reference. It is known
that the chloride ion acts as a pressor or contributes to the pressor
effect in formulations of sodium chloride (Kurtz et al., N. Engl. J. Med.
(1987) 317:1043, which is incorporated herein by reference). Given the
disclosure herein, it will be well within the ability of one skilled in
the art to select and screen pharmaceutically-acceptable potassium salts
for the ability to lower blood pressure using well known methods and
techniques. Desirably, a potassium salt will be selected which is
therapeutically effective in amounts readily achievable in humans while
being relatively well tolerated.
Different salts may be chosen depending on particular routes of
administration and preferred modes of formulation. Additionally, it may be
preferred to select potassium salts which, upon administration, produce a
slight systemic alkalinization, which alkalinization itself may contribute
to a vasodilatory effect that augments a specific vasodilatory effect
conferred by the potassium ion. A bicarbonate component or metabolite
generated promptly after administration or ingestion of the salt may thus
not only alkalinize the blood, but it may affect the distribution of
fluids between the vascular and extravascular compartments. Blood pH and
bicarbonate levels may be determined using well accepted methods long
known to those skilled in the arts.
The potassium salts which may be thus administered are preferably selected
from the group consisting of potassium bicarbonate (KHCO.sub.3), potassium
phosphate (K.sub.2 HPO.sub.4 or a mixture of K.sub.2 HPO.sub.4 and
KH.sub.2 PO.sub.4), potassium gluconate (C.sub.6 H.sub.11 KO.sub.7) and
potassium citrate (C.sub.6 H.sub.5 K.sub.3 O.sub.7) The use of potassium
bicarbonate and potassium phosphate is particularly preferred in this
invention.
The preparation, isolation and purification of these salts are well known
to those skilled in the art, as they are commonly employed in a
therapeutic setting for a variety of uses other than described herein.
Specific preparation procedures for each salt are described in general
terms in Remington's Pharmaceutical Sciences, Mack Publishing Company,
Easton, Pa., 16th Ed., 1982, which is incorporated herein by reference.
Administration of a non-halide potassium salt as an active compound may be
in a pharmaceutical composition described hereinafter and can be via any
of the accepted modes of administration for agents which are known to
affect hypertension. These methods include oral, parenteral, and other
modes of systemic administration. Different non-halide potassium salts may
be admixed and simultaneously administered, or benefit may be gained in
some instances by their separate, sequential administration.
Depending on the intended mode, the compositions may be in the form of
solid, semi-solid or liquid dosage forms, such as, for example, tablets,
capsules, pills, powders, granules, crystals, liquids, suspensions, or the
like, preferably in unit-dosage forms suitable for administration of
relatively precise dosages. The compositions may include a conventional
pharmaceutical carrier or excipient and, in addition, may include other
medical agents, pharmaceutical agents, carriers, etc.
The amount of the non-halide potassium salt administered in accordance with
the present invention will, of course, be dependent on the subject being
treated, the severity of the affliction, the manner of administration, and
the judgment of the prescribing physician. However, an effective dose of
potassium bicarbonate, for instance, will be in the range of 50-300
mmoles/70 kg/day, preferably 50-250 mmoles/70 kg/day. Dosages may be
adjusted by monitoring the effects of the amount administered and
adjusting subsequent amounts as appropriate.
Many of the potassium salts of the invention may be administered in
relatively large amounts without serious side effects, although
indiscriminate use of potassium salts may produce toxic manifestations of
hyperkalemia and gastrointestinal irritation. In cases where the compound
is administered to prevent the emergence of hypertension in normotensive
subjects susceptible to hypertension, or those suffering from only mild or
borderline hypertension, the dose may be adjusted accordingly to lower
maintenance levels.
For solid compositions, the non-halide potassium salts such as potassium
bicarbonate may be provided separately or may be compounded with
conventional nontoxic solid carriers such as, for example, pharmaceutical
grades of mannitol, lactose, starch, magnesium stearate, talcum,
cellulose, glucose, sucrose, magnesium carbonated, and the like. Liquid
pharmaceutically-administrable compositions can be prepared, for example,
by dissolving the salt, such as potassium bicarbonate, and optional
pharmaceutical adjuvants in a carrier, such as, for example, water,
aqueous dextrose, glycerol, and the like, to thereby form a solution or
suspension. If desired, the pharmaceutical composition to be administered
may also contain minor amounts of nontoxic auxiliary substances such as pH
buffering agents and the like, for example, sorbitan monolaurate,
triethanolamine, sodium acetate, triethanolamine oleate, etc. Actual
methods of preparing such dosage forms are known, or will be apparent, to
those skilled in this art; see, for example, Remington's Pharmaceutical
Sciences, Mack Publishing Company, Easton, Pa., 16th Ed., 1982, which is
incorporated herein by reference. The composition or formulation to be
administered will, in any event, contain a quantity of the non-halide
potassium salt in an amount effective to lower the systolic and/or
diastolic blood pressure and alleviate or ameliorate the symptoms thereof
or prevent their emergence in the subject being treated.
For oral administration, a pharmaceutically-acceptable nontoxic composition
is formed by the incorporation of any of the normally employed excipients
such as, for example, pharmaceutical grades of mannitol, lactose, starch,
magnesium stearate, talcum, cellulose, glucose, sucrose, magnesium
carbonate, and the like. Such compositions take the form of solutions,
suspensions, tablets, pills, capsules, powders, granules, crystals,
sustained-release formulations, and the like. Such compositions may
contain about 10-100% active ingredient, preferably about 25-90%. As a
dietary supplement potassium bicarbonate, for example, may be supplied as
granules or powder and applied directly to foodstuffs or dissolved in
drinking water as a convenient means of administration.
The compositions useful in the methods of the invention may be supplied in
containers having printed instructions which direct the user to employ the
compositions in the methods and for the purposes described herein.
Accordingly, said containers having such instructions are considered part
of the present invention. The instructions for use may be printed on the
container or on a separate sheet which is included with the container.
Among other things, the instructions, may for example, direct the user to
employ the composition in addition to a normal dietary intake of salt, and
may also state that the purpose of such method is to inhibit or otherwise
prevent symptoms of or associated with hypertension. The instructions may
be directed to normotensive individuals who may be predisposed to
hypertension and/or to those already diagnosed as having essential
hypertension.
The methods of the invention may also find use in diagnosing individuals
suffering from or predisposed to hypertension. More particularly,
typically a baseline blood pressure for an individual undergoing said
diagnosis is first determined. Then a non-halide potassium salt useful in
the present invention is administered according to the methods herein
described. Usually the composition will be administered in an amount and
for a time sufficient to produce a measurable lowering of blood pressure
in individuals with hypertension or predisposed to developing hypertension
and who may ultimately may be treatable with the therapeutic methods of
the invention. If a person is thus identified as having a drop in blood
pressure from the baseline, a physician may then elect to initiate an
appropriate therapy or further monitor the patient.
The following examples illustrate some particularly preferred, non-limiting
embodiments of the invention.
EXAMPLE 1
Effect of Potassium Bicarbonate in Hypertensive Patients
Studies were performed in two men (ages 55 and 57) with essential
hypertension to demonstrate that a non-halide salt of potassium, potassium
bicarbonate, lowered blood pressure. In both patients, hypertension was
confirmed on at least three occasions in an out-patient setting after the
patient had been sitting quietly for all least 10 minutes. In patient 1,
the blood pressure ranged from 141/85 to 157/94 mm Hg; in patient 2, it
ranged from 144/93 to 156/100 mm Hg. Neither of the patients had clinical
signs or symptoms of pheochromocytoma or renal-artery stenosis, and
neither had clinical or laboratory evidence of impaired cardiac, renal, or
hepatic function. Urinalysis and the serum concentrations of creatinine,
sodium, and potassium were within normal limits in both.
All medications were stopped for each individual for at least four weeks
before the beginning of the study. Both patients remained hospitalized
throughout the study, where physical activity consisted only of daily
walks. Throughout the study, each patient ate a constant amount of a
nutritionally adequate whole-foods diet intrinsically low in sodium
chloride (approximately 10 mmoles NaCl/70 kg body weight/day). A sodium
chloride supplement was added in an amount sufficient to increase total
sodium intake to 140 meq/day/70 kg. The diet also provided, per 70 kg/day,
approximately 55 mmoles of potassium, 375 mg of calcium and 820 mg of
phosphorus.
In each patient, the total number of calories provided was determined from
the estimated amount of energy required to keep body weight constant. The
diet contained, as a percentage of total calories, 35% fat, 56%
carbohydrate, and 9% protein. The specific ingredients of each meal were
constant throughout the study. Fluid intake was fixed at 3150 ml/ 70
kg/day.
A 10-day steady-state control period preceded the experimental period.
Throughout the experimental period, both patients took an aqueous solution
containing potassium bicarbonate, 1.0 mmoles/ml of solution; each patient
ingested 200 mmoles of potassium bicarbonate/70 kg/day in three divided
doses, with meals, on each day of the study, for a total of 15 days.
Blood pressure was measured in the nondominant arm at 8 A.M., Noon, 4 P.M.,
8 P.M., and 10 P.M. of each day, with an automated oscillometric device
(Dinamap, 1846P). In this manner, observer bias was avoided. At each
measurement session, after the patient had been supine for 10 minutes,
five measurements of systolic and diastolic pressure and heart rate were
obtained and the average of the last four measurements were calculated.
The measurements were repeated with the patient in the upright position at
each session. The measurements were averaged to yield values for daily
systolic and diastolic blood pressures. Mean arterial pressure was
calculated as (systolic pressure-diastolic pressure)/3+ diastolic
pressure.
The results of the study are shown in FIG. 1. The figure plots the
difference of each day's mean arterial pressure (MAP) from the average MAP
for the entire control period, represented by the horizontal zero line.
Bars extending above the zero line indicate MAP values exceeding the
control period average, and vice versa. Filled bars represent one patient,
unfilled bars, the other.
Both patients had significant reductions in systolic, diastolic, and mean
arterial pressures occurring promptly on initiating potassium bicarbonate
treatment (day 1) and persisting for the 15-day treatment period. Heart
rate increased during potassium bicarbonate treatment. Subject No. 1
manifested a significant rebound overshoot of blood pressure when the
potassium bicarbonate was discontinued, and Subject No. 2 manifested a
similar tendency early in the recovery period. No adverse effects of
potassium bicarbonate administration were observed in either subject.
EXAMPLE 2
Effect of Potassium Bicarbonate in Normotensive Individuals
In a study performed similarly to that described in Example 1, the effect
of potassium bicarbonate on the blood pressure in normotensive individuals
was determined. The group consisted of five men, ages 40-53. The
equilibration or control period consisted of 7 days, the treatment with
potassium bicarbonate 8 days, and the recovery period an additional 8
days. Each subject ingested a daily potassium bicarbonate supplement of
100 meq/70 kg/day, making the total potassium intake approximately 150
meq/70 kg/day. The subjects were fed a diet having an intrinsic low-sodium
chloride content (less than 10 meq sodium and chloride/day/70 kg body
weight) and a normal potassium content (52 meq/day/70 kg body weight). A
sodium chloride supplement was added sufficient to increase total sodium
intake to 140 meq/70 kg/day.
The results of the study on the normotensive subjects is shown in FIG. 2.
Each day's bar represents the groups' average change in mean arterial
pressure from the control for that day. As with the hypertensive
individuals, the administration of potassium bicarbonate resulted in
significant reductions in mean arterial pressures, occurring promptly on
initiating potassium bicarbonate treatment and persisting for the
treatment period. The reduction in mean arterial pressures was also
manifested during a portion of the recovery period. Thus potassium
bicarbonate was shown to be effective in lowering blood pressure in
normotensive individuals and may readily find prophylactive use in
preventing the onset of hypertension in individuals identified as
predisposed to the condition.
EXAMPLE 3
Effect of Potassium Bicarbonate in Normotensive Post-Menopausal Women
In six post-menopausal women (ages 52-65) who were not hypertensive,
potassium bicarbonate was administered in an amount of 120 mmoles per kg
body weight per day for 18 days. A significant and sustained reduction in
both systolic and diastolic blood pressures resulted (see FIG. 3).
Blood pressures were measured without observer bias by use of an automated
blood pressure reader-recorder, which in addition, gave improved accuracy
by performing quadruplicate readings at each measurement session.
The studies were performed while the patients resided in the University of
California General Clinical Research Center (Moffitt Hospital). Throughout
the period of residence, the patients ate a constant diet of known
composition, comprising (per 60 kg body weight) 546 mg calcium, 948 mg
phosphorus, 60 meq sodium, and 56 meq potassium. A supplement of sodium
chloride of 60 mmoles/day was provided, making total sodium intake 120 meq
per 60 kg body weight per day. Fluid intake was fixed.
The subjects were allowed 10 days for their bodies to equilibrate and adapt
to the fixed diet. There then followed, immediately and in succession, a
12-day control period (CONTROL) prior to initiation of KHCO.sub.3
administration, an 18-day period of KHCO.sub.3 administration, and a
12-day recovery period after discontinuation of KHCO.sub.3.
FIG. 3 shows the changes in systolic (upper panel) and diastolic (lower
panel) blood pressures. For each subject, the average value of systolic
blood pressure for the entire CONTROL period was subtracted from each
day's systolic blood pressure, thereby generating a "difference from
CONTROL" value for every day of the study, including the individual
control days. For each day of the study, the average of the daily
"differences from CONTROL" were calculated for the entire group of six
subjects, and those were plotted in the figure as vertical bars. Vertical
bars extending below the zero line represent decreases in systolic blood
pressure relative to the average control value; vertical bars extending
above the zero line represent increases in systolic blood pressure
relative to the control value. A similar procedure was used for diastolic
blood pressure.
The KHCO.sub.3 administration resulted in a prompt and sustained reduction
in both systolic and diastolic blood pressures. After discontinuation of
KHCO.sub.3 the pressures gradually returned to control.
The results obtained in this experiment demonstrate that KHCO.sub.3 lowers
blood pressure in normotensive post-menopausal women.
From the foregoing, it will be appreciated that the present invention
provides methods which effectively ameliorate/prevent hypertension in
humans. Because many of the non-halide potassium salts such as potassium
bicarbonate are naturally-occurring and readily available, their use as a
dietary supplement or otherwise present the possibility of a purely
nutritional approach to hypertension, thereby avoiding the disadvantages
of conventional pharmacological intervention.
Although the present invention has been described in some detail by way of
illustration and example for purposes of clarity and understanding, it
will be obvious that certain changes and modifications may be practiced
within the scope of the appended claims.
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